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The neurobiology of love reviews

  1. 1. Neuroendocrinology Letters No.3 June Vol.26, 2005 Copyright © 2005 Neuroendocrinology Letters ISSN 0172–780X www.nel.eduThe Neurobiology of LoveTobias Esch1, 2 & George B. Stefano21,2 Charité - University Medicine Berlin, Institute for General Practice and Family Medicine, Schumannstrasse 20/21, 10117 Berlin, Germany.2 Neuroscience Research Institute, State University of New York, College at Old Westbury, Old Westbury, NY 11568, USA. R EVI EWCorrespondence to: Dr. G.B. Stefano, Neuroscience Research Institute, State University of New York, College at Old Westbury, Old Westbury, NY 11568-0210, USA . FAX : 516-876-2727, PHONE : 516-876-2732, EMAIL : gstefano@sunynri.orgSubmitted: June 21, 2005 Accepted: June 23, 2005Key words: love; stress; limbic system; reward; pleasure; endogenous morphine; dopamine; attachment; sexNeuroendocrinol Lett 2005; 26(3):175–192 PMID: 15990719 NEL260305R01 © Neuroendocrinology Letters www.nel.eduAbstract Love is a complex neurobiological phenomenon, relying on trust, belief, pleasure ARTICL E and reward activities within the brain, i.e., limbic processes. These processes crit- ically involve oxytocin, vasopressin, dopamine, and serotonergic signaling. More- over, endorphin and endogenous morphinergic mechanisms, coupled to nitric oxide autoregulatory pathways, play a role. Naturally rewarding or pleasurable activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex, and reproduction. Yet, a broad basis of common signaling and beneficial neurobiological features exists with con- nection to the love concept, thereby combining physiological aspects related to maternal, romantic or sexual love and attachment with other healthy activities or neurobiological states. Medical practice can make use of this concept, i.e., mind/ body or integrative medicine. Thus, love, pleasure, and lust have a stress-reducing and health-promoting potential, since they carry the ability to heal or facilitate beneficial motivation and behavior. In addition, love and pleasure ensure the sur- vival of individuals and their species. After all, love is a joyful and useful activity that encompasses wellness and feelings of well-being. INTRODUCTION What an interesting phenomenon love is! associated with consensual sexual activity, or theAlmost everybody can relate to a state of “being or willing, and even eager, participation of the indi-falling in love” even though it is difficult to define viduals involved [31]. However, only recently haslove. In addition, depending on the background the biology of love, and in particular its neurobi-or “current state” we get a vast number of variant ological aspects, become a focus of basic science.answers to our questions about love. Medical, or health, implications related to the love Following common knowledge, love is a strong, physiology are still speculative, i.e., mainly notpassionate affection for a person [31]. Hence, the proven. Although at first it may sound logical thatOxford English Dictionary defines love as an love – given its biological function to ensure theintense feeling of deep affection or fondness for a survival of a species via social attachment, gather-person or a thing, a sexual passion, or sexual rela- ing, copulation and reproduction – is a phyloge-tions, in general. Thus, love is an emotion often netically healthy activity, neurobiological research
  2. 2. Tobias Esch and George B. Stefanohas only started to examine the possible mechanisms ing” experience can even induce aversion [173]. Addic-underlying this assumption and its consequences for tive drugs, in contrast, immediately build up high appe-the individual organism and associated ontogenetic tence levels that are not released completely or only forhealth outcomes and benefits [26,31]. a short time after consumption [130,131,153]. This frus- In this report, evidence for common neurobiologi- trating fact produces even more appetence: One cancal pathways underlying the love phenomenon will be not stop the pleasure-seeking activity that now startsfound. Love’s neurobiological mechanisms will also be to control normal behaviors (i.e., motivational toxicity)discussed in the light of medicine and health. [57]. While natural activities are controlled by feedback mechanisms that activate aversive centers (i.e., aversive What is love? motivation), no such restrictions bind the responses to artificial stimuli [17,200]. Thus, love and addiction are Attachment, commitment, intimacy, passion, grief evolutionarily and behaviorally interconnected, butupon separation, and jealousy are but a few of the they are not same, at least not in relation to artificialemotionally-loaded terms used to describe that which drug ingestion. Being “addicted to love,” however, referslove represents [26,77,193]. In science, however, love to this interconnection.appears to be a hypothetical and multi-dimensional The key element for achieving beneficial effects isconstruct with many interpretations and implications ‘balance’, i.e., aiming at a state of dynamic balance/re-[26]. Love and its various emotional states and behav- balance, that is, having biological feedback and controliors are rarely investigated by scientific means. In part, systems in place that keep natural autoregulatory path-this may be due to the fact that love has always been ways within a certain, healthy range [54,57]. Thus, lovethe domain of poets and artists, maybe psychologists can be