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<html lang="en">
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<div id="top_issue1">
<h3>Issue №1. Love and science</h3>
<p>Our first issue is devoted to the famous mysterious feeling - Love. We have collected articles describing scientific views on it.</p>
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<p>Article №1</p>
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<figure>
<img src="img/main_doubledate.png">
<figcaption>Illustration by <span class="person" content="Sophie Blackall" id="person-1">Sophie Blackall</span></figcaption>
</figure>
<h2 data-src="https://news.harvard.edu/gazette/story/2018/02/scientists-find-a-few-surprises-in-their-study-of-love/">When <span class="keyWord" content="love">love</span> and <span class="keyWord" content="science">science</span> double date</h2>
<p class="subtitle">Sure, your heart thumps, but let’s look at what’s happening physically and psychologically</p>
<div class="article_desc">
<p class="byline">By <span class="person" content="Alvin Powell" id="person-2">Alvin Powell</span>, Harvard Staff Writer</p>
<p class="publicationDate">February 13, 2018</p>
</div>
<blockquote class="citation_block_small">
“They gave each other a smile with a future in it.”<br>
—<span class="person" content="Ring Lardner" id="person-3">Ring Lardner</span>
</blockquote>
<p><span class="keyWord" content="love">Love’s</span> warm squishiness seems a thing far removed from the cold, hard reality of <span class="keyWord" content="science">science</span>. Yet the two do meet, whether in lab tests for surging <span class="keyWord" content="hormone">hormones</span> or in austere chambers where MRI scanners noisily thunk and peer into <span class="keyWord" content="brain">brains</span> that ignite at glimpses of their soulmates.</p>
<p>When it comes to thinking deeply about <span class="keyWord" content="love">love</span>, poets, philosophers, and even high school boys gazing dreamily at girls two rows over have a significant head start on <span class="keyWord" content="science">science</span>. But the field is gamely racing to catch up.</p>
<p>One database of scientific publications turns up more than 6,600 pages of results in a search for the word “<span class="keyWord" content="love">love</span>”. <span class="organization" content="The National Institutes of Health" id="organization-1">The National Institutes of Health (NIH)</span> is conducting 18 clinical trials on it (though, like <span class="keyWord" content="love">love</span> itself, NIH’s “<span class="keyWord" content="love">love”</span> can have layered meanings, including as an acronym for a study of Crohn’s disease). Though not normally considered an intestinal ailment, <span class="keyWord" content="love">love</span> is often described as an illness, and the smitten as lovesick. Comedian <span class="person" content="George Burns" id="person-4">George Burns</span> once described <span class="keyWord" content="love">love</span> as something like a backache: <span class="citation">“It doesn’t show up on X-rays, but you know it’s there.”</span></p>
<p><span class="person" content="Richard Schwartz" id="person-5"><a href="https://www.mcleanhospital.org/profile/richard-schwartz" target="_blank">Richard Schwartz</a></span>, associate professor of psychiatry at <span class="organization" content="Harvard Medical School" id="organization-2"><a href="http://www.hms.harvard.edu/" target="_blank">Harvard Medical School</a> (HMS)</span> and a consultant to <span class="organization" content="McLean" id="organization-3"><a href="http://www.mcleanhospital.org/" target="_blank">McLean</a></span> and <span class="organization" content="Massachusetts General" id="organization-4"><a href="http://www.massgeneral.org/" target="_blank">Massachusetts General</a> (MGH) hospitals</span>, says it’s never been proven that <span class="keyWord" content="love">love</span> makes you physically sick, though it does raise levels of <span class="keyWord" content="cortisol">cortisol</span>, a stress <span class="keyWord" content="hormone">hormone</span> that has been shown to suppress immune function.</p>
<p><span class="keyWord" content="love">Love</span> also turns on the <span class="keyWord" content="neurotransmitter">neurotransmitter</span> <span class="keyWord" content="dopamine">dopamine</span>, which is known to stimulate the <span class="keyWord" content="brain">brain’s</span> pleasure centers. Couple that with a drop in levels of serotonin — which adds a dash of obsession — and you have the crazy, pleasing, stupefied, urgent <span class="keyWord" content="love">love</span> of infatuation.</p>
<p>It’s also true, <span class="person" content="Richard Schwartz" id="person-6">Schwartz</span> said, that like the moon — a trigger of its own legendary form of madness — <span class="keyWord" content="love">love</span> has its phases.</p>
<p><span class="citation">“It’s fairly complex, and we only know a little about it,”</span> <span class="person" content="Richard Schwartz" id="person-7">Schwartz</span> said. <span class="citation">“There are different phases and moods of <span class="keyWord" content="love">love</span>. The early phase of <span class="keyWord" content="love">love</span> is quite different”</span> from later phases.</p>
<p>During the first love-year, serotonin levels gradually return to normal, and the “stupid” and “obsessive” aspects of the condition moderate. That period is followed by increases in the <span class="keyWord" content="hormone">hormone</span> <span class="keyWord" content="oxytocin">oxytocin</span>, a <span class="keyWord" content="neurotransmitter">neurotransmitter</span> associated with a calmer, more mature form of <span class="keyWord" content="love">love</span>. The <span class="keyWord" content="oxytocin">oxytocin</span> helps cement bonds, raise immune function, and begin to confer the health benefits found in married couples, who tend to live longer, have fewer strokes and heart attacks, be less depressed, and have higher survival rates from major surgery and cancer.</p>
<p><span class="person" content="Richard Schwartz" id="person-8">Schwartz</span> has built a career around studying the <span class="keyWord" content="love">love</span>, hate, indifference, and other <span class="keyWord" content="emotion">emotions</span> that mark our complex relationships. And, though <span class="keyWord" content="science">science</span> is learning more in the lab than ever before, he said he still has learned far more counseling couples. His wife and sometime collaborator, <span class="person" content="Jacqueline Olds" id="person-9"><a href="http://www.mcleanhospital.org/biography/jacqueline-olds" target="_blank">Jacqueline Olds</a></span>, also an associate professor of psychiatry at <span class="organization" content="Harvard Medical School" id="organization-5">HMS</span> and a consultant to <span class="organization" content="McLean" id="organization-6">McLean</span> and <span class="organization" content="Massachusetts General" id="organization-7">MGH</span>, agrees.</p>
<figure>
<img src="img/2_doubledate.png">
<figcaption>Spouses <span class="person" content="Richard Schwartz" id="person-10">Richard Schwartz</span> and <span class="person" content="Jacqueline Olds" id="person-11">Jacqueline Olds</span>, both associate professors of psychiatry, have collaborated on a book about marriage. <span class="person" content="Stephanie Mitchell" id="person-12">Stephanie Mitchell</span>/Harvard Staff Photographer</figcaption>
</figure>
<h3>More knowledge, but struggling to understand</h3>
<p><span class="citation">“I think we know a lot more scientifically about <span class="keyWord" content="love">love</span> and the <span class="keyWord" content="brain">brain</span> than we did a couple of decades ago, but I don’t think it tells us very much that we didn’t already know about <span class="keyWord" content="love">love</span>,”</span> <span class="person" content="Richard Schwartz" id="person-13">Schwartz</span> said. <span class="citation">“It’s kind of interesting, it’s kind of fun [to study]. But do we think that makes us better at <span class="keyWord" content="love">love</span>, or helping people with <span class="keyWord" content="love">love</span>? Probably not much.”</span></p>
<p><span class="keyWord" content="love">Love</span> and companionship have made indelible marks on <span class="person" content="Richard Schwartz" id="person-14">Schwartz</span> and <span class="person" content="Jacqueline Olds" id="person-15">Olds</span>. Though they have separate careers, they’re separate together, working from discrete offices across the hall from each other in their stately <span class="place">Cambridge</span> home. Each has a professional practice and independently trains psychiatry students, but they’ve also collaborated on two books about loneliness and one on marriage. Their own union has lasted 39 years, and they raised two children.</p>
<blockquote><span class="citation citation_block_big">“I think we know a lot more scientifically about <span class="keyWord" content="love">love</span> and the <span class="keyWord" content="brain">brain</span> than we did a couple of decades ago … But do we think that makes us better at <span class="keyWord" content="love">love</span>, or helping people with <span class="keyWord" content="love">love</span>? Probably not much.”</span><br> —<span class="person" content="Richard Schwartz" id="person-16">Richard Schwartz</span>, associate professor of psychiatry, <span class="organization" content="Harvard Medical School" id="organization-8">Harvard Medical School</span></blockquote>
<p><span class="citation">“I have learned much more from doing couples therapy, and being in a couple’s relationship” than from <span class="keyWord" content="science">science</span>, <span class="person" content="Jacqueline Olds" id="person-17">Olds</span> said. “But every now and again, something like the fMRI or chemical studies can help you make the point better. If you say to somebody, ‘I think you’re doing this, and it’s terrible for a relationship,’ they may not pay attention. If you say, ‘It’s corrosive, and it’s causing your <span class="keyWord" content="cortisol">cortisol</span> to go way up,’ then they really sit up and listen.”</span></p>
<p>A side benefit is that examining other couples’ trials and tribulations has helped their own relationship over the inevitable rocky bumps, Olds said.</p>
<p><span class="citation">“To some extent, being a psychiatrist allows you a privileged window into other people’s triumphs and mistakes,” <span class="person" content="Jacqueline Olds" id="person-18">Olds</span> said. “And because you get to learn from them as they learn from you, when you work with somebody 10 years older than you, you learn what mistakes 10 years down the line might be.”</span></p>
<p>People have written for centuries about <span class="keyWord" content="love">love</span> shifting from passionate to companionate, something <span class="person" content="Richard Schwartz" id="person-19">Schwartz</span> called “both a good and a sad thing.” Different couples experience that shift differently. While the passion fades for some, others keep its flames burning, while still others are able to rekindle the fires.</p>
<p><span class="citation">“You have a tidal-like motion of closeness and drifting apart, closeness and drifting apart,” <span class="person" content="Jacqueline Olds" id="person-20">Olds</span> said. “And you have to have one person have a ‘distance alarm’ to notice the drifting apart so there can be a reconnection … One could say that in the couples who are most successful at keeping their relationship alive over the years, there’s an element of companionate <span class="keyWord" content="love">love</span> and an element of passionate <span class="keyWord" content="love">love</span>. And those each get reawakened in that drifting back and forth, the ebb and flow of lasting relationships.”</span></p>
<h3>Children as the biggest stressor</h3>
<p>Children remain the biggest stressor on relationships, <span class="person" content="Jacqueline Olds" id="person-21">Olds</span> said, adding that it seems a particular problem these days. Young parents feel pressure to raise kids perfectly, even at the risk of their own relationships. Kids are a constant presence for parents. The days when child care consisted of the instruction “Go play outside” while mom and dad reconnected over cocktails are largely gone.</p>
<p>When not hovering over children, America’s workaholic culture, coupled with technology’s 24/7 intrusiveness, can make it hard for <span class="keyWord" content="partner">partners</span> to pay attention to each other in the evenings and even on weekends. It is a problem that Olds sees even in environments that ought to know better, such as psychiatry residency programs.</p>
<p><span class="citation">“There are all these sweet young doctors who are trying to have families while they’re in residency,” <span class="person" content="Jacqueline Olds" id="person-22">Olds</span> said. “And the residencies work them so hard there’s barely time for their relationship or having children or taking care of children. So, we’re always trying to balance the fact that, in psychiatry, we stand for psychological good health, but [in] the residency we run, sometimes we don’t practice everything we preach.”</span></p>
<blockquote><span class="citation citation_block_big">“There is too much pressure … on what a romantic <span class="keyWord" content="partner">partner</span> should be. They should be your best friend, they should be your lover, they should be your closest relative, they should be your work <span class="keyWord" content="partner">partner</span>, they should be the co-parent, your athletic <span class="keyWord" content="partner">partner</span>. … Of course everybody isn’t able to quite live up to it.”</span><br> —<span class="person" content="Jacqueline Olds" id="person-23">Jacqueline Olds</span>, associate professor of psychiatry, <span class="organization" content="Harvard Medical School" id="organization-9">Harvard Medical School</span></blockquote>
<p>All this busy-ness has affected non-romantic relationships too, which has a ripple effect on the romantic ones, <span class="person" content="Jacqueline Olds" id="person-24">Olds</span> said. A respected national social survey has shown that in recent years people have gone from having three close friends to two, with one of those their romantic <span class="keyWord" content="partner">partner</span>.</p>
<p><span class="citation">“Often when you scratch the surface … the second [friend] lives 3,000 miles away, and you can’t talk to them on the phone because they’re on a different time schedule,” <span class="person" content="Jacqueline Olds" id="person-25">Olds</span> said. “There is too much pressure, from my point of view, on what a romantic <span class="keyWord" content="partner">partner</span> should be. They should be your best friend, they should be your lover, they should be your closest relative, they should be your work <span class="keyWord" content="partner">partner</span>, they should be the co-parent, your athletic <span class="keyWord" content="partner">partner</span>. There’s just so much pressure on the role of spouse that of course everybody isn’t able to quite live up to it.”</span></p>
<p>Since the rising challenges of modern life aren’t going to change soon, <span class="person" content="Richard Schwartz" id="person-26">Schwartz</span> and <span class="person" content="Jacqueline Olds" id="person-27">Olds</span> said couples should try to adopt ways to fortify their relationships for life’s long haul. For instance, couples benefit from shared goals and activities, which will help pull them along a shared life path, <span class="person" content="Richard Schwartz" id="person-28">Schwartz</span> said.</p>
<p><span class="citation">“You’re not going to get to 40 years by gazing into each other’s eyes,” <span class="person" content="Richard Schwartz" id="person-29">Schwartz</span> said. “I think the fact that we’ve worked on things together has woven us together more, in good ways.”</span></p>
<h3>Maintain curiosity about your <span class="keyWord" content="partner">partner</span></h3>
<p>Also important is retaining a genuine sense of curiosity about your <span class="keyWord" content="partner">partner</span>, fostered both by time apart to have separate experiences, and by time together, just as a couple, to share those experiences. <span class="person" content="Richard Schwartz" id="person-30">Schwartz</span> cited a study by <span class="person" content="Robert Waldinger" id="person-31">Robert Waldinger</span>, clinical professor of psychiatry at <span class="organization" content="Massachusetts General" id="organization-10">MGH</span> and <span class="organization" content="Harvard Medical School" id="organization-11">HMS</span>, in which couples watched videos of themselves arguing. Afterwards, each person was asked what the <span class="keyWord" content="partner">partner</span> was thinking. The longer they had been together, the worse they actually were at guessing, in part because they thought they already knew.</p>
<p><span class="citation">“What keeps <span class="keyWord" content="love">love</span> alive is being able to recognize that you don’t really know your <span class="keyWord" content="partner">partner</span> perfectly and still being curious and still be exploring,” <span class="person" content="Richard Schwartz" id="person-32">Schwartz</span> said. “Which means, in addition to being sure you have enough time and involvement with each other — that that time isn’t stolen — making sure you have enough separateness that you can be an object of curiosity for the other person.”</span></p>
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<p><span class="organization">Indian J Endocrinol Metab.</span> <span class="publicationDate">2016 Jul-Aug</span>; 20(4): 558–563.</p>
<p>PMCID: PMC4911849</p>
<p> doi: <a href="https://doi.org/10.4103%2F2230-8210.183479" target="_blank">10.4103/2230-8210.183479</a></p>
<p>PMCID: <a href="https://pubmed.ncbi.nlm.nih.gov/27366726" target="_blank">27366726</a></p>
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<h2 data-src="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911849/">The <span class="keyWord", content="neuroendocrinology" style="word-wrap: break-word;">neuroendocrinology</span> of <span class="keyWord", content="love">love</span></h2>
<p class="byline">By <span class="person" content="Krishna G. Seshadri" id="person-1">Krishna G. Seshadri</span></p>
<hr>
<h3>Abstract</h3>
<p>Romantic <span class="keyWord", content="love">love</span> could be considered as a collection of activities associated with the acquisition and retention of <span class="keyWord", content="emotion">emotions</span> needed to survive and reproduce. These <span class="keyWord", content="emotion">emotions</span> change the individual's behavioural strategies in a way that will increase the likelihood of achieving these goals. <span class="keyWord", content="love">love</span> may be defined as an emergent property of an ancient cocktail of neuropeptides and <span class="keyWord", content="neurotransmitter">neurotransmitters</span>. It appears that lust, attachment and attraction appear to be distinct but intertwined processes in the <span class="keyWord", content="brain">brain</span> each mediated by its own <span class="keyWord", content="neurotransmitter">neurotransmitters</span> and circuits. These circuits feed on and reinforce each other. Sexual craving is mediated by testosterone and oestrogen and has the amygdala as an important centre. Attraction is mediated by <span class="keyWord", content="hormone">hormones</span> of stress and reward including <span class="keyWord", content="dopamine">dopamine</span>, norepinephrine <span class="keyWord", content="cortisol">cortisol</span> and the serotinergic system and has the nucleus accumbens the ventral tegmental area as key mediators.</p>
<p><strong>Keywords:</strong> <span class="keyWord", content="love">love</span>, monogamy, <span class="keyWord", content="neuroendocrinology">neuroendocrine</span>, <span class="keyWord", content="oxytocin">oxytocin</span>, prairie vole, vasopressin</p>
<hr>
<blockquote><span class="citation_block_big">
<i>He will not know what all but he do know.<br>
And as he errs, doting on Hermia's eyes.<br>
So I, admiring of his qualities.<br>
Things base and vile, holding no quantity.<br>
<span class="keyWord", content="love">love</span> can transpose to form and dignity.<br>
<span class="keyWord", content="love">love</span> looks not with the eyes, but with the mind.<br>
And therefore is winged Cupid painted blind.<br>
Nor hath <span class="keyWord", content="love">love</span>'s mind of any judgment taste.<br>
Wings and no eyes figure unheedy haste.</span><br>
—<span class="person" content="William Shakespeare" id="person-2">William Shakespeare</span><br>
<span class="literature">Midsummer Night's dream</span> (1.1.232-243)</i>
</blockquote>
<h3>Introduction</h3>
<p>From an evolutionary perspective romantic <span class="keyWord", content="love">love</span> could be considered as a collection of activities associated with the acquisition and retention of <span class="keyWord", content="emotion">emotions</span> needed to survive and reproduce. These <span class="keyWord", content="emotion">emotions</span> change the individual's behavioral strategies in a way that will increase the likelihood of achieving these goals.[<a href="#ref1">1</a>] The enduring question for <span class="keyWord", content="science">science</span> has been that if these evolutionarily determined behaviors have a biologic substrate and correlation with activation of specific <span class="keyWord", content="brain">brain</span> areas (and <span class="keyWord", content="hormone">hormones</span>)?[<a href="#ref2">2</a>] This review attempts to summarize our current understanding of the <span class="keyWord", content="neuroendocrinology">neuroendocrinology</span> of romantic <span class="keyWord", content="love">love</span>.</p>
<h3>A Definition of <span class="keyWord", content="love">Love</span></h3>
<p>While poets and philosophers are more adept at defining <span class="keyWord", content="love">love</span>, for the purposes of this review, this particular definition seems to be apt: <span class="keyWord", content="love">love</span> is an emergent property of an ancient cocktail of neuropeptides and <span class="keyWord", content="neurotransmitter">neurotransmitters</span>.[<a href="#ref3">3</a>]</p>
<h3>The Dichotomy Between Courtship and Sex</h3>
<p>Despite the intimate intertwining of the sexual drive with courtship, for over 4 decades investigators have suggested that these processes may be distinct [<a href="#ref4">4</a>] but operate in tandem [Table 1]. Human romantic <span class="keyWord", content="love">love</span> (hereafter just <span class="keyWord", content="love">love</span>) is cross-cultural, universal, and associated with distinct physiologic, psychological, and behavioral traits.[<a href="#ref5">5</a>] Many of these traits are also characteristic of mammalian courtship which includes increased energy, focused attention, obsessive following, affiliative gestures, possessive mate guarding, goal-oriented behavior, and motivation to win a preferred <span class="keyWord", content="partner">partner</span>.[<a href="#ref2">2</a>]</p>
<p><strong>Table 1</strong></p>
<div class="caption">Comparison of three motivations involved in “<span class="keyWord", content="love">love</span>”</div>
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<img src="img/IJEM-20-558-g001.jpg">
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<p>In humans, <span class="keyWord", content="love">love</span> often begins when an individual starts to regard another individual as special and unique. This is followed by focused attention, aggrandizement of traits and worth of the object of attention, and minimizing of his or her faults. There is increased ecstasy when things go well, despair when they do not and separation anxiety when apart.[<a href="#ref6">6</a>] Emotional dependence, empathy, sacrifice, and obsessive thinking are common. Sexual desire, intense sexual possessiveness, and mate guarding are present, but the emotional union appears to supersede the craving for sex. Rejection triggers protest and rage, moving into resignation and despair. It has been suggested that <span class="keyWord", content="love">love</span> as a preference system is associated with action and conditioning of specific <span class="keyWord", content="neuroendocrinology">neuroendocrine</span> pathways.</p>
<h3><span class="keyWord", content="love">Love</span> as a Primordial Drive</h3>
<p>It has been proposed the <span class="keyWord", content="love">love</span> is not primarily an <span class="keyWord", content="emotion">emotion</span> but a motivation system (i.e., a system oriented around the planning and pursuit of a specific want or need) designed to enable suitors to build and maintain an intimate relationship with a specific mating <span class="keyWord", content="partner">partner</span>.[<a href="#ref7">7</a>] Functional magnetic resonance imaging (MRI) studies demonstrate the involvement of areas associated with motivation and goal-oriented behavior in <span class="keyWord", content="love">love</span> suggesting that <span class="keyWord", content="love">love</span> is a primary motivation system a fundamental human mating drive.[<a href="#ref8">8</a>] Several lines of evidence support this view that <span class="keyWord", content="love">love</span> is not an <span class="keyWord", content="emotion">emotion</span> but motivation and are reviewed elsewhere. (8) <span class="keyWord", content="love">love</span> also appears to be stronger than sex drive-those rejected by sexual overtures rarely kill themselves or others. Abandoned lovers sometimes stalk, commit suicide homicide, or fall into clinical depression.[<a href="#ref7">7</a>]</p>
<h3>Stress as an Initiator/Facilitator of <span class="keyWord", content="love">love</span></h3>
<p>The early phase of <span class="keyWord", content="love">love</span> represents an extreme neurobiological state somewhat contradictory in a physiologic sense from subsequent phases and states. Stress appears to be the trigger for a quest for pleasure, proximity, and closeness. As a norm, moderate stress encourages social interaction.</p>
<p>Within a homeostatic range, stress-related physiologic processes including the <span class="keyWord", content="hormone">hormones</span> of the hypothalamo-pituitary adrenal axis can help develop and promote social bonding.[<a href="#ref9">9</a>] Indeed, some of the signs commonly associated with love-anxiety palpitations increased peristalsis are manifestations of the stress response (albeit in a pleasurable way). Indeed, subjects in <span class="keyWord", content="love">love</span> show higher levels of <span class="keyWord", content="cortisol">cortisol</span> when compared to controls.[<a href="#ref10">10</a>] This “<span class="keyWord", content="love">love</span> induced hypercortisolemia” may represent a nonspecific stress response to change that characterizes early phases of relationships or a physiologic state of alertness that may help overcome neophobia. Irrespective, this stress response appears to be important in the formation of social contact and attachment.</p>
<p>Central norepinephrine may also be involved. Increased activity of norepinephrine generally produces alertness energy sleeplessness and loss of appetite, increased attention, and increased memory for new stimuli which characterize (the earlier) phases of human <span class="keyWord", content="love">love</span>.[<a href="#ref11">11</a>] Norepinephrine is also associated with peripheral sympathetic nervous systems including increased heart rate, sweating trembling which may explain this experience in <span class="keyWord", content="love">love</span>.[<a href="#ref12">12</a>]</p>
<p>Positive social interactions and pair bonding (see below) appear to alleviate stress through <span class="keyWord", content="oxytocin">oxytocin(OT)</span> facilitating security and support. It appears therefore that initial anxiety and stress is an inherent component of early <span class="keyWord", content="love">love</span> which reaches its fulfillment through “the chill” rendered by <span class="keyWord", content="love">love</span> and deep relationships. These appear to be mediated by a complex interaction between pathways that link stress response to reward mechanisms. Indeed, serotonin-dependent pathways such as the amygdala appear to interact with <span class="keyWord", content="oxytocin">OT</span> (see below). <span class="keyWord", content="oxytocin">OT</span> administration appears to decrease anxiety by inhibiting amygdala activity.[<a href="#ref13">13</a>]</p>
<h3>Gonadal <span class="keyWord", content="hormone">hormones</span></h3>
<p>The role of gonadal <span class="keyWord", content="hormone">hormones</span> in this regard appears to be facilitatory but peripheral in <span class="keyWord", content="love">love</span>. Sex <span class="keyWord", content="hormone">hormones</span> may exert developmental effects on neural systems involved in social attachments and may mediate both genetic and environmental influences on the propensity to <span class="keyWord", content="love">love</span> and form attachments.[<a href="#ref14">14</a>] Testosterone receptors are distributed in the hypothalamus. Testosterone through these receptors may suppress levels or activity of serotonin which apparently increases aggressiveness. Testosterone further enhances vasopressin levels in the medial amygdala lateral hypothalamus and pre-optical medial area which are involved in aggressive behaviors.[<a href="#ref15">15</a>] Gonadal <span class="keyWord", content="hormone">hormones</span> may further regulate <span class="keyWord", content="oxytocin">OT</span> and vasopressin through indirect mechanisms. However, social attachment does occur even in the absence of gonadal steroids suggesting that gonadal <span class="keyWord", content="hormone">hormones</span> are only a small piece of an intricately knit puzzle that form the complex phenomenon called <span class="keyWord", content="love">love</span>.</p>
<p>Gender differences evident on functional imaging in the <span class="keyWord", content="partner">partner</span> preference and early phases of <span class="keyWord", content="love">love</span> warrant mention. Men show more activity in a region of the right posterior dorsal insula (an area correlating with penile turgidity and viewing of beautiful faces) and in regions associated with the integration of visual stimuli. Women tend to show more activity than men in regions associated with attention, memory, and emotion. Courting men respond more strongly than women to visual signals of youth and beauty. Women appear to be more attracted to men who offer status and resources.[<a href="#ref16">16</a>]</p>
<h3>Vasopressin <span class="keyWord", content="oxytocin">oxytocin</span> and “Pair Bonding”</h3>
<p>Pair bonding is a very bland scientific term for enduring (romantic) relationships (attachment) and is seen in >5% of the mammalian species.[<a href="#ref17">17</a>] Pair bonding across species is defined as an enduring preferential association formed between two sexually mature adults and is characterized by selective contact, affiliation, and copulation with the <span class="keyWord", content="partner">partner</span> over a stranger.[<a href="#ref18">18</a>] These are associated with other complex behaviors including mate guarding and biparental care of the young.</p>