viewed as a dynamic process that represents theand clinicians, but has certainly not been considered result of different components probably subserved byto be right within the scope of common experimen- distinct neural substrates at different times [118]. Astal science, i.e., neurobiology research [26]. Emotions such, some steps can be identified, e.g., its beginningand feelings such as attachment, couple and parental (“falling in love”), which is the process of attraction,bonding, and even love – presumably typical of higher followed by the attachment process that, in some cases,mammals and neglected for centuries by the exper- can last forever [118].imental sciences – have now come into the focus of Selective social attachments and the propensity toneuroscientific research in order to elucidate their bio- develop social bonds are necessary features of the lovelogical mechanisms and pathways [118]. Thus, know- concept [26]. Furthermore, this concept is associatedledge on the neurobiology of love has yet to evolve, with parental as well as sexual behaviors [26]. Bothand only recently, exciting research has brought to sur- types of attachment and love, i.e., sexual or roman-face detailed information on molecular and physiolog- tic versus parental or maternal, can provide a sense ofical “ingredients” of the love phenomenon, as described safety and reduce anxiety or stress – important for alater on. healthy life and, e.g., balanced way of decision making The concept of love involves having an emotional [26,57]. Biologically, to “fall in love” is the first step inbond to someone for whom one yearns, as well as hav- pair formation [117], involving attachment and bond-ing sensory stimulation that one desires [105]. The ing as well as romantic, sexual, and parental behav-word “love,” however, derives etymologically from iors and experiences, e.g., lust, pleasure, joy and hap-words meaning “desire,” “yearning” and “satisfaction” piness [57]. Clearly, love has a positive connotation.and shares a common root with “libido” [105,137,168]. However, it seems to be a rather complex phenomenonThus, the psychological sense of love can be interpreted and not only implicates sensational elements or behav-as referring to the satisfaction of a yearning, which may iors, i.e., sensation- and approval-seeking, but also psy-be associated with the obtaining of certain sensory chological, emotional and neurobiological portions.stimulation [105]. Love therefore possesses a close con- In the end, it all has to serve biological goals: Its func-nection not only with reward and pleasure phenomena, tion exceeds that of reproduction alone, since love alsobut also with appetitive and addictive behaviors [57]. facilitates the establishment of long-lasting relation- Naturally rewarding activities like love boost a flood ships that are related to trust and belief and may ensureof stimulating signaling molecules [54,57,191]. How- support or protection under challenging circumstancesever, this stimulation may not be as strong or enduring [48,51,117,171]. Thus, love – and the act of falling inas that achievable by addictive drugs – natural rewards love, in particular – represents a physiological and tran-may not, like some artificial drugs, completely surpass sient state that is related to specific, i.e., biologically use-normal physiology [57]. The distinction between nat- ful, behaviors, possibly involving beneficial behavioralural and artificial rewards can also be made by the changes and social interactions [117].build-up of appetence. Natural rewards, i.e., pleasur- The most accepted form of an enduring social bond,able experiences like eating or sex, usually depend on a within the love concept, is maternal attachment [26].preceding build-up of appetence (e.g., sexual desire) to The idea of motherly love [76] implies a selective behav-fully develop their pleasure potential [78,172,173]. Fol- ioral response by the parent to its offspring, i.e., paren-lowing the pleasurable experience, appetence decreases tal love [26]. Hence, the tender intimacy and selflessnessand then needs a certain time span to reach its former of a mother’s love for her infant occupies a unique andlevels and intensity. During this time, the same “appetiz- exalted position in human conduct [10]. It provides one176 Neuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X
  3. 3. The Neurobiology of Love Figure . Stress and its relation to social bond formation and love. References see text. HPA – hypothalamic-pituitary-adrenal (axis).of the most powerful motivations for human actions Love and stressand behaviors [10]. Sexual behavior, on the other hand,is closely related to attachment as well, but they are Love, e.g., when experiencing symptoms such asnot synonymous [26]. Sexual activity can occur in sweating, heart beat acceleration, increased bowel peri-the absence of social attachment, and many forms of stalsis and even diarrhea, can be quite a stressful expe-attachment exist that do not involve sexual behaviors rience. However, love is certainly known, primarily, for[26]. However, in humans, the most desired sexual part- its relation to feelings that we usually like to experi-ner is often – and simultaneously – the object of strong ence. This intense sensational and emotional state hasfeelings of attachment [26]. inspired artists, and therefore, biologists have concluded In monogamous mammals, pair bonds provide a that art, when it is associated with biological phenom-social matrix for sexual