<p>Pair bonding evolved most likely, as an adaptive response to the need of additional parental investment in the rearing of the young and mechanisms through which this relationship was preserved (mate guarding). In other words, romantic relationships and their persistence (through monogamy) was an evolutionary necessity in species in which bi-parental care of the offspring was critical. There are clear benefits to both <span class="keyWord", content="partner">partners</span> of the relationships as well. In humans, individuals in stable marital relationships live longer than single individuals cross demographic groups. High levels of intimacy correlate negatively with depression and positively with immune function and cardiovascular health.[<a href="#ref19">19</a>]</p>
<p>Most of our knowledge on the neuroendocrinology of intimacy is based on the work on the prairie vole (Microtus ochrogaster) a humble but socially monogamous model from the grasslands of the central United States. In this harsh grassland with scarce resources, the prairie vole evolved into a monogamous animal with breeding pairs living together until one <span class="keyWord", content="partner">partner</span> dies; the surviving <span class="keyWord", content="partner">partner</span> does not find another mate. The male prairie vole is highly paternal, helps with nest building guards the nest from conspecific strangers. In general, an animal with low levels of aggression, the male displays enhanced levels of aggression toward strange males. It displays high levels of paternal behavior to litters; this extends to juveniles even after a second litter is born.</p>
<p>Arginine vasopressin (AVP) <span class="keyWord", content="oxytocin">OT</span> and <span class="keyWord", content="dopamine">dopamine (DA)</span> have been reported to be important in regulating social behavior including sexual behavior, aggression, and maternal care. While there are no differences in AVP and <span class="keyWord", content="oxytocin">OT</span> neurons or their distribution between the monogamous prairie voles and their polygamous cousins, remarkable differences are seen in the receptor distribution (the V1aR and <span class="keyWord", content="oxytocin">OT</span> receptor [OTR]) and their densities. Interestingly, these densities are stable across the lifespan of the vole. These differences may explain by subtle differences in the promoter region the V1aR and the OTR.[<a href="#ref20">20</a>] The human version of this gene has similar polymorphisms. It is possible that epigenetic modifications of the OTR are also involved.[<a href="#ref21">21</a>]</p>
<p>In the male prairie vole, cohabitation with mating appears to increase AVP synthesis in the bed nucleus of the stria terminalis and AVP release in the limbic system. In the female chemosensory clues altered OTR density in the AOB. Activation of the <span class="keyWord", content="oxytocin">OT</span> and vasopressin receptors in these centers might result in the development of a conditioned <span class="keyWord", content="partner">partner</span> preference in prairie voles. Antagonism of the OTR impairs the formation of pair bonds. This effect appears to be larger in the female.</p>
<p>Knockdown of VP production in the paraventricular nucleus of the hypothalamus in the zebra finch increases aggressiveness in the male decreases it the female and reduces gregariousness in both. Knockdown of <span class="keyWord", content="oxytocin">OT</span> reduces gregariousness, pair bonding, nest cup ownership and side by side perching in females and induces hyperphagia in males.[<a href="#ref22">22</a>] An association between arginine vasopressin receptor 1A polymorphism and human pair bonding behavior analogous to voles has been reported.</p>
<p>AVP activity in the ventral palladium affects <span class="keyWord", content="partner">partner</span> preference. V1aR activation in this region is necessary for pair bond formation.[<a href="#ref23">23</a>] Similarly, activation of the <span class="keyWord", content="oxytocin">OT</span> in the nucleus accumbent (NA) also contributes to <span class="keyWord", content="partner">partner</span> preference and pair bonding.</p>
<p>Functional MRI studies of human <span class="keyWord", content="partner">partners</span> in long-term relationships show activation the ventral palladium putamen the anterior cingulate cortex and the mid-insular cortex.[<a href="#ref24">24</a>] The ventral putamen/palladium region in particular corresponds to the distribution of V1a receptors in the prairie vole. The areas appear, and connections appear to be distinct but related to those for maternal <span class="keyWord", content="love">love</span>. Maternal <span class="keyWord", content="love">love</span> activated specific different areas including the lateral orbit frontal cortex but also some same areas as (romantic) <span class="keyWord", content="love">love</span> including medial insula, the anterior cingulate gyrus, and caudate nucleus. Both appear to share areas rich in <span class="keyWord", content="oxytocin">OT</span> and AVP receptors.</p>
<h3><span class="keyWord", content="love">Love</span> as a Reward</h3>
<p>From the very beginning of our efforts, in understanding the biologic basis of <span class="keyWord", content="love">love</span> it has been clear that it involves reward centers in the <span class="keyWord", content="brain">brains</span>. In this <span class="keyWord", content="love">love</span> and addictions (such as by drugs) are somewhat interconnected the one key difference is that naturally rewarding activities such as <span class="keyWord", content="love">love</span> are controlled by feedback mechanisms that activate aversive centers that limit the destructive qualities of addiction seen with drugs.[<a href="#ref25">25</a>] <span class="keyWord", content="love">Love</span> activates specific regions in the reward system. The effects include a reduction in emotional judgment and reduced fear and also reduced depression and enhanced mood. It also leads to a reduced need to assess the social validity of that person.[<a href="#ref26">26</a>] It thus appears to deactivate areas mediating negative <span class="keyWord", content="emotion">emotions</span>, avoidance behavior critical social assessment and, on the other hand, triggers mechanisms involved in pleasure reward and appetitive motivation [<span class="figure"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911849/figure/F1/" target="_blank">Figure 1</a></span>].[<a href="#ref27">27</a>]</p>
<figure>
<img src="img/IJEM-20-558-g002.jpg">
</figure>
<figcaption class="caption"><span class="figure"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911849/figure/F1/" target="_blank">Figure 1</a></span><br>
Nuclei associated with motivations collectively involved in “<span class="keyWord", content="love">love</span>”
</figcaption>
<p>Studies which have examined the <span class="keyWord", content="oxytocin">OT</span> and AVP receptors strongly suggest that the activation of these receptors in the reward circuitry is important for the development of pair bonding. As a critical part of the reward process, <span class="keyWord", content="dopamine">DA</span> appears to be central to the maintenance of <span class="keyWord", content="love">love</span>. Differences in <span class="keyWord", content="dopamine">DA</span> and its receptor distribution densities have been reported in vole studies (vide above). Dopaminergic pathways appear to be more specific for <span class="keyWord", content="partner">partner</span> preference that attachment.[<a href="#ref28">28</a>]</p>
<p>While several <span class="keyWord", content="dopamine">DA</span> systems exist in the <span class="keyWord", content="brain">brain</span>, the mesolimbic <span class="keyWord", content="dopamine">DA</span> system appears to be the most important in this respect. Both D1 and D2 receptors though partially functional antagonists are both significantly expressed in the NA. Other <span class="keyWord", content="dopamine">DA</span> receptors (D3-5) are also linked to the limbic system and are substantially present in the amygdala and the hippocampus. Their functions include reward and motivation and appear to share common morphologic evolutionary and molecular roots. Endogenous opioids may also be involved in this process.</p>
<p>Early studies that involved functional MRI, which used the <span class="keyWord", content="partner">partner</span>'s photograph as a visual stimuli confirm the involvement of the right ventral segmental area (VTA) which is a central region of the <span class="keyWord", content="brain">brain</span>'s reward system [<a href="#ref29">29</a>] associated with pleasure, general arousal, focused attention, and motivation to pursue and acquire rewards.[24] The VTA projects into several regions including the caudate nucleus which plays a role in reward detection, expectation, representation of goals, and integration of sensory inputs to prepare for action. These appear to be true of both early intense (7.4 months) and a little later and not so intense <span class="keyWord", content="love">love</span> (28.8 months).[<a href="#ref30">30</a>]</p>
<h3>The Role of Sexual Activity</h3>
<p>Clearly, sexual activity is an important component of the reinforcement of the reward system, and this appears to reinforce attachment. Increasing levels of testosterone and oestrogen promote <span class="keyWord", content="dopamine">DA</span> release.[<a href="#ref31">31</a>] Similarly, elevated activity of dopaminergic pathways appear to increase the release of testosterone and oestrogen. The relationship between elevated central <span class="keyWord", content="dopamine">DA</span> sex steroids, sexual arousal, and performance appears to be conserved in humans (7). The sympathetic nervous system also appears to contribute.</p>
<p>Behavioral data support the complementary but distinct pathways for <span class="keyWord", content="love">love</span> and sex drive: (a) While sexual drive is often expressed toward a range of individuals while <span class="keyWord", content="love">love</span> is focused on one particular individual (b) the sex drive can be quelled when satiated; <span class="keyWord", content="love">love</span> does not decrease with coitus and persists unabated for months or years. Sex drive enables individuals to initiate courtship and mating with a range of <span class="keyWord", content="partner">partners</span>; <span class="keyWord", content="love">love</span> focuses mating energy to specific individuals conserving time and metabolic energy (6).</p>
<p>Pleasure and reward activate behavioral patterns that get memorized for the goal of repetition and faster and better recognition later. There is clear evidence to support a connection between attachment behaviors and pleasure pathways that involve hippocampal mechanisms.</p>
<p>The VP is a major target of the NA. The interaction of <span class="keyWord", content="oxytocin">OT</span>, AVP, and the <span class="keyWord", content="dopamine">DA</span> systems within the reward circuitry appears to be the foundation of monogamy. It is hypothesized that in monogamous species (such as the prairie vole) sex triggers the activity of AVP in the ventral pallidum and <span class="keyWord", content="oxytocin">OT</span> in the NA and facilitates <span class="keyWord", content="dopamine">DA</span> release in these reward regions which in turn motivates the male and female to prefer a current mating <span class="keyWord", content="partner">partner</span> and initiates attachment or pair bonding. In promiscuous species, the male feels the attraction but does not associate the pleasurable feeling with a specific <span class="keyWord", content="partner">partner</span> and so does not initiate long-term attachment (23). The relationship with the <span class="keyWord", content="dopamine">DA</span> reward systems also appears weaker in these species.[<a href="#ref32">32</a>] Complex interactions between gonadal reward and sympathetic systems demonstrate there are distinct but overlapping neural networks involved in <span class="keyWord", content="love">love</span> and sex the latter contributing to the reinforcement of the former. Their interdependence also distinguishes romantic <span class="keyWord", content="love">love</span> from more platonic attachments including friendship and maternal <span class="keyWord", content="love">love</span> (vide above).</p>
<p>It is interesting to extrapolate this to humans. Humans engage in sexual activity throughout the cycle which may serve to strengthen the pair bond. Interestingly and in contrast to other species human females have enlarged mammary tissue independent of lactation. Breast and nipple stimulation are integral to human sexual activity.[<a href="#ref33">33</a>] Nipple stimulation during lactation is one of the most potent stimulus for <span class="keyWord", content="oxytocin">OT</span> release.[<a href="#ref34">34</a>] This part of sexual activity may reinforce pair bonding in humans. <span class="keyWord", content="oxytocin">OT</span> levels are elevated in women during orgasm and AVP in men increase during sexual arousal adding validity to the notion that sexual activity indeed reinforces the bond. In the postpartum state when sexual activity and desire decreases probably as a trade off in reproductive interests. This appears to be mediated by <span class="keyWord", content="oxytocin">OT</span> through activation of reward centers in the VTA.<a href="#ref1">[35]</a></p>
<p>Thus, the neuroendocrine system for sexual attraction and <span class="keyWord", content="partner">partner</span> attachment appear to work in tandem in a monogamous species motivating individuals to prefer a specific mating <span class="keyWord", content="partner">partner</span> and also motivating them to form an attachment to this mate. In nonmonogamous species, sexual attraction and <span class="keyWord", content="partner">partner</span> attachment appear to operate independently. The neuroendocrine networks that mediate these complex relationships appear to themselves be complex, flexible, and interdependent and facilitate individuals of myriad species with the range of motivations, emotions, and behaviors necessary to pursue their species-specific reproductive strategy.[8]</p>
<h3>Conclusion</h3>
<p>Landmark studies in the prairie vole coupled with functional MRI studies have helped us understand the complex interplay of distinct pathways that mediate sexual attraction, romantic <span class="keyWord", content="love">love</span> maternal <span class="keyWord", content="love">love</span>, and platonic friendships. Further ongoing research is attempting to delineate the biologic basis of complex traits including fidelity, trust, and spirituality. The role of modification of these <span class="keyWord", content="neurotransmitter">neurotransmitters</span> particularly <span class="keyWord", content="oxytocin">OT</span> in the therapy of autism, in trust deficit and in behavioral diseases requires further delineation. For example, <span class="keyWord", content="oxytocin">OT</span> is generally regarded as a <span class="keyWord", content="hormone">hormone</span> that enhances trust behavior. However, its administration of <span class="keyWord", content="oxytocin">OT</span> in women who have a forgiving attitude increases the chance that they may punish betrayal.[<a href="#ref36">36</a>] Thus, the response to therapy with <span class="keyWord", content="oxytocin">OT</span> (and by inference other peptides) appears to be conditional to differences in the individual. These include sex and hormonal status, variations in the OTR, early experiences, epigenetic changes, and neuroplasticity.[<a href="#ref37">37</a>] Large scale trials will further clarify the role of peptide therapy in modulating behavior. And whether successful or not, manipulating <span class="keyWord", content="love">love</span> and <span class="keyWord", content="emotion">emotions</span> hoists a slew of ethical red flags. At the time of this writing, however, romantic <span class="keyWord", content="love">love</span> retains its mystique continues to tantalize it has revealed some secrets but has manage concealed the vital.</p>
<h3>Financial support and sponsorship</h3>
<p>Nil.</p>
<h3>Conflicts of interest</h3>
<p>There are no conflicts of interest.</p>
<h3>References</h3>
<hr>
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<h2 data-src="https://www.sciencedirect.com/science/article/pii/S2666497621000813"><span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span>: Myths, metaphors and mysteries</h2>
<div class="article_desc">
<p class="publicationDate">February 2022, 100107</p>
<p class="byline">By <span class="person", content="C. Sue Carter", id="person1">C. Sue Carter</span></p>
<p><a href="https://doi.org/10.1016/j.cpnec.2021.100107">https://doi.org/10.1016/j.cpnec.2021.100107</a></p>
<p><sup>a</sup><span class="organization", content="Kinsey Institute", id="organization1">Kinsey Institute</span>, <span class="organization", content="Indiana University", id="organization2">Indiana University</span>, Bloomington, USA</p>
<p><sup>b</sup>Department of Psychology, <span class="organization", content="University of Virginia", id="organization3">University of Virginia</span></span>, Charlottesville, USA</p>
</div>
<blockquote class="citation_block_big">
<h3>Highlights</h3>
<ul>
<li><span class="keyWord", content="oxytocin">oxytocin</span> is a peptide molecule with functions that support a sense of safety, sociality, as well as survival and reproduction.</li>
<li><span class="keyWord", content="oxytocin">oxytocin</span> is associated with social and neuroimmune solutions to chronic stress.</li>
<li>The related, but more primitive, peptide vasopressin supports more individualistic survival strategies.</li>
<li>Controversies and myths surround the properties of <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span>.</li>
</ul>
</blockquote>
<h3>Abstract</h3>
<p><span class="keyWord", content="oxytocin">oxytocin</span> is a peptide molecule with a multitude of physiological and behavioral functions. Based on its association with reproduction - including social bonding, sexual behavior, birth and maternal behavior - <span class="keyWord", content="oxytocin">oxytocin</span> also has been called “the <span class="keyWord", content="love">love</span> <span class="keyWord", content="hormone">hormone</span>.” This essay specifically examines association and parallels between <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span>. However, many myths and gaps in knowledge remain concerning both. A few of these are described here and we hypothesize that the potential benefits of both <span class="keyWord", content="love">love</span> and <span class="keyWord", content="oxytocin">oxytocin</span> may be better understood in light of interactions with more ancient systems, including specifically <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> and the immune system. <span class="keyWord", content="oxytocin">Oxytocin</span> is anti-inflammatory and is associated with recently evolved, social solutions to a variety of challenges necessary for mammalian survival and reproduction. The shared functions of <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> have profound implications for health and longevity, including the prevention and treatment of excess inflammation and related disorders, especially those occurring in early life and during periods of chronic threat or disease.</p>
<h3>Keywords</h3>
<p><span class="keyWord", content="oxytocin">Oxytocin</span>; Vasopressin; Immune system; Social behavior; Stress; <span class="keyWord", content="love">Love</span></p>
<hr>
<h3>1. Overview</h3>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> was the first peptide molecule to be biochemically identified [<a href="#ref1">1</a>]. The <span class="keyWord", content="oxytocin">oxytocin</span> molecule has properties and functions essential to mammalian behavior and to understanding human origins [<a href="#ref2">2</a>] which are only now being described [<a href="#ref3">3</a>,<a href="#ref4">4</a>]. Interest in <span class="keyWord", content="oxytocin">oxytocin</span> has increased exponentially, especially over the last two decades. At present approximately 30,000 research papers listed on <i>Pubmed</i> deal in some way with <span class="keyWord", content="oxytocin">oxytocin</span>. However, despite this massive effort, the study of <span class="keyWord", content="oxytocin">oxytocin</span> remains associated with myths and mysteries.</p>
<p>This perspective essay considers a series of questions which are fundamental to understanding <span class="keyWord", content="oxytocin">oxytocin</span>, but which also have been sources of repeated controversy and misunderstandings: What is <span class="keyWord", content="oxytocin">oxytocin</span> and why is this molecule difficult to measure? Is there a unique receptor for <span class="keyWord", content="oxytocin">oxytocin</span>? Is <span class="keyWord", content="oxytocin">oxytocin</span> a <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/stress-hormone"><u>stress <span class="keyWord", content="hormone">hormone</span></u></a>? Are the actions of <span class="keyWord", content="oxytocin">oxytocin</span> sexually-dimorphic? Why is awareness of <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> and the immune system essential to understanding <span class="keyWord", content="oxytocin">oxytocin</span>? What is social behavior and how does <span class="keyWord", content="oxytocin">oxytocin</span> influence sociality? And of course, why is <span class="keyWord", content="oxytocin">oxytocin</span> sometimes called “the <span class="keyWord", content="hormone">hormone</span> of <span class="keyWord", content="love">love</span>”?</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> has effects on social connection, a perception of safety, and also immunology and inflammation. Of particular importance in understanding <span class="keyWord", content="oxytocin">oxytocin</span> are its interactions with the immune system [<a href="#ref5">5</a>], as well as the anti-inflammatory effects of mitochondria [<a href="#ref6">6</a>,<a href="#ref7">7</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> regulates and is regulated by glia [<a href="#ref8">8</a>] and the immune system [<a href="#ref9">9</a>]. Furthermore, <span class="keyWord", content="oxytocin">oxytocin</span> mediates behavioral and immune consequences that are attributed to the microbiota [<a href="#ref10">10</a>,<a href="#ref11">11</a>].</p>
<p>All of these have consequences for health and wellbeing. As described below, recent studies are helping to explain some of the myths and controversies associated with <span class="keyWord", content="oxytocin">oxytocin</span>. The mechanisms linking <span class="keyWord", content="love">love</span> and <span class="keyWord", content="oxytocin">oxytocin</span> to each other remain both metaphorical and mysterious, but a mystery worth exploring.</p>
<h3>2. So, what exactly is <span class="keyWord", content="oxytocin">oxytocin</span>?</h3>
<p>The “what is <span class="keyWord", content="oxytocin">oxytocin</span>” question should be easy to answer. The use of the word <span class="keyWord", content="oxytocin">oxytocin</span> is not new. The website of the<span class="organization", content="National Institutes of Mental Health", id="organization4">National Institutes of Mental Health</span> states that the term <span class="keyWord", content="oxytocin">oxytocin</span> was already in the use in the 1800s and perhaps as early as the 1500s.</p>
<p><a href="https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/clinics-and-labs/lcmr/snge/vpot/some-selected-history-of-oxytocin-and-vasopressin">https://www.nimh.nih.gov/research/research-conducted-at-nimh/research-areas/clinics-and-labs/lcmr/snge/vpot/some-selected-history-of-oxytocin-and-vasopressin</a>. As originally used, the word <span class="keyWord", content="oxytocin">oxytocin</span> appears to have referred to a <i>process</i> of “swift birth.” However, in current usage <span class="keyWord", content="oxytocin">oxytocin</span> most often describes a <i>specific molecule</i>.</p>
<p>Although modern dictionaries usually translate the derivation of the word <span class="keyWord", content="oxytocin">oxytocin</span> as “swift birth,” as described in an email from <span class="person", content="Roger Guillemin", id="person2">Roger Guillemin</span>, “<span class="keyWord", content="oxytocin">oxytocin</span>”, the English spelling, may have been a “mistaken translation”? (<a href="#ref153">Box 1</a>). <span class="person", content="Roger Guillemin", id="person2">Dr. Guillemin</span> is a Nobel <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/lauric-acid"><u>laurate</u></a> and sometimes described as father of the field of <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neuroendocrine-system"><u><span class="keyWord", content="neuroendocrinology">neuroendocrinology</span></u></a>. <span class="person", content="Roger Guillemin", id="person2">Guillemin</span> suggested that <span class="keyWord", content="oxytocin">oxytocin</span> translates to “sharp” birth and proposed that “ocytocin” (still used in French) would have been a more accurate translation of the Greek symbols intended to describe the functional capacity of this molecule to induce a quick birth.</p>
<blockquote>
<article id="ref153"><strong>BOX 1</strong></article><br>
<span class="citation_block_big">
<p>THE MYSTERIOUS ORIGINS OF THE WORD “<span class="keyWord", content="oxytocin">OXYTOCIN</span>. (An historical aside)</p>
<p><strong>This excerpt is from an email correspondence with <span class="person", content="Roger Guillemin", id="person2">Roger Guillemin</span>. It came following a talk I had given at the <span class="organization", content="Salk Institute", id="organization5">Salk Institute</span>. In that presentation I showed a portrait of <span class="person", content="Antoine Lavoisier", id="person3">Antoine Lavoisier</span>(father of modern chemistry), his wife, <span class="person", content="Marie-Anne Paulze Lavoisier", id="person4">Marie-Anne</span>, and instruments for collecting oxygen – a picture I sometimes used to symbolize the notion that loving relationships are based on biochemistry.</p></strong>
<p>…. As per <span class="person", content="Antoine Lavoisier", id="person3">Lavoisier</span>, the word oxygen comes from the Greek ὀξύς/oxys, acid, sharp and γενής/genês, generates, because <span class="person", content="Antoine Lavoisier", id="person3">Lavoisier</span> thought that the substance oxygen was involved in producing acids in combination with other substances (still true though not exclusive …). <span class="keyWord", content="oxytocin">Oxytocin</span> is a totally different story. It is actually a mistake for ocytocin.</p>
<p>The etymology is ὠκύς/ocys fast and τόκος/birth, delivery. Note the κ (kappa) always translates as c (ocytocin) different from the ξ (ksi) always translated as x as in oxygen. I went over on and on with texts in Greek, <span class="person", content="Herodotes", id="person5">Herodotes</span>, <span class="person", content="Hippocrates", id="person6">Hippocrates</span>, where I found the words ὠκύς τόκος, as in 'ωκυτοκιος ′ωκυτοκιοv ὠκυτόκου all in phrases referring to speedy birth, never as ὀξύς as for oxygen (acid generating) So the correct word is OCYTOCIN.</p>
<p>Well maybe here's the last word in a story told me, many years ago by <span class="person", content="Roger Acher", id="person7">Roger Acher</span> whose name you recognize of course... At some meeting <span class="person", content="Vincent du Vigneaud", id="person8">duVigneaud</span> was talking about his early work on isolation of <span class="keyWord", content="oxytocin">oxytocin</span> when this French participant (?) got up and said …</p>
<p>“ Sir, with all due respect please note that the correct word is ocytocin and I can show the etymology” to which <span class="person", content="Vincent du Vigneaud", id="person8">duVigneaud</span> is supposed to have answered. “ listen I don't care about all your grammar... all I know is that stuff comes from the pituitary of oxen... so that's <span class="keyWord", content="oxytocin">oxytocin</span> by me..." I knew <span class="person", content="Vincent du Vigneaud", id="person8">duVigneaud</span> quite well and I bet the story is true …</p>
<p><strong>I still have not been able to find out who first originated <span class="keyWord", content="oxytocin">OXYTOCIN</span>.</strong></p></span>
<p>—<span class="person", content="Roger Guillemin", id="person2">Roger Guillemin</span> May 29, 2013.</p>
</blockquote>
<p>Genomic studies, tracing the evolutionary origins of these molecules, further question the accuracy of this name [<a href="#ref12">12</a>]. <span class="person", content="Constantina Theofanopoulou", id="person9">Theofanopoulou</span> and her colleagues have suggested the need for a “universal nomenclature for <span class="keyWord", content="oxytocin">oxytocin</span>-vasotocin ligand and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/receptor-family"><u>receptor families</u></a>”. One family, that they propose to call “vasotocin,”, would consist of the molecules that are currently called <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/argiprestocin"><u>vasotocin</u></a> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> (<a href="#ref154">Table 1</a>). A second chemical family they propose to call “<span class="keyWord", content="oxytocin">oxytocin</span>”, would consist of <span class="keyWord", content="oxytocin">oxytocin</span>, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/mesotocin"><u>mesotocin</u></a> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/isotocin"><u>isotocin</u></a>. These authors argue that a more accurate naming system would be based on the relative affinity of ligands to receptors. Following this system, the molecules now called mesotocin and isotocin, would be called <span class="keyWord", content="oxytocin">oxytocin</span>. Of course, calling these three structurally different molecules “<span class="keyWord", content="oxytocin">oxytocin</span>”, offers opportunity for other sources of confusion and controversy.</p>
<table>
<caption><strong><article id="ref154">Table 1.</article></strong>Amino acid sequences in the vasotocin-<span class="keyWord", content="oxytocin">oxytocin</span> family of peptides.<sup><a href="#ref158">a</a></sup></caption>
<tr>
<th>
Amino acid position
</th>
<th>
1
</th>
<th>
2
</th>
<th>
3
</th>
<th>
4
</th>
<th>
5
</th>
<th>
6
</th>
<th>
7
</th>
<th>
8
</th>
<th>
9
</th>
<th>
Expressed in (among others)<sup><a href="#ref158">a</a></sup>
</th>
</tr>
<tr>
<td>
Vasotocin
</td>
<td>
Cys-
</td>
<td>
Tyr-
</td>
<td>
<strong>Ile-</strong>
</td>
<td>
Gln-
</td>
<td>
Asn-
</td>
<td>
Cys-
</td>
<td>
Pro-
</td>
<td>
<strong>Arg-</strong>
</td>
<td>
Gly (NH2)
</td>
<td>
Non-mammalian vertebrates and fetuses
</td>
</tr>
<tr>
<td>
Vasopressin
</td>
<td>
Cys-
</td>
<td>
Tyr-
</td>
<td>
<strong>Phe-</strong>
</td>
<td>
Gln-
</td>
<td>
Asn-
</td>
<td>
Cys-
</td>
<td>
Pro-
</td>
<td>
<strong>Arg-</strong>
</td>
<td>
Gly (NH2)
</td>
<td>
Mammals
</td>
</tr>
<tr>
<td>
<span class="keyWord", content="oxytocin">Oxytocin</span>
</td>
<td>
Cys-
</td>
<td>
Tyr-
</td>
<td>
<strong>Ile-</strong>
</td>
<td>
Gln-
</td>
<td>
Asn-
</td>
<td>
Cys-
</td>
<td>
Pro-
</td>
<td>
<strong>Leu-</strong>
</td>
<td>
Gly (NH2)
</td>
<td>
Mammals
</td>
</tr>
<tr>
<td>
Mesotocin
</td>
<td>
Cys-
</td>
<td>
Tyr-
</td>
<td>
<strong>Ile-</strong>
</td>
<td>
Gln-
</td>
<td>
Asn-
</td>
<td>
Cys-
</td>
<td>
Pro-
</td>
<td>
<strong>Ile-</strong>
</td>
<td>
Gly (NH2)
</td>
<td>
Non-eutherian tetrapods & birds
</td>
</tr>
<tr>
<td>
Isotocin
</td>
<td>
Cys-
</td>
<td>
Tyr-
</td>
<td>
<strong>Ile-</strong>
</td>
<td>
<strong>Ser-</strong>
</td>
<td>
Asn-
</td>
<td>
Cys-
</td>
<td>
Pro-
</td>
<td>
<strong>Ile-</strong>
</td>
<td>
Gly (NH2)
</td>
<td>
Ray-finned fishes
</td>
</tr>
<tr>
<td>
<p class="formula"><article id="ref158">a</article><sub>[<a href="#ref15">15</a>]</sub></p>
</td>
</tr>