behavior [26]. Mating promotes ena like love and reproduction, is part of an adapta-social preferences [26,207], possibly because oxytocin tional process ensuring survival [11,46,50,183,208].and/or vasopressin are released during sexual interac- Hence, love or lust, and the joy that is imbedded in thetions. We see that sexual, romantic, or parental love and love concept, seem to be not only individually reward-attachment overlap: Maternal and romantic love share a ing but also behaviorally and biologically advantageouscommon and crucial evolutionary purpose, namely the experiences, thereby protecting the species [46,57,146].maintenance and perpetuation of the species [10]. Both Questions like these have recently become a focus ofensure the formation of firm bonds between individu- evolutionary psychology, a field of sociobiology [46],als by making this behavior a rewarding experience. It again demonstrating the integrative character of loveis possible that they share a similar evolutionary ori- research.gin, and it is likely that they also share some common In recent reviews on the role of stress in humanneurobiology [10]. attachment, it has been discussed that stressors can Behavioral theories and models of attachment and trigger a search for pleasure, proximity and close-love have focused on either caregiver-infant interac- ness, i.e., attachment behaviors, thereby promotingtions or adult pair bonding [26]. Obviously, similari- the re-balancing of altered physiological and psycho-ties exist between the behaviors associated with parent- logical states [57,169]. It is surmised that some degreeinfant and adult romantic attachments. In fact, several of strong, yet manageable, stress may be necessary forinvestigators have suggested that these types of love very strong bonds to form [169]. However, if socializ-share common biological substrates [26,62,140]. We, ing “in the face of stress” does not occur, diseases maytherefore, focus on the neurobiological commonali- be introduced [26,55,58,59,60]. Forced isolation, anxi-ties between parental and romantic love in the follow- ety, fear, and other forms of stress are associated withing, however, not excluding remarks on interesting and increased levels of stress hormones like cortisol, i.e.,important differences, when indicated. enhanced hypothalamic-pituitary-adrenal (HPA) axisNeuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X 177
  4. 4. Tobias Esch and George B. Stefanoactivity [26,58,60]. Such conditions or experiences nor- are, in part, present in simpler organisms devoid of cog-mally tend to encourage social interactions (Figure 1). nition [180].However, excessive stress (i.e., chronic) that could com- Feelings of security and support lead to the facilita-promise health and survival, e.g., (hyper)intense grief, tion of trust and belief (see below), including “meaningmay lead to depression or the breakdown of social rela- and spirituality,” thereby inducing positive motivationtionships [60,152]. This correlation between chronic or and behavior [57,170,171]. We will focus upon the spe-massive stress could finally inhibit the new forming of cific neurobiological pathways and signaling moleculesbonds and attachments, leading to social and physiolog- that are involved later on, showing that lust, pleasureical deprivation, or regulatory imbalances and inflexi- and love have physiological correlates, i.e., CNS rewardbility, thereby compromising healthy (auto)regulation and motivation circuitries [14,46,57,136]. In species that[26,51,52]. However, within a homeostatic range, stress- form heterosexual pairs, rewarding sexual activities arerelated physiological processes, including hormones of associated with the formation of social attachments andthe HPA axis, can promote the development of social bonds [28]. Sexual behavior, however, can also be physi-bonding [43]. In addition, positive social interactions ologically stressful for both sexes [26], as described ear-may help to create physiological states that are anxio- lier. Adrenal steroids, vasopressin, oxytocin, dopamine,lytic and stress reducing, i.e., health promoting [26,48, and endogenous opioids as well as opiates and higher52,54]. Thus, balance is a key concept in social bonding levels/pulses of nitric oxide (NO) are released duringand love, including related neurobiology (see below). pleasurable activities like sexual behaviors (e.g., ‘making While acute stress obviously induces subsequent love’) [25,54,57,121,145,159,186,217], indicating neuro-reproductive behaviors and social contact, chronic biological pathways that are linked to stress responsestress may lead to a strong reduction in the abilities to and reward mechanisms likewise.propagate [46]. Furthermore, with an increasing popu- Within the context of varying stimuli evoking NOlation density, as shown for example in rodents and pri- release, emotional stresses such as fear and anxietymates, social stress and aggression rise, accompanied can induce cardiovascular alterations, such as cardiacby enhanced infertility rates, susceptibility to infec- arrhythmia [159]. These are some of the same eventstions, blood pressure, atherosclerosis, neural, cardiovas- that occur when one is exposed to sexually chargedcular, and renal damage or diseases [48,51,55,56,58,59, stimuli, or engaged in sexual act [112,113,163,205].60,162]. It is important for biological organisms to pos- These cardiovascular events are initiated at the levelsess programs and strategies that buffer against stress