</table>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> and its targets have consequences that remain essential to coordinating mammalian behavior and reproduction with environmental demands, including functions such as defense in the face of pathogens <a href="#ref12">[13]</a>, immunological responses, mitochondrial functions and basic cellular metabolism [<a href="#ref6">6</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> also can function as a <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neurotransmitter"><span class="keyWord", content="neurotransmitter"><u>neurotransmitter</u></span></a> and neuromodulator [<a href="#ref14">14</a>]. Perhaps even calling <span class="keyWord", content="oxytocin">oxytocin</span> a “<span class="keyWord", content="hormone">hormone</span>” is a misnomer?</p>
<h3>3. The variable chemistry of the molecule called <span class="keyWord", content="oxytocin">oxytocin</span></h3>
<p>In 1953 <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a>, were identified biochemically [<a href="#ref1">1</a>]. The gene for <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxytocin-receptor"><u><span class="keyWord", content="oxytocin">oxytocin</span> receptor</u></a> have been well understood for several decades. But again, the story is not that simple.</p>
<p>Canonical forms of <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin consist of peptide molecules composed of nine amino acids, with a three amino acid tail (implicated in <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/ligand-binding"><u>ligand binding</u></a> to the receptor) and a six amino acid ring (implicated in coupling with G-coupled protein receptors (GCPR) [<a href="#ref17">17</a>]. The ring in this structure is formed by the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/disulfide"><u>disulfide</u></a> bonds in two cysteines (positions 1 and 6). (<a href="#ref155">Fig. 1</a>; <a href="#ref154">Table 1</a>). Vasopressin differs from <span class="keyWord", content="oxytocin">oxytocin</span> by two amino acids, one at position 3 (in the ring) and one at position 8 (in the tail). <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/argiprestocin"><u>Vasotocin</u></a>, considered the ancestral peptide from which both evolved, differs from vasopressin by one amino acid at position 3 and from <span class="keyWord", content="oxytocin">oxytocin</span> by one amino acid at position 8.</p>
<hr>
<figure>
<img src="img/1-s2.0-S2666497621000813-gr1.jpg">
<figcaption><article id="ref155">Fig. 1. Canonical structures of <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a>.</article></figcaption>
</figure>
<hr>
<p>One interesting difference between the structure of <span class="keyWord", content="oxytocin">oxytocin</span> versus other major peptides in this family (<a href="#ref154">Table 1</a>) is the unique sequence of three amino acids in the tail at positions 7–9 (PLG: proline-leucine-glycine), which is also known as melanocyte-inhibiting factor (MIF-1). MIF-1 has pain-modulating effects via interactions with opioid and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/dopaminergic-system"><u>dopaminergic systems</u></a> (reviewed [<a href="#ref3">3</a>]). The structure of MIF-1 is not found in vasopressin or <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/mesotocin"><u>mesotocin</u></a>. This may be just one of many clues regarding what makes <span class="keyWord", content="oxytocin">oxytocin</span> unique.</p>
<p>A common feature shared by canonical <span class="keyWord", content="oxytocin">oxytocin</span> and other members of this chemical family is the presence of the disulfide bonds connecting the two cysteines and creating the ring structure of these molecules. The rings in these peptides are capable of opening to create linear molecules. It has been proposed that the linear form of <span class="keyWord", content="oxytocin">oxytocin</span> or fragments of <span class="keyWord", content="oxytocin">oxytocin</span> may be of particular importance to its anti-inflammatory and anti-oxidant effects [<a href="#ref18">18</a>].</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> with <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/leucine"><u>leucine</u></a> (at position 3) and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/isoleucine"><u>isoleucine</u></a> (at position 8) is found in most, but not all, mammals. However, species-specific variants in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/peptide-sequence"><u>amino acid sequences</u></a> for <span class="keyWord", content="oxytocin">oxytocin</span> have been discovered recently and associated with different patterns of sociality. For example, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/amino-acid-substitution"><u>amino acid substitutions</u></a> at position 8 (and in some cases also position 3) exist in New World versus Old World monkeys. Substitutions of one or more amino acid also may produce not only different <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/binding-affinity"><u>binding affinities</u></a>, but also differential capacities to desensitize the <span class="keyWord", content="oxytocin">oxytocin</span> receptor, and thus potentially allow longer durations or strengths of action.</p>
<p>It has been suggested that in comparison to canonical <span class="keyWord", content="oxytocin">oxytocin</span>, the <span class="keyWord", content="oxytocin">oxytocin</span>-like variants found in highly social New World monkeys may be not only better able to bind to the <span class="keyWord", content="oxytocin">oxytocin</span> receptor, but also less likely to bind to the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin-v1a-receptor"><u>vasopressin V1a receptor</u></a> [<a href="#ref19">19</a>]. Associated with these novel variants is male parental behavior, a defining behavioral trait of many species of New World monkeys. Remarkably, after receiving one novel form of <span class="keyWord", content="oxytocin">oxytocin</span>, described as Pro8-<span class="keyWord", content="oxytocin">oxytocin</span> and previously associated with parental behavior and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/social-monogamy"><u>social monogamy</u></a> in New World monkeys, nonparental male rats were more likely to show parenting behavior toward infants [<a href="#ref20">20</a>]. Findings of this sort continue to support the notion that, irrespective of nomenclature, the exact chemistry of <span class="keyWord", content="oxytocin">oxytocin</span>-like molecules matters and small structural differences can have functional consequences.</p>
<h3>4. Are measurements of <span class="keyWord", content="oxytocin">oxytocin</span> meaningful?</h3>
<p>The structural characteristics and especially the “sticky” sulfur bonds in <span class="keyWord", content="oxytocin">oxytocin</span> influence its functional availability within tissues. The capacity of <span class="keyWord", content="oxytocin">oxytocin</span> to bind to other biological entities also has contributed to controversy regarding the quantification of <span class="keyWord", content="oxytocin">oxytocin</span>. Current antibody-based methodologies provide snapshots of <span class="keyWord", content="hormone">hormone</span> levels, and are most often used in plasma or saliva. These have proven useful when considering correlations with behavioral patterns and responses to external stimuli. For example, levels of <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> rise after cold-stressors or music [<a href="#ref21">21</a>] and <span class="keyWord", content="oxytocin">oxytocin</span> levels have been individually correlated with electrical activity in the <span class="keyWord", content="brain">brain</span> specifically in response to social cues [<a href="#ref22">22</a>]. These measurements are of most value within a given study [<a href="#ref23">23</a>]. Furthermore, as described below other molecules capable of transporting <span class="keyWord", content="oxytocin">oxytocin</span>, including RAGE (“receptor for advanced glycation end-products”), may create biochemical interference in antibody-based assays [<a href="#ref24">24</a>,<a href="#ref25">25</a>]. This in turn is likely to contribute to variation in estimates of the amount of endogenous <span class="keyWord", content="oxytocin">oxytocin</span> in bodily fluids.</p>
<p>Perhaps, rather than dealing with the dynamic and variable characteristics of the <span class="keyWord", content="oxytocin">oxytocin</span> system as controversies or myths [<a href="#ref26">26</a>], it may be more helpful to conceptualize bodily fluids as dynamic delivery and/or storage systems. These in turn function as components of the body's active defense systems, providing local availability of <span class="keyWord", content="oxytocin">oxytocin</span>, especially in response to threatening conditions such as infection or inflammation [<a href="#ref27">27</a>].</p>
<h3>5. Is <span class="keyWord", content="oxytocin">oxytocin</span> a “pituitary” <span class="keyWord", content="hormone">hormone</span>?</h3>
<p><span class="person">Sir Henry Dale</span> identified the presence of a substance in <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypophysis-extract"><u>pituitary extracts</u></a> that could facilitate <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/uterine-contraction"><u>uterine contraction</u></a>. <span class="person">Dale</span> is usually given credit for discovering <span class="keyWord", content="oxytocin">oxytocin</span>, although in his original 1906 paper he did not specifically call this molecule “<span class="keyWord", content="oxytocin">oxytocin</span>” [<a href="#ref28">28</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> does have classical hormonal functions, since it is stored in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/posterior-pituitary"><u>posterior pituitary</u></a>, released into the blood stream, and carried to target tissues throughout the body. However, <span class="keyWord", content="oxytocin">oxytocin</span> is not actually synthesized in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/pituitary-gland"><u>pituitary gland</u></a>, but in fact is produced in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypothalamus"><u>hypothalamus</u></a>.</p>
<p>Hypothalamic neurons which synthesize <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> do extend processes to the posterior pituitary gland; there these peptides are released into the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/systemic-circulation"><u>systemic circulation</u></a>, coordinating birth, lactation, sexual responses, water and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/mineral-homeostasis"><u>mineral homeostasis</u></a>, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/cardiovascular-physiology"><u>cardiovascular function</u></a> and metabolism in bones and muscles, to name only a few. Hypothalamic cells also release both <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin directly into the <span class="keyWord", content="brain">brain</span> with local effects on specific tissues and functions [<a href="#ref29">29</a>]. For these reasons <span class="keyWord", content="oxytocin">oxytocin</span> is now commonly described as a “hypothalamic <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neuropeptide"><u>neuropeptide</u></a>”, rather than a <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypophysis-hormone"><u>pituitary <span class="keyWord", content="hormone">hormone</span></u></a>. But perhaps even that distinction is not totally accurate?</p>
<h3>6. Is <span class="keyWord", content="oxytocin">oxytocin</span> primarily a hypothalamic <span class="keyWord", content="hormone">hormone</span>?</h3>
<p>Although the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypothalamus"><u>hypothalamus</u></a> is often cited as the primary source of <span class="keyWord", content="oxytocin">oxytocin</span>, the <span class="keyWord", content="oxytocin">oxytocin</span> molecule is synthesized in other parts of the body. In fact, based on gene expression for <span class="keyWord", content="oxytocin">oxytocin</span>, in the female rat uterus near the time of parturition <span class="keyWord", content="oxytocin">oxytocin</span> levels are reportedly 70 fold higher than any other place in the body, including the hypothalamus. As originally explained by Lefebvre, Zingg and their colleagues,<span class="citation_block_small"><strong><i>“endogenous circulating <span class="keyWord", content="oxytocin">OT</span> appears not to participate in the induction of labor… and the finding of <span class="keyWord", content="oxytocin">OT</span> messenger RNA and peptide in the uterus suggests a solution for this paradox. During parturition, OT may act primarily as a local mediator and not as a circulating <span class="keyWord", content="hormone">hormone</span>”</i></strong></span>[<a href="#ref30">30</a>].</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> also appears in extremely high levels at sites of inflammation. In ovarian cancer tumors the levels of <span class="keyWord", content="oxytocin">oxytocin</span> were up to 200 times greater than in plasma [<a href="#ref27">27</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> levels measured in these tumors were negatively associated with an inflammatory cytokine, interleukin-6 (IL-6). A higher level of <span class="keyWord", content="oxytocin">oxytocin</span> within tumors also was correlated with mortality in advanced cases of ovarian cancer, an effect that was mediated by IL-6. This research further implicates locally synthesized <span class="keyWord", content="oxytocin">oxytocin</span> as an anti-inflammatory agent and an important component of the immune response [<a href="#ref31">31</a>].</p>
<h3>7. Is there a “unique” <span class="keyWord", content="oxytocin">oxytocin</span> receptor and why does this matter?</h3>
<p>In a comprehensive review of the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxytocin-receptor"><u><span class="keyWord", content="oxytocin">oxytocin</span> receptor</u></a> Jurek and Neumann [<a href="#ref32">32</a>] state… <i>“The many facets of <span class="keyWord", content="oxytocin">oxytocin</span>are, on a molecular basis, brought about by a single receptor.”</i> When compared to related peptides, <span class="keyWord", content="oxytocin">oxytocin</span> generally binds most readily to the <span class="keyWord", content="oxytocin">oxytocin</span> receptor and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/g-protein-coupled-receptor"><u>GPCRs</u></a> are an important mechanism for <span class="keyWord", content="oxytocin">oxytocin</span>'s action. GPCRs have the capacity to respond to different ligands and transduce information across cell membranes, triggering subcellular processes [<a href="#ref4">4</a>] and thus influencing downstream transcription. Differences in subcellular signaling can have an array of functions that may include the expression of social behavior [<a href="#ref33">33</a>].</p>
<p>A separate set of GCPRs are described as <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> receptors. Of these the vasopressin V1a and V1b receptors found in the nervous system, can be targets for both <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin [<a href="#ref34">34</a>,<a href="#ref35">35</a>]. In the genetic absence of <span class="keyWord", content="oxytocin">oxytocin</span> the vasopressin system may assume some, but not all, of the functions of <span class="keyWord", content="oxytocin">oxytocin</span>, acting in part via sensitized <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin-receptor"><u>vasopressin receptors</u></a> [<a href="#ref36">36</a>]. As described below interactions between <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin are most obvious under threatening conditions.</p>