of cingulated, amygdalar, and hypothalamic CNS pro-and social isolation [46]. Hence, love can be such a cesses, as well as their projections into higher level cere-mechanism [46]. On the other hand, higher animals bral cortex, further altering heart rate under stressful orbear a mechanism within themselves that negatively sexually aroused conditions [82]. Neurons in the insu-selects individuals with unsuitable behavioral abili- lar cortex, the central nucleus of the amygdala, and theties, leading to infertility or, ultimately, death [85]. Thus, lateral hypothalamus, owing to their role in the inte-stress and love are biologically interconnected: Individ- gration of emotional and ambient sensory input, mayuals that possess better or more effective strategies to be involved in the emotional link to the cardiovascu-cope with stress also show better immune functions lar phenomena [83]. These include changes in cardiacand sexual performance, and thus have a direct ben- autonomic tone, with a shift from the cardioprotec-efit for survival and reproduction, i.e., they possess an tive effects of parasympathetic predominance to mas-advantage for passing on not only their genes in gen- sive cardiac sympathetic activation [84]. This auto-eral, but also their coping methods [46,55]. Repro- nomic component, carried out with parasympatheticduction therefore not only relies on technical abilities and sympathetic preganglionic cells via subcorticalto love and copulate but much more on psychologi- nuclei from which descending central autonomic path-cal means to “do the right thing,” i.e., overcome stress- ways arise, may, therefore, be a major pathway in howful situations and cope with challenges, and even the emotional states may affect cardiovascular function andability to relax [46,52,182]. Hence, evolution positively health [159,186].selected for biological mechanisms that help to cope Furthermore, oxytocin, a major player in love phys-with stress, that is, facilitate stress reduction and adap- iology, has also been associated with stress reductiontive behaviors – experiences like pleasure, lust and love [26]. In humans [27,30,197,198], oxytocin inhibits[54,57]. Taken together, happiness, pleasure and well- sympathoadrenal and stress response activity, includ-being, as well as touch, social contact and support, are ing the release of adrenal corticoids (Figure 1). Therelated to the love concept and, via stress reduction and effects of oxytocin on pair bonding or other forms ofprotection, represent a distinct and important evolu- social attachment may therefore be related to the auto-tionary factor [46,76,100]. This may be the reason why nomic, i.e., autoregulatory, role of oxytocin in stresshigher biological organisms tend to be pleasure-seek- reduction [26]. Steroid exposures, as seen, for exam-ers [46,57,76,100]. After all, these psychological phe- ple, during highly stressful experiences, have the capac-nomena have a biological match, and it is imbedded ity to produce both structural and behavioral changesin central nervous system (CNS) structures and path- [55,58,60,70], including changes that may alter the pro-ways, e.g., neurobiological reward and pleasure path- pensity for social behavior [26]. Here, early develop-ways [54,57]. Interestingly, the physiological processes ment seems to be of particular interest: Prenatal and perinatal stress or treatments with stress hormones, as178 Neuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X
  5. 5. The Neurobiology of Lovewell as ontogenetic experiences like varying amounts since they show sensible and variant patterns that dif-of parent-young interaction, can affect adult patterns fer over day and night and between individuals expe-of social and sexual behaviors later in life [26,158,203]. riencing different levels of stress. Additionally, cortisolGlucocorticoid levels are high in late pregnancy and depends on emotional states in a much broader sense:may decline at delivery [26]. Hence, progesterone and Emotional lability is associated with a more labile reg-the glucocorticoids have comparable chemical struc- ulation of cortisol and testosterone secretion, meaningtures and share many physiological and behavioral that an observable intraindividual variability of basalproperties and may, therefore, occasionally exert similar stress hormone secretion may contribute to the vasteffects on peptide binding [143]: These steroids could interindividual variability noticed in psychoneuroen-act separately, or in concert, to influence social behav- docrine stress research [4]. Hence, statements on corti-ior [26]. Thus, social preferences, upon which attach- sol levels with regard to stress, love, and gender differ-ments are formed, may be developmentally altered by ences have to be drawn carefully.stress and/or steroid hormones, i.e., HPA axis activity, Evidence for attachment formation comes fromespecially when administered or encountered in early behavioral changes associated with mammalian birth,phases of life [26]. Moreover, treatment with vasopres- lactation, and sexual interactions [26]. Mammaliansin, another key player (see below), during the first birth is clearly a stressful experience. In the mother,week of life in rats has shown to reduce gene expres- physiological events preceding and accompanying par-sion for the oxytocin receptor in the paraventricu- turition involve exceptionally high levels of adrenallar nucleus (PVN) during adulthood [138,199]. Since activity and the release of various peptides, includingvasopressin is integrated in the HPA axis and sensitive endogenous opioid peptides, oxytocin, and vasopres-to androgens, i.e., steroids, it has been speculated that sin [99,107]. As mentioned before, stressful experiencesdevelopmental changes associated with perinatal stress or challenges may encourage increased social behav-or gender-dependent androgenization could alter the iors and attachment [26]. Hence, comparatively highsubsequent sensitivity of the oxytocinergic system [26]. levels of HPA axis activity or other indicators of stressFurthermore, male prairie voles, and to a much lesser or sympathetic arousal, and a subsequent release ofextent females, that were exposed to vasopressin injec- oxytocin, have been measured under conditions thattions during the first week of their life were, as adults, commonly precede or are associated with the forma-more aggressive towards intruders than were untreated tion of social bonds [26]. These bonds, as illustrated,animals [26]. Thus, hormones involved in the love phys- may than buffer against stress, facilitating social sup-iology, such as vasopressin, demonstrate a relationship port, security, and closeness, since the presence ofbetween early development, stress, physiological “love a partner may provide a social form of stress reliefsignaling,” and subsequent social or protective behav- [26,52,79]. Taken together, positive social behaviors,iors. including social bonds, may reduce HPA axis activity Subjects in love show higher cortisol levels as com- and stress, and central neuropeptides, including vaso-pared with those not experiencing this state [117]. This pressin and oxytocin, have been implicated both incondition of love-related hypercortisolemia may repre- social bonding and the central control of the HPA axissent a non-specific indicator of changes that occur dur- [26]. Threatening or challenging situations may there-ing the early phase of a relationship, thereby reflecting fore encourage the return to a secure base or otherwisethe somewhat stressful condition or a general arousal strengthen social bonds [139]. Oxytocin, however, isassociated with the initiation of social contact [117]. capable of inducing positive social behaviors and both,This physiological state of alertness, associated with oxytocin and social interactions, decrease activity in thelove, may help to overcome neophobia, although this HPA axis, i.e., stress [26,41,48,52,55,58,60,198]. Socialis still a speculative aspect [117]. Such positive stress interactions and attachments then activate endocrineappears to be important for the formation of social or autoregulatory signaling systems that are able to fur-contact and attachment, since a moderate level of ther reduce stress, i.e., HPA (hyper)reactivity, yet mod-stress has been demonstrated to promote this kind ulating emotions and the related autonomic nervousof relationship, i.e., social bonding [26,42,43,79,109, system’s involvement, thereby, perhaps, accounting for117,123]. Thus, love seems to be a complex phenom- health benefits that are attributed to loving relation-enon and, with regard to stress, an ambiguous experi- ships (Figure 1).ence, i.e., double-edged sword: Love itself can be stress-ful, but it potentially serves to lower stress levels over Motivation and behaviorthe long term. Furthermore, an association betweenHPA axis activation, following stressful experiences, Motivation concerns aspects of intention or activa-and the development of social attachment becomes tion [57]. Consequently, it lies at the core of biologi-obvious, which, in turn, promotes physiological states cal, cognitive and social regulation [157]. Motivationthat reduce anxiety and related negative sensations [81, is highly valued in health care since it produces behav-108,125,169]. Interestingly, given elevated cortisol as a ioral changes or adjustments and can mobilize others tonon-specific marker of early love states, no differences act [157]. A large amount of behavior can be explainedin cortisol levels between women and men in love were by simple processes of approaching pleasant and avoid-observed over the long term [117]. But here, we have ing painful stimuli, i.e., motivational behaviors [177].to consider that cortisol levels are difficult to measure, Hence, motivation may be divided into two categoriesNeuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X 179
  6. 6. Tobias Esch and George B. Stefano– appetitive and aversive motivation [57]. Appetitive iors, including affiliation, attachment formation andmotivation concerns behaviors directed towards goals reproduction. However, some states may encouragethat are normally associated with positive or hedonic, self-defensive or aggressive behaviors – states that may,i.e., pleasurable, processes (food, recreational drugs, sex but not in every single case, be incompatible or difficultetc.) [57]. In contrast, aversive motivation involves get- to combine with love and attachment [149]. Peptidergicting away from hedonically unpleasant conditions [17]. autoregulation systems, involving oxytocin, may serveConsequently, two fundamental forces rule motivation to inhibit defensive behaviors associated with stress,and subsequent behavior: Pleasure and pain [57]. It has anxiety and fear (Figure 1). In addition, they may allowbeen suggested that pleasure may be associated with positive social interactions to develop [26]. However,beneception, events that facilitate survival and, thus, these same peptidergic