<p>Receptors responsive to <span class="keyWord", content="oxytocin">oxytocin</span> are abundant in the nervous, reproductive and immune systems including on <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/microglia"><u>microglia</u></a> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/astrocyte"><u>astrocytes</u></a> [<a href="#ref9">9</a>]. These receptors are cell-type specific [<a href="#ref14">14</a>]. Awareness of local effects of <span class="keyWord", content="oxytocin">oxytocin</span> is providing critical information regarding tissue-specific actions of <span class="keyWord", content="oxytocin">oxytocin</span>, especially in the nervous system [<a href="#ref4">4</a>]. In one of many recent examples, <span class="keyWord", content="oxytocin">oxytocin</span> receptors on astrocytes in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/amygdala"><u>amygdala</u></a> have been implicated in a neural circuit that can reduce anxiety [<a href="#ref37">37</a>]. Studies such as these provide additional evidence for interactions between <span class="keyWord", content="oxytocin">oxytocin</span>, components of the immune system and neural function.</p>
<p>The crystal structure of the GCPR <span class="keyWord", content="oxytocin">oxytocin</span> receptor was recently described [<a href="#ref38">38</a>], offering fresh clues to the specific capacity of different kinds of molecules to bind to the <span class="keyWord", content="oxytocin">oxytocin</span> receptor and moderate its function. This research revealed that the functions of the <span class="keyWord", content="oxytocin">oxytocin</span> receptor are affected via positive allosteric stimulation by magnesium (Mg++) and other <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/divalent-cation"><u>divalent cations</u></a>, as well as negative allosteric regulation by sodium (Na+).</p>
<p>Some of the short-term consequences of <span class="keyWord", content="oxytocin">oxytocin</span> act via ion channel receptors [<a href="#ref39">39</a>]. Gaseous molecules, including <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hydrogen-sulfide"><u>hydrogen sulfide</u></a> (H2S) and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/nitric-oxide"><u>nitric oxide</u></a> (NO), also have been implicated in the rapid actions of <span class="keyWord", content="oxytocin">oxytocin</span>, helping to explain the role of <span class="keyWord", content="oxytocin">oxytocin</span> in the regulation of both the autonomic and cardiovascular systems [<a href="#ref40">40</a>]. Clearly, GPCRs - even those originally described as <span class="keyWord", content="oxytocin">oxytocin</span> receptors - are only one mechanism through which <span class="keyWord", content="oxytocin">oxytocin</span> functions. The availability of multiple mechanisms for responding to <span class="keyWord", content="oxytocin">oxytocin</span>, often with different time courses, has consequences for the effects of <span class="keyWord", content="oxytocin">oxytocin</span> throughout the body.</p>
<h3>8. Is <span class="keyWord", content="oxytocin">oxytocin</span> a “female” <span class="keyWord", content="hormone">hormone</span>?</h3>
<p>The first myth concerning <span class="keyWord", content="oxytocin">oxytocin</span>'s functions arose when the molecule was identified as a female reproductive <span class="keyWord", content="hormone">hormone</span>, without known effects in males. Male and female mammals do use different biological and behavioral strategies and functions both for reproduction and for survival. Patterns of sex differences are reported in the production of <span class="keyWord", content="oxytocin">oxytocin</span>, the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxytocin-receptor"><u><span class="keyWord", content="oxytocin">oxytocin</span> receptor</u></a> and their functional consequences [<a href="#ref41">41</a>]. Dozens of studies also reveal sex differences in response to exogenous peptides, including <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> [<a href="#ref42">42</a>,<a href="#ref43">43</a>]. These sex differences are managed in part by steroid-peptide interactions [<a href="#ref44">44</a>,<a href="#ref45">45</a>], and also may reflect sex differences in the functions of mitochondria and the immune system [<a href="#ref8">8</a>,<a href="#ref46">46</a>], in turn relevant to managing inflammation and reproductive demands, as well as sexual differentiation [<a href="#ref47">47</a>].</p>
<p>Sex differences in <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin are especially likely to be detected in response to stressful experiences during the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/perinatal-period"><u>perinatal period</u></a> [<a href="#ref48">48</a>]. Under these conditions vasopressin has been more often implicated in males [<a href="#ref49">49</a>,<a href="#ref50">50</a>], while CRF and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/adrenergic-system"><u>adrenergic systems</u></a> (including norepinephrine) may be critical to managing chronic stressors in females [<a href="#ref51">51</a>]. However, a role for <span class="keyWord", content="oxytocin">oxytocin</span> in coping with stress also has been identified in male rodents [<a href="#ref52">53</a>]. This involves the capacity of estrogens and androgenic metabolites (specifically 3 β diol) to differentially stimulate <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/estrogen-receptor"><u>estrogen receptors</u></a>, including the estrogen receptor (ER) β. The ER β found in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypothalamus"><u>hypothalamus</u></a> can affect the release of <span class="keyWord", content="oxytocin">oxytocin</span>, and reduce measures of anxiety and inflammation. Thus, although usually identified with females, steroidal systems including estrogen receptors and <span class="keyWord", content="oxytocin">oxytocin</span> have important consequences for stress management in males.</p>
<p>Sex differences in physiology and behavior also appear during reactions to stressful experience during the perinatal period and there is increasing evidence implicating inflammation in sexual differentiation [<a href="#ref47">47</a>]. Given the importance of <span class="keyWord", content="oxytocin">oxytocin</span> as an anti-inflammatory molecule, it is likely that <span class="keyWord", content="oxytocin">oxytocin</span> moderates certain aspects of masculinization, possibly reducing the neural consequences of androgens. Differential roles for sex steroids and the <span class="keyWord", content="oxytocin">oxytocin</span>-vasopressin system also can have major consequences for species differences in social behavior [<a href="#ref44">44</a>].</p>
<p>Complex interactions among genetic sex, gonadal steroids, stress and immune factors and lifespan development are difficult to parse experimentally. However, these are very important pathways to consider since they help to sculpt the connections among social support and wellbeing.</p>
<h3>9. Is <span class="keyWord", content="oxytocin">oxytocin</span> an “anti-stress” <span class="keyWord", content="hormone">hormone</span>?</h3>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> has been described as a <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/stress-hormone"><u>stress <span class="keyWord", content="hormone">hormone</span></u></a> [<a href="#ref53">53</a>], a stress-coping molecule [<a href="#ref54">54</a>], or both [<a href="#ref29">29</a>]. In general, <span class="keyWord", content="oxytocin">oxytocin</span> has central roles in coping with challenge. <span class="keyWord", content="oxytocin">Oxytocin</span> modulates stress reactivity and facilitates restoration following periods of challenge and has many interactions with the hypothalamic-pituitary-adrenal (HPA) axis, immune and autonomic systems [<a href="#ref3">3</a>,<a href="#ref32">32</a>]. In addition, time is a critical factor in understanding this aspect of <span class="keyWord", content="oxytocin">oxytocin</span>'s functions. <span class="keyWord", content="oxytocin">Oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> are both released under conditions of acute demands, including sexual orgasm [<a href="#ref54">54</a>], ejaculation [<a href="#ref56">56</a>], birth [<a href="#ref57">57</a>], <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/pair-bonding"><u>pair bond</u></a> formation [<a href="#ref58">58</a>], intense exercise [<a href="#ref59">59</a>], severe pain or shock-trauma [<a href="#ref40">40</a>,<a href="#ref60">60</a>] and sodium challenge [<a href="#ref61">61</a>]. In all of these cases at least one of the roles for <span class="keyWord", content="oxytocin">oxytocin</span> and social connections may be to calm the organism and reduce inflammation [<a href="#ref62">62</a>], helping systems return to <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/homeostasis"><u>homeostasis</u></a>, while also predicting upcoming allostatic demands [<a href="#ref63">63</a>].</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> also has the capacity to increase its own synthesis and release [<a href="#ref64">64</a>]; this feature of <span class="keyWord", content="oxytocin">oxytocin</span> accounts in part for its extensive use to facilitate parturition [<a href="#ref57">57</a>]. Even in nonpregnant animals, stimulating the release of <span class="keyWord", content="oxytocin">oxytocin</span> or administering exogenous <span class="keyWord", content="oxytocin">oxytocin</span> is capable of increasing the subsequent synthesis of endogenous <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref65">65</a>]. The ability of <span class="keyWord", content="oxytocin">oxytocin</span> to feed forward and increase its own synthesis could be critical to coping with chronic challenges - especially in a social context. Vasopressin also has the capacity to feed forward, an effect that can be increased by androgens [<a href="#ref66">66</a>]. However, in general the long-term effects of vasopressin are different, and in many contexts opposite from those of <span class="keyWord", content="oxytocin">oxytocin</span> (reviewed [<a href="#ref32">32</a>]).</p>
<p>The effects of <span class="keyWord", content="oxytocin">oxytocin</span> during responses to challenge occur against a functional background of interactions between vasopressin and corticotropin releasing <span class="keyWord", content="hormone">hormone</span> (CRH). Vasopressin and CRH are often co-localized and can initially amplify the effects of each other, increasing activity in the HPA axis [<a href="#ref49">49</a>]. However, during chronic stress vasopressin, versus CRH, provides a mechanism allowing “escape” from glucocorticoid-regulated negative feedback [<a href="#ref50">50</a>]. Under chronic stress, <span class="keyWord", content="oxytocin">oxytocin</span>'s capacity to downregulate defense systems may be especially relevant, allowing social and psychological safety to modulate both the HPA axis and emotional reactivity.</p>
<p>Particularly important to understanding the stress-related consequences of <span class="keyWord", content="oxytocin">oxytocin</span> is its capacity to regulate chronic pain [<a href="#ref67">67</a>]. Whether <span class="keyWord", content="oxytocin">oxytocin</span>'s role in reducing pain is via the <span class="keyWord", content="oxytocin">oxytocin</span> and/or <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin-receptor"><u>vasopressin receptor</u></a> is still being debated [<a href="#ref68">68</a>,[<a href="#ref69">69</a>]. There is evidence that <span class="keyWord", content="oxytocin">oxytocin</span> can induce analgesia through effects on the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin-v1a-receptor"><u>vasopressin V1a receptor</u></a> [<a href="#ref70">70</a>]. Vasopressin may have a different time course of action, serving in the early stages of a stressful experience when a pro-inflammatory response is important. <span class="keyWord", content="oxytocin">Oxytocin</span> seems to be particularly relevant during repeated or chronic stressors, possibly through its capacity to counteract the pro-inflammatory effects of vasopressin as well as the capacity to signal social safety [<a href="#ref8">8</a>].</p>
<p>Positive or negative experiences can adjust reactivity in the HPA axis, as well as the <span class="keyWord", content="oxytocin">oxytocin</span> system across the lifespan. This is especially apparent around the time of birth, when <span class="keyWord", content="oxytocin">oxytocin</span> can upregulate the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxytocin-receptor"><u><span class="keyWord", content="oxytocin">oxytocin</span> receptor</u></a> [<a href="#ref71">71</a>]. For example, postnatal exposure to <span class="keyWord", content="oxytocin">oxytocin</span> or parental nurture interferes with <i>de novo</i> <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/methylation"><u>methylation</u></a> of the <span class="keyWord", content="oxytocin">oxytocin</span> receptor which occurs in the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/puerperium"><u>postpartum period</u></a>. Under these conditions <span class="keyWord", content="oxytocin">oxytocin</span> and/or positive nurture is associated with upregulation of the expression of the <span class="keyWord", content="oxytocin">oxytocin</span> receptor and increasing indications of sociality in later life [<a href="#ref72">72</a>,<a href="#ref73">73</a>]. The developmental effects of vasopressin are less well studied [<a href="#ref74">74</a>]. However, research in rodents suggests that - especially in males - early exposure to vasopressin upregulates emotional reactivity and aggression, with consequences across the life cycle [<a href="#ref75">75</a>,<a href="#ref76">76</a>].</p>
<p>Both immediate demands and the history of each individual also can influence responses to <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin. For example, research, primarily in nonhuman animals suggests that vasopressin's effects are most obvious after a history of adversity, especially when compared to high levels of early nurture [<a href="#ref77">77</a>]. The social history of an individual can alter the threshold for responding to <span class="keyWord", content="oxytocin">oxytocin</span>, vasopressin and other stress-related molecules [<a href="#ref74">74</a>]. This likely reflects adjustments to the sensitivity of both vasopressin and <span class="keyWord", content="oxytocin">oxytocin</span> systems, with later consequences for the capacity to manage inflammation and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress"><u>oxidative stress</u></a>, of importance in many stressful contexts.</p>
<h3>10. Ancient molecules and the evolution of a social solution to the stress of life</h3>
<p>Many of the properties of <span class="keyWord", content="oxytocin">oxytocin</span> are best appreciated in the context of its' evolutionary history and interactions with even more ancient molecules. <span class="keyWord", content="oxytocin">oxytocin</span>-like molecules facilitate social and reproductive interactions in both vertebrates and invertebrates [<a href="#ref78">78</a>]. Precursors for <span class="keyWord", content="oxytocin">oxytocin</span> and the related peptide <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> existed prior to the preCambrian explosion when atmospheric oxygen levels on Earth increased, permitting a dramatic increase in multicellular organisms. The evolution of these peptides was associated with the transition to living on dry land, the need to regulate bodily fluids and nutrients and to deal with exposure to elevated levels of oxygen [<a href="#ref79">79</a>]. However, oxygen is potentially dangerous. <span class="keyWord", content="oxytocin">oxytocin</span>'s anti-inflammatory and anti-oxidant properties also may have helped to protect the mammalian nervous system during exposure to atmospheric oxygen.</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> evolved from <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/mesotocin"><u>mesotocin</u></a> possibly as long as 400 million years ago [<a href="#ref81">81</a>], preceding and facilitating the origins of mammals and lactation [<a href="#ref82">82</a>]. Many types of organisms exhibit <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/viviparity"><u>viviparity</u></a>, but milk from a <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/mammary-gland"><u>mammary gland</u></a> and the genes responsible for milk production are uniquely expressed in <i>Mammalia</i>, including monotremes, marsupials and eutherian mammals [<a href="#ref83">83</a>]. Supporting a gradual evolutionary change, monotremes, egg-laying mammals that also lactate, produce both mesotocin and <span class="keyWord", content="oxytocin">oxytocin</span>.</p>