systems, including reward path-benefit the organism or species from an evolutionary ways that elicit pleasurable feelings and appetitive moti-perspective [196]. Pain, on the other hand, is associated vation, can be related, in some cases, to arousal, stresswith nociception [57]. The latter describes conditions or even stress reduction: The positive and even health-that may have undesirable biological consequences promoting aspect of appetitive motivation, and its pos-for an organism [17,196]. However, pain and pleasure sible association with stress reduction, love and attach-potentially merge into one another [57]. With regard ment, may, as a “side-product,” facilitate a pleasure-loveto specialized brain compartments involved in motiva- search, that is, a desire to socialize that may also intro-tional processes, the physiological substrate for appe- duce addictive behaviors (as discussed above).titive or aversive motivation primarily lies within the Steroid hormones, related to stress physiology andlimbic system [34,50,60,86,186] (see below). the reproduction cycle, can influence oxytocin receptor Reward and punishment are functionally and ana- binding in the CNS, particularly in the olfactory-limbic-tomically interconnected [57]. A crucial component hypothalamic axis, which has been implicated in socialof CNS reward and motivation circuitries, as they are and sexual behaviors [93]. For example, progesteronesteering behavior, are nerve cells that originate in the and/or glucocorticoids are capable of inhibiting func-ventral tegmental area (VTA), near the base of the brain tions of oxytocin or its receptor within the CNS, while[57]. These cells send projections to target regions in the possibly increasing oxytocin receptor binding in otherfrontal brain, most notably to a structure deep beneath parts, i.e., limbic [71]. Hence, site-specific modulationthe frontal cortex, i.e., nucleus accumbens [130,131]. of peptide binding by specific steroid hormones couldThe essential neurotransmitter of this connection is account for at least some of the regulator effects of ste-dopamine. Clearly, the VTA or mesolimbic dopamine roids, or stress, on maternal or sexual motivation andsystem represents a rather old, but very effective, part behavior [26].of motivational physiology and behavior [57]. However,in mammals (humans), the neurobiology of behavior, Trust and beliefincluding reward circuit involvement, is far more com-plex, and it is integrated with several other brain regions Trust and belief often have a negative connota-that serve to enrich an experience with emotion, as an tion in science[170,171,186]. For example, the placeboexample. In addition, these brain regions also direct effect seen in medicine is frequently said to be fraudu-the individual’s response or actual behaviors toward lent since it obviously relies on trust of a patient or his/rewarding stimuli, including food, sex and social inter- her belief in a certain doctor or therapy [54,57,170,171,action [132]. For example, the amygdala helps to assess 186]. Effects like these, that are subjective by nature,whether an experience is pleasurable or aversive (and are from an “objective science perspective,” regularlywhether it should be repeated or avoided) and further held to be illusory or unscientific [54]. However, trusthelps to forge connections between an experience and and belief undoubtedly play a major role in health, sci-other cues [130,131]. The hippocampus participates in ence, and medicine [48,57,170,171,186]. It has been sug-recording memories of an experience, including where, gested that the placebo effect is basically mediated bywhen, and with whom it occurred [132]. The frontal dopaminergic – and possibly morphinergic – rewardcortex, however, coordinates and processes all informa- mechanisms and that this placebo-related reward phys-tion and consequently determines the ultimate behav- iology is associated with positive therapy expectations,ior [57]. Finally, the VTA-accumbens pathway acts as a i.e., expected clinical benefits [36,54,57,186]. Hence,measuring tool and regulator of reward: it tells the other placebo effects may involve anticipatory pleasure andbrain centers how rewarding an activity is [132]. The positive motivation [57]. The placebo response, asmore rewarding an activity is deemed, the more likely described, relies on trust and belief, and this connectionthe individual is to remember and repeat it [132]. has its neurobiological roots predominantly in limbic or The tendency to approach or avoid particular social frontal/prefrontal brain activity [36,37,119,167].stimuli or biological objects is fundamental to attach- The brain’s reward and motivation circuits, respon-ment behaviors [26]. Some stimuli may be innately sible for the placebo physiology, include different CNSpositive or elicit positive responses, while others, par- regions that may serve various separate functions, butticularly those that are novel or produce a sense of inse- overlap in their reward signaling pathways (see below).curity, can be aversive or fear-inducing, even eliciting Almost all of these structures and mechanisms exhibitstress responses [26,55,58,60]. Specific physiological some form of association with cognitive functions, truststates may facilitate positive or beneficial social behav- or belief [54,69,186]. Hence, belief has an emotional180 Neuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X
  7. 7. The Neurobiology of Lovecomponent in that the brain’s motivation and reward vation of the brain’s reward system produces changescircuitry, linked to memory processes, will be rein- ranging from slight mood elevation to intense plea-forced with a positive emotional valence attached to sure and euphoria, and these physiological states usu-the person, idea, or thing that is believed [54,170,186]. ally help to direct behavior towards natural rewards, i.e.,This emotionalized memory, potentially accompanied love [2,16,57,156,213].by “somatic markers” (e.g., pleasant bodily sensations Neurobiologists have long known that the eupho-that may escort an emotion), sets the “feeling tone,” i.e., ria induced by drugs of abuse, sex, or other things weit strongly influences what feels right to a person [57, enjoy, arises because all these factors ultimately boost186]. Pleasure and emotion may reinforce a belief or the activity of the brain’s reward systems [57]. These aretrigger positive physiological reactions even against made up of complex circuits of nerve cells that evolvedrationality [183,184]. Thus, belief in a doctor, ther- to make us feel flush after eating or sex – things we needapy, sexual partner etc., as well as the belief in love, in to do to survive and pass along our genes [130,131].general (i.e., religious beliefs), may stimulate naturally Reward pathways are evolutionarily ancient like lim-occurring health processes [54,57,65,170,185]. These bic structures. In fact, these pathways are essentially ofsubjective processes may predominantly be based on limbic origin [54,57]. For example, prefrontal or orbi-endogenous autoregulatory signaling molecules like tofrontal cortices, cingulate gyrus, amygdala, hippo-endorphins and endocannabinoids, possibly originat- campus, and nucleus accumbens participate in theing in limbic pathways [54,182,186]. Moreover, belief reward physiology [186]. The lateral orbitofrontal cor-affects mesocortical-mesolimbic appraisal of a plea- tex, for instance, is activated with pleasant visual, tac-surable experience, leaving one, for example, well and tile, or olfactory stimuli, with its response dependingrelaxed [57]. Taken together, the subjective modula- on pleasantness rather than intensity of stimulationtion of incoming information in the brain – e.g., fol- [10,63,97,155]. Memories of the pleasure of wellness,lowing prior stimulation of the sensory organs – may i.e., “remembered wellness,” are accessible to this systembe an important factor in love, pleasure, and placebo through hippocampal mechanisms [54]. With regard tophenomena. This may be particularly true when pos- frequent CNS reward “tracks,” activation of the medialitive qualities or experiences like pleasant sensations, forebrain bundle (MFB), as it courses through the lat-touch, attention, and feelings of protection, in general, eral hypothalamus to the ventral tegmentum, has beenare involved [54,57,65,185]. shown to produce robust rewarding effects [17,135]. An important neurotransmitter here is dopamine [57,212]. Limbic functions: Reward and pleasure Electrophysiological and neurochemical techniques revealed that CNS stimulation can activate a descend- The biological mechanism mediating behavior moti- ing component of the MFB which is synaptically cou-vated by events commonly associated with pleasure is pled at the ventral tegmentum to the ascending meso-called ‘reward’ [57]. It is usually governing normal limbic dopamine system, i.e., nucleus accumbens [15,behavior through pleasurable experiences [17]. Plea- 17,57,132,135,212]. Thus, pleasure induction involves asure, however, describes a ‘state or feeling of happi- circuitous reward pathway, first activating a descendingness or satisfaction resulting from an experience that MFB component and then, as described, the ascendingone enjoys’ [1]. Pleasure is a subjective phenomenon, mesolimbic dopamine pathway.i.e., subjective quality. It is the ‘good feeling’ that comes Pleasure and reward may not only serve entertain-from satisfying homeostatic needs such as hunger, sex, ment or enjoyment, but may also govern behavior, sex-and bodily comfort [57]. Hence, an intimate associa- ual reproduction, and personal growth [57]. The stri-tion between reward and pleasure exists [17,132]. In atum (caudate nucleus, putamen, globus pallidus), forneurobiology, pleasure is a competence or function of example, contains cells that respond to food and drinkthe reward and motivation circuitries that are imbed- reward [10], and it is activated by monetary rewardded in the CNS. Anatomically, these reward pathways stimuli [47,102,165] or psychomotor stimulants, e.g.,are particularly linked to the brain’s limbic system [50, cocaine [18], as well as sexual arousal [8,10,61,96,151].54,57,58,60,154]. Hence, a hypothalamic activation specific to roman- Love has the capacity to influence the autonomic- tic love could reflect the component of erotic arousalemotional integration system, i.e., limbic system [54, inherent to this sentiment [8,10,61,96]. Regions com-160]. Here, the autonomic nervous system (ANS) and monly activated in love, as known so far, are stronglyemotions are wired together. Furthermore, sympathetic involved in reward physiology, comparable to an acuteactivity and stress hormone production are imbedded administration of euphoria-inducing drugs, such asin underlying autoregulatory circuits [50,52,60]. An cocaine [10,18,164]. It has therefore been speculatedassociation of love with emotions, neurotransmitter that the particular subregions in the reward and moti-and stress hormone production (Figure 1), autonomic vation systems activated in love phenomena and phys-responses, behavior, and mood states becomes obvi- iology reveal a general, i.e., non-specific and modality-ous [54]. The influence of love on vital functions such independent, network that is specialized to mediateas breath, respiratory rate, blood pressure, and cardiac attachment [10]. However, psychomotor stimulants,output, as a result of the autonomic-emotional integra- opiates, and natural rewards like food and sex, seem totion, can lead to a different consciousness, or altered predominantly activate the reward pathways by theirstate of mind, when in love [49,54]. Hence, an acti- molecular or pharmacological actions in the VTA andNeuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X 181