<p>Peptides structurally identified as canonical <span class="keyWord", content="oxytocin">oxytocin</span> have been identified in jawless fish and in cartilaginous dogfish [<a href="#ref82">82</a>]. However, the <span class="keyWord", content="oxytocin">oxytocin</span> found in fish does not appear to have been the ancestral source of mammalian <span class="keyWord", content="oxytocin">oxytocin</span>. It is hypothesized that <span class="keyWord", content="oxytocin">oxytocin</span> in fish arose as a function of “random genetic drift,” while “selection evolution” led to the independent emergence and maintenance of <span class="keyWord", content="oxytocin">oxytocin</span> in mammals [<a href="#ref80">80</a>].</p>
<p>Many other biologically active molecules, including common <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neurotransmitter"><u><span class="keyWord", content="neurotransmitter">neurotransmitters</span></u></a> and variations on the CRH molecule existed prior to the preCambrian explosion [<a href="#ref84">84</a>]. In that context the evolution of the specific molecule known as <span class="keyWord", content="oxytocin">oxytocin</span> is comparatively recent. Furthermore, in comparison to the “primitive” anatomy of vasopressin-secreting neurons, hypothalamic neurons producing <span class="keyWord", content="oxytocin">oxytocin</span> have very complex branching patterns [<a href="#ref79">79</a>], forming feedback networks reaching from the brainstem to the cortex [<a href="#ref85">85</a>].</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span>'s functions also are intertangled at many levels with the ancient immune system, helping to manage challenges across the lifespan [<a href="#ref5">5</a>,<a href="#ref86">86</a>]. For example, RAGE is a component of the immune system that serves as a carrier molecule facilitating <span class="keyWord", content="oxytocin">oxytocin</span>'s movement across tissues, including placental and blood <span class="keyWord", content="brain">brain</span> barriers [<a href="#ref87">87</a>]. CD 38 is another immune system molecule that regulates <span class="keyWord", content="oxytocin">oxytocin</span>. CD 38 is located on cells throughout the immune system and was initially described as an “immune cell marker”. It is now understood that CD 38 also is essential for the calcium-dependent release of <span class="keyWord", content="oxytocin">oxytocin</span>. Both CD 38 and RAGE also are implicated in maternal behavior and other forms of sociality [<a href="#ref5">5</a>]. Research on these interactions supports the importance of interactive functions of <span class="keyWord", content="oxytocin">oxytocin</span>, the immune system and positive sociality. Although CD 38 is essential to the normal functioning of <span class="keyWord", content="oxytocin">oxytocin</span> system, apparently CD 38 is not required by the vasopressin system [<a href="#ref86">86</a>], suggesting another unique feature linking the <span class="keyWord", content="oxytocin">oxytocin</span> and immune systems.</p>
<h3>11. The effects of <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin are hierarchical and context-dependent</h3>
<p>In healthy individuals who have experienced high levels of early nurture, <span class="keyWord", content="oxytocin">oxytocin</span> can have immediate benefits in response to stressors, including allowing a return to <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/homeostasis"><u>homeostasis</u></a> [<a href="#ref33">33</a>], more accurate appraisals of threat versus safety and future risks [<a href="#ref88">88</a>] and prediction of future allostatic demands [<a href="#ref63">63</a>]. However, under extreme or repeated stress, and especially in individuals that have experienced high levels of adversity in early life, the consequences of high levels of <span class="keyWord", content="oxytocin">oxytocin</span> are less predictable. In part this could be because under these conditions vasopressin receptors are triggered [<a href="#ref74">74</a>,<a href="#ref89">89</a>]. Interactions among <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin probably help to explain what have been called “paradoxical” effects of <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref90">90</a>], including negative responses to exogenous <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref35">35</a>].</p>
<p>During social encounters <span class="keyWord", content="oxytocin">oxytocin</span> potentially inhibits the defensive and more primitive actions of vasopressin and other stress-related pathways. <span class="keyWord", content="oxytocin">Oxytocin</span>, may reduce the perception of threat, allowing animals to engage in prosocial interactions and in some cases develop selective relationships. However, under conditions of adversity or trauma across the lifespan, pathways dependent on vasopressin may dominate, even when <span class="keyWord", content="oxytocin">oxytocin</span> is administered or otherwise abundant. For example, during a difficult <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/childbirth"><u>childbirth</u></a>, maternal physiological systems may default to mechanisms that are regulated by vasopressin [<a href="#ref91">91</a>] and/or effects of <span class="keyWord", content="oxytocin">oxytocin</span> on the vasopressin receptor [<a href="#ref69">69</a>,<a href="#ref70">70</a>]. In another example, after receiving exogenous <span class="keyWord", content="oxytocin">oxytocin</span> individuals with a history of early life adversity or mood disorders may show negative emotional reactions, resembling those that might be expected following vasopressin [<a href="#ref92">92</a>,<a href="#ref93">93</a>].</p>
<p>In summary, <span class="keyWord", content="oxytocin">oxytocin</span> both regulates and is regulated by components of the immune system including glia [<a href="#ref89">89</a>]. Evidence is growing for other relationships between <span class="keyWord", content="oxytocin">oxytocin</span> and the immune system [<a href="#ref5">5</a>] as well as the capacity to affect the anti-inflammatory actions of mitochondria [<a href="#ref67">67</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> also has consequences for the release of gaseous transmitters, such as H2S or <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/nitric-oxide"><u>NO</u></a>, with potential protective effects throughout the body [<a href="#ref40">40</a>]. Furthermore, <span class="keyWord", content="oxytocin">oxytocin</span> apparently mediates behavioral and immune consequences that are attributed to the microbiota [<a href="#ref10">10</a>,<a href="#ref11">11</a>].</p>
<h3>12. What does it mean to be called a “social neuropeptide”?</h3>
<p>It has become common to described <span class="keyWord", content="oxytocin">oxytocin</span> as a social <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neuropeptide"><u>neuropeptide</u></a> and hundreds of studies describe the role of <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> in the neurobiology of social behavior. However, exactly what this means needs additional consideration. States of perceived threat, versus safety, influence the capacity for and expression of positive social behaviors (reviewed [<a href="#ref89">89</a>]). Constructs like social behavior [<a href="#ref94">94</a>], social recognition [<a href="#ref95">95</a>], social salience [<a href="#ref96">96</a>] and even maternal behavior [<a href="#ref97">97</a>] are difficult to differentiate from the general tendency of mammals to avoid danger and seek safety, especially in response to novel social stimuli.</p>
<p>Awareness of emotional context and the history of each individual, including prior experiences of safety versus threat, are particularly critical in understanding the consequences of <span class="keyWord", content="oxytocin">oxytocin</span> and vasopressin [<a href="#ref98">98</a>]. However, the capacity of <span class="keyWord", content="oxytocin">oxytocin</span> to influence responses to social cues may not be readily apparent until the individual is faced with a challenge, including for example a newborn infant. As another example, cues of sickness can be powerful in eliciting social avoidance [<a href="#ref99">99</a>] [<a href="#ref8">8</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> can override social avoidance [<a href="#ref100">100</a>] promoting social interactions even in the face of biological threat <a href="#ref1013">[13]</a>. Here again, cross-reactivity among <span class="keyWord", content="oxytocin">oxytocin</span>, vasopressin and the immune system offers mechanisms for adaptive responses to specific social stimuli [<a href="#ref101">101</a>].</p>
<h3>13. Is <span class="keyWord", content="oxytocin">oxytocin</span> “the <span class="keyWord", content="hormone">hormone</span> of <span class="keyWord", content="love">love</span>?”</h3>
<p>Single molecules – even ones as versatile as <span class="keyWord", content="oxytocin">oxytocin</span> - cannot explain the intricacies of a behavioral construct like <span class="keyWord", content="love">love</span>. A host of neural systems, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/neurotransmitter"><u><span class="keyWord", content="neurotransmitter">neurotransmitters</span></u></a> and neuromodulators, especially <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/catecholamine"><u>catecholamines</u></a>, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/indoleamine"><u>indoleamines</u></a>, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/acetylcholine"><u>acetylcholine</u></a>, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/endorphin"><u>endogenous opioids</u></a>, sex steroids, molecules of the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypothalamic-pituitary-adrenal-axis"><u>HPA axis</u></a>, including CRF and corticosterone, and inflammatory cytokines, interact in the regulation of the <span class="keyWord", content="oxytocin">oxytocin</span> system [<a href="#ref102">102</a>]. For example, of particular importance are <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/gamma-aminobutyric-acid"><u>GABA</u></a> [<a href="#ref103">103</a>], serotonin [<a href="#ref104">104</a>], <span class="keyWord", content="dopamine">dopamine</span> [<a href="#ref105">105</a>], and opioids [<a href="#ref106">106</a>,<a href="#ref107">107</a>]. All of these chemicals are more ancient than <span class="keyWord", content="oxytocin">oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> [<a href="#ref84">84</a>]. However, most of these molecules and their evolved interactions with mammalian biochemistry have been implicated in the neurobiology of <span class="keyWord", content="love">love</span> [<a href="#ref108">108</a>], as well as physiological reactions to threat.</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> does support physically intimate forms of sociality and nurture and plays a critical role in infant feeding. Unique properties of <span class="keyWord", content="oxytocin">oxytocin</span> also were involved in the evolution of the capacity to form lasting attachments [<a href="#ref109">109</a>]. Acting on various target tissues and neuroendocrine pathways <span class="keyWord", content="oxytocin">oxytocin</span> helps to regulate emotional states including those that are experienced by the human nervous system as <span class="keyWord", content="love">love</span>. In this context, <span class="keyWord", content="oxytocin">oxytocin</span> became known as “the <span class="keyWord", content="hormone">hormone</span> of <span class="keyWord", content="love">love</span>” [<a href="#ref110">110</a>].</p>
<p>Mammalian maternal behavior, acting through <span class="keyWord", content="oxytocin">oxytocin</span>, was originally suggested as a model for “<span class="keyWord", content="love">love</span>” [<a href="#ref111">111</a>]. However, studies of genetically mutant mice unexpectedly revealed that maternal care continued in the absence of <span class="keyWord", content="oxytocin">oxytocin</span> and its receptor [<a href="#ref112">112</a>]. Parental behaviors are the product of a complex and potentially redundant neurobiology. In a strict sense <span class="keyWord", content="oxytocin">oxytocin</span> is not “the” <span class="keyWord", content="hormone">hormone</span> of mother's <span class="keyWord", content="love">love</span> [<a href="#ref113">113</a>,<a href="#ref114">144</a>].</p>
<p>Young mammals are especially salient stimuli, with the potential to attract attention and elicit care, apparently even in the absence of <span class="keyWord", content="oxytocin">oxytocin</span>. In some contexts, young animals, including offspring, also can serve as threats, inducing avoidance or attack. To engage in parenting, mammals must selectively overcome cues of threat, while permitting defense against possible dangers. For example, early research showed that responses to infants increased in anosmic virgin female rats, suggesting the olfactory cues from pups inhibited maternal-like behaviors [<a href="#ref115">115</a>].</p>
<p>However, <span class="keyWord", content="oxytocin">oxytocin</span> may serve mammals as a kind of insurance policy against over reaction to their young or other environmental stressors [<a href="#ref116">116</a>]. For example, a postpartum surge in <span class="keyWord", content="oxytocin">oxytocin</span> helps to expel the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/placenta"><u>placenta</u></a> and could support initial bonding between the mother and child [<a href="#ref117">117</a>]. Whether the mechanisms through which <span class="keyWord", content="oxytocin">oxytocin</span> serves to influence approach behavior are specific to parental-young interactions, or perhaps represent a more general reduction in reactivity to threats, deserves additional research [<a href="#ref118">118</a>,<a href="#ref119">119</a>].</p>
<h3>14. Is <span class="keyWord", content="oxytocin">oxytocin</span> a metaphor for <span class="keyWord", content="love">love</span> and safety?</h3>
<p>The word “<span class="keyWord", content="love">love</span>” has many meanings and interpretations [<a href="#ref120">120</a>,<a href="#ref121">121</a>]. <span class="keyWord", content="love">Love</span> can be described as a metaphor, albeit with physical and psychological manifestations [<a href="#ref122">122</a>,<a href="#ref123">123</a>]. Of course, even repeated associations across different levels of analysis do not prove causation. However, within <span class="keyWord", content="science">science</span> most definitions of <span class="keyWord", content="love">love</span> involve selective behaviors and attachments [<a href="#ref109">109</a>]. Using this limited definition, remarkable parallels can be identified between the functions and properties of <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> (<a href="#ref156">Table 2</a>). The features and functions of <span class="keyWord", content="oxytocin">oxytocin</span> and social attachments suggest that these apparently diverse constructs have shared roots. As described here, it can be argued that <span class="keyWord", content="oxytocin">oxytocin</span> is a component of an embodied biological system that supports the benefits of secure relationships.</p>
<hr>
<table>
<caption><strong><article id="ref156">Table 2.</article></strong>Parallels between functions and properties of <span class="keyWord", content="oxytocin">OXYTOCIN</span> and <span class="keyWord", content="love">LOVE</span>.</caption>