  8. 8. Tobias Esch and George B. Stefanonucleus accumbens, as well as amygdala and other relief that follows copulation may show different pat-related structures, i.e., mesolimbic or frontal/prefrontal terns in males and females, i.e., behavioral and physio-areas [15,57,130,131]. Ventral tegmental activation, as logical gender differences [28]. Finally, the activated sys-described, involves dopamine signaling [57]. Other tems, including sympathetic nervous system and stressneurotransmitters (e.g., GABA, glutamate, serotonin, response pathways, calm down in both sexes, leadingthe stress hormones noradrenaline and cortisol, as to an overall sense of well-being that involves pleasurewell as acetylcholine, nitric oxide, endorphins/opioid and reward activity [54,57]. Interestingly, an experi-peptides, and endocannabinoids) may also play a criti- mental treatment with vasopressin has been showncal role in reward physiology [57,154,204]. In addition, to be closely associated with increased activity in theendogenous morphine/opiate production may be of nucleus accumbens, thereby pointing, again, towardsimportance [54,57,64,65,159,183,217]. reward physiology involvement, which is important for Feeding, maternal behavior, or sexual activity can both sexes [26,67,209].each be facilitated by opiate activation of the reward Based on the known functions of the catecholamines,system [75,128,195]. The origin of the VTA (i.e., ven- e.g., norepinephrine and dopamine, it is likely thattral tegmental dopamine system) seems to provide catecholamines are involved in pair bond formation,an important neurochemical interface where opiates as shown above [26]. Dopamine agonists, capable ofand opioid peptides of exogenous or endogenous ori- inducing reward and pleasure, release oxytocin, andgin can activate a CNS mechanism involved in appeti- interactions between oxytocin and dopamine havetive motivation and reward [17,54]. Obviously, endog- been reported in rats [106,161]. Additionally, highenous morphinergic signaling plays a significant role levels of oxytocin receptor binding have been dem-here [54,57]. This is especially true since endogenous onstrated in the nucleus accumbens of prairie volesmorphine biosynthesis, found in humans, vertebrates, [87], which is “equipped” with intense dopamine sig-mammals, and invertebrates [54,148,159,217], involves naling (see above). Given the link between dopamineelements of dopamine synthesis and its metabolism [53, and endogenous morphine via common precursors, we54,57,189,218], thereby linking two critical signaling surmise morphine’s involvement here as well [73,219].systems[219]. Specifically, endogenous morphine pro- Interactions between oxytocin and catecholamines mayduction has been demonstrated in limbic tissues, e.g., therefore provide a mechanism for rewarding or rein-hippocampus and amygdala [12,159,176,217]. Mor- forcing pair bonding [26]. Furthermore, catecholaminesphinergic signaling has further been found to release may be necessary to activate or reward various behav-constitutive NO [38], thus linking endogenous mor- iors, including arousal and selective attention, and mayphine and NO to limbic reward and pleasure pathways also regulate the effects of oxytocin and vasopressin in[57]. Taken together, limbic areas are connected to the the CNS [26,144]. Taken together, it seems plausiblefrontal/prefrontal cortex which integrates emotion, that pleasurable sensations produced by sexual activ-memory, belief, expectation, motivation and reward ities would provide mechanisms that reinforce behav-processing, i.e., affective and motivational responses ior, thereby promoting its repetition [159]. In the con-[116,186]. Also, prefrontal mechanisms may trigger text of adaptive behavior and its necessity in evolution,dopamine, NO, and opiate release in the midbrain it would appear that the pleasure generated by sexual[201]. After all, the VTA serves as a appetitive motiva- stimulation, orgasm or intercourse would be selected-tion system for diverse behaviors, including sex, since for evolutionarily [159]. Consequently, pleasure can beit controls both normal and pathological behaviors seen as an effective and important adaptive mechanism,[15,16,17,54]. the function of which is to ensure the procreation and Mating, i.e., sexual intercourse or sexual stimulation, survival of a species [57,159].releases oxytocin [25]. Together with vasopressin, thispeptide is a key neurobiological transmitter in love and The neurophysiology of lovepair bonding [39]. Moreover, vasopressin production, asit is directly inducible by sexual stimulation, may also Falling in love, given the initial uncertainty, lets ourbe enhanced by testosterone release, as part of the sex