<tr>
<th>
<strong><i>FUNCTIONS (among many)</i></strong>
</th>
<th>
<strong><span class="keyWord", content="love">LOVE</span></strong>
</th>
<th>
<strong><span class="keyWord", content="oxytocin">OXYTOCIN</span></strong>
</th>
</tr>
<tr>
<td>
MODERN (evolutionarily recent)
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Associated with SELECTIVE sociality & bonds
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Supporting parental investment
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Metaphor for SAFETY
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Selectively rewarding
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Anti-inflammatory/Anti-oxidant
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Anxiolytic/Analgesic
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Allows immobilization without fear
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Sexually dimorphic
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
<tr>
<td>
Epigenetically tuned and Context dependent
</td>
<td>
+
</td>
<td>
+
</td>
</tr>
</table>
<hr>
<p>Both <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> are linked to the health benefits of safety including emotional and physical support [<a href="#ref124">124</a>]. Both also have adaptive interactions with more primitive and individualistic systems, including processes needed to manage threat, inflammation and disease. These more archaic mechanisms support individual survival in the short-term, but prolonged activation of the immune system can be dangerous for long-term health.</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> interact with other defensive systems, including the autonomic and immune systems, and also regulate the emotional states necessary for perceptions of safety [[<a href="#ref63">63</a>],[<a href="#ref63">63</a>]]. These coordinate the capacity of an organism to selectively exhibit behavioral and emotional states necessary for active versus passive defense, including the alertness and mobility needed for escape from threat, danger or pain [<a href="#ref126">126</a>]. Peptide-mediated behavioral and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/autonomic-function"><u>autonomic functions</u></a> also can influence the capacity for the voluntary immobility without fear, required for social interactions including maternal and sexual behaviors [<a href="#ref127">127</a>].</p>
<p>Of particular importance to mammalian survival are both early nurture and lasting and secure relationships [<a href="#ref128">128</a>] which may be facilitated by <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref129">129</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> has an essential role in lactation, facilitates the capacity to give birth and may allow mammals to become attached to their infants even under conditions of extreme challenge, such as those associated with human birth and child rearing [<a href="#ref116">116</a>]. Lactating women are uniquely able to manage stressors [<a href="#ref130">130</a>]. A postpartum surge in <span class="keyWord", content="oxytocin">oxytocin</span> helps to expel the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/placenta"><u>placenta</u></a> and could support initial bonding between the mother and child [<a href="#ref117">117</a>]. The development of offspring also is modulated by <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref131">131</a>], with effects that can be protective after a surgical birth [<a href="#ref132">132</a>]. Furthermore, infants reared on human milk receive a cocktail containing optimal nutrition, as well as <span class="keyWord", content="oxytocin">oxytocin</span> itself and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/probiotic-agent"><u>probiotic</u></a> bacteria [<a href="#ref7">7</a>,<a href="#ref11">11</a>].</p>
<p>The <span class="keyWord", content="oxytocin">oxytocin</span> system is an intrinsic component in the capacity of experiences, including both nurture and adversity, to manage adaptations in the mammalian body. The <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/epigenomics"><u>epigenetic</u></a> consequences associated with modifying the <span class="keyWord", content="oxytocin">oxytocin</span> system can be detected across the lifespan, but especially around the time of birth when newborns must anticipate the demands of their future environments [<a href="#ref7">7</a>,<a href="#ref103">103</a>]. Early life is a period when mammals are particularly sensitive to the need for nurture and when the effects of <span class="keyWord", content="oxytocin">oxytocin</span> are most likely to create epigenetic change [[<a href="#ref71">71</a>], [<a href="#ref72">72</a>], [<a href="#ref73">73</a>]].</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> and positive social experiences play a critical role in <span class="keyWord", content="brain">brain</span> development [<a href="#ref94">94</a>,<a href="#ref133">133</a>]. Early experiences also are implicated in the capacity to create lasting attachments [<a href="#ref134">134</a>]. As discussed elsewhere, <span class="keyWord", content="oxytocin">oxytocin</span> was permissive in the evolution of the human nervous system [<a href="#ref2">2</a>], with the resultant large neocortex necessary for consciousness, language and even spirituality. This capacity in modern humans is required for relationships to be experienced and expressed [<a href="#ref135">135</a>]. Furthermore, accurate appraisal of future threats [<a href="#ref136">136</a>], the relevance of social stimuli [<a href="#ref119">119</a>], and the development of a complex <span class="keyWord", content="brain">brain</span> and autonomic nervous system demand <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref2">2</a>].</p>
<p>Both the health benefits of <span class="keyWord", content="oxytocin">oxytocin</span> and the capacity for <span class="keyWord", content="love">love</span> rely on interactions with more ancient physiological systems, including the immune and vasopressin systems [<a href="#ref3">3</a>,<a href="#ref81">81</a>,<a href="#ref137">137</a>]. The patterns of behavior regulated by vasopressin also are adaptive and in the functional absence of <span class="keyWord", content="oxytocin">oxytocin</span> the effects of vasopressin may be associated with fear, self-defense and in some cases aggression [<a href="#ref89">89</a>]. Understanding the factors that regulate these reactions provides novel insight into the complexity, power and possible dangers associated with <span class="keyWord", content="love">love</span> or its absence.</p>
<p>Biologically-active molecules, such as <span class="keyWord", content="oxytocin">oxytocin</span>, are sometimes treated as if they are manifestations of a well-understood chemical reality. Of course, <span class="keyWord", content="oxytocin">oxytocin</span> is part of a larger physiological equation. Here we have examined specific examples of interactions of <span class="keyWord", content="oxytocin">oxytocin</span> with vasopressin and the immune system. These have implications for all aspects of human health, and especially therapeutic strategies for the prevention and treatment of diseases associated with stress, adversity, trauma and inflammation.</p>
<h3>15. Gaps in knowledge and a work in progress</h3>
<p><span class="keyWord", content="oxytocin">Oxytocin</span> and <span class="keyWord", content="love">love</span> have shared properties and functions (<a href="#ref156">Table 2</a>). Accurately calibrating reactions in response to or in anticipation of challenge are of particular importance to survival and eventually reproduction <a href="#ref138">138</a>. A general feature of both <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> is the capacity to modulate more primitive defense systems including threat or fear. Many of the biological associations between <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> are only apparent under conditions of physiological challenge. Loving and secure relationships, in part through the dynamic actions of <span class="keyWord", content="oxytocin">oxytocin</span>, are especially critical in the face of threat [<a href="#ref89">89</a>]. The effects of both <span class="keyWord", content="oxytocin">oxytocin</span> and secure relationships may be most easily detected in response to stressful and chronic experiences, including sickness [<a href="#ref13">13</a>,<a href="#ref99">99</a>] and social isolation [<a href="#ref8">8</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> also may help to explain the benefits of companion animals [<a href="#ref139">139</a>], including the processes that led to canid domestication [<a href="#ref140">140</a>].</p>
<p><span class="keyWord", content="oxytocin">Oxytocin</span>'s role in reducing emotional threat may be of particular importance in understanding the consequences of social isolation or during disrupted relationships, and especially in women [<a href="#ref42">42</a>]. Animal research also indicates that the mechanisms through which isolation is so devastating involve dynamic and sexually-dimorphic changes in <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref65">65</a>,<a href="#ref141">141</a>,<a href="#ref142">142</a>]. Interactions between <span class="keyWord", content="oxytocin">oxytocin</span>, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin"><u>vasopressin</u></a> and immune systems are important to complex “paradoxical” effects of exogenous <span class="keyWord", content="oxytocin">oxytocin</span> [<a href="#ref89">89</a>], and could help to explain why it has proven difficult to create pharmaceuticals based on these peptides [<a href="#ref3">3</a>]. However, the nature of these interactions remains at present poorly understood.</p>
<p>Discussed elsewhere is evidence for a major role of the autonomic nervous system in mediating social connection and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/emotionality"><u><span class="keyWord", content="emotion">emotion</span> regulation</u></a> [<a href="#ref3">3</a>,<a href="#ref125">125</a>.]. The autonomic system also regulates immunity and is implicated in autoimmune disorders [<a href="#ref143">143</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> and vasopressin both affect the complex coupling of sympathetic and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/parasympathetic-function"><u>parasympathetic functions</u></a> [<a href="#ref63">63</a>,<a href="#ref144">144</a>.]. The relationship between <span class="keyWord", content="oxytocin">oxytocin</span>, vasopressin and the autonomic nervous system deserves deep analysis.</p>
<p>Excess inflammation and <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress"><u>oxidative stress</u></a> have been implicated in virtually every known physical and emotional disorder [<a href="#ref145">145</a>]. <span class="keyWord", content="oxytocin">Oxytocin</span> functions in part through its capacity to serve as a component of mammalian defense systems with both anti-inflammatory and anti-oxidant effects [<a href="#ref146">146</a>] [<a href="#ref147">147</a>]. The detrimental effect of oxygen also is managed in part by the anti-inflammatory and anti-oxidant properties of <span class="keyWord", content="oxytocin">oxytocin</span>. This may be a clue to an ancient and reoccurring link between <span class="keyWord", content="oxytocin">oxytocin</span> and oxygen. This link is found in responses to immune challenges and excess inflammation, including mitochondrial activity [<a href="#ref6">6</a>,<a href="#ref148">148</a>], responses to pathogenic viruses [<a href="#ref149">149</a>], and in protection of the fetus during live birth [<a href="#ref103">103</a>].</p>
<p>Broad metaphorical meanings have been attached to both the concept of <span class="keyWord", content="love">love</span> and the functions of <span class="keyWord", content="oxytocin">oxytocin</span>. Compared to other biologically active molecules <span class="keyWord", content="oxytocin">oxytocin</span> is recently evolved. <span class="keyWord", content="oxytocin">Oxytocin</span> links individuals to others, and also supports the benefits of sociality. Survival strategies based on connection, cooperation, the support of offspring and perceived safety are critical to emotional and physical health [<a href="#ref150">150</a>]. There is evidence that the mechanisms for the benefits of <span class="keyWord", content="oxytocin">oxytocin</span> and secure relationships offer potential, but at present largely untapped, insights into disease, <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/cellular-senescence"><u>cellular aging</u></a> and longevity [<a href="#ref151">151</a>,<a href="#ref152">152</a>].</p>
<p>Myths and mysteries surround <span class="keyWord", content="love">love</span>. Despite popular assumptions that “<span class="keyWord", content="love">love</span> overcomes fear” and “<span class="keyWord", content="love">love</span> heals,” as a subject for serious study <span class="keyWord", content="love">love</span> may be considered frivolous. We argue here that <span class="keyWord", content="oxytocin">oxytocin</span> has broad consequences that resemble in part an embodied metaphor for <span class="keyWord", content="love">love</span>. However, like <span class="keyWord", content="love">love</span>, the <span class="keyWord", content="oxytocin">oxytocin</span> system also has proven difficult to identify, measure and study and the controversies associated with <span class="keyWord", content="oxytocin">oxytocin</span> are far from resolved. The same adaptive biochemical properties that make <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> difficult to study may also help to explain their potential as components of “Nature's medicine” [<a href="#ref3">3</a>].</p>
<p>A deeper awareness of the biology of relationships is essential to understanding what it means to be “human.” Mechanisms through which these systems are integrated has profound implications for human health [<a href="#ref3">3</a>]. However, interactions among the pieces of the peptide-immune-behavioral puzzle are only now being recognized. Embedded in the biology of <span class="keyWord", content="love">love</span> and <span class="keyWord", content="oxytocin">oxytocin</span> are secrets to the social solutions that optimize living in a dangerous world. Put simply, without <span class="keyWord", content="oxytocin">oxytocin</span> and <span class="keyWord", content="love">love</span> mammals may survive, but not thrive. How this occurs remains one of life's great mysteries.</p>
<h3>Declaration of interests</h3>
<p>None.</p>
<h3>Acknowledgments</h3>
<p class="pubnote">Research described here from the author's laboratory was funded by the <span class="organization", content="National Institutes of Health", id="organization6">National Institutes of Health</span>, most recently by <a href="https://www.sciencedirect.com/science/article/pii/S2666497621000813#gs1"><u>HD P01 07575</u></a> and <a href="https://www.sciencedirect.com/science/article/pii/S2666497621000813#gs1"><u>HD R01 098117</u></a> and support from the <span class="organization", content="Fetzer Institute", id="organization7">Fetzer Institute</span>. The editorial suggestions and other supportive inputs of <span class="person", content="Stephen Porges", id="person9">Stephen Porges</span>, <span class="person", content="Alex Horn", id="person10">Alex Horn</span>, <span class="person", content="John M. Davis", id="person11">John M. Davis</span>, <span class="person", content="Marcy Kingsbury", id="person12">Marcy Kingsbury</span> and <span class="person", content="Robert Dantzer", id="person13">Robert Dantzer</span> are gratefully acknowledged. Because of space limitations I apologize to investigators whose primary work is not fully recognized and refer the reader to additional references in earlier reviews.</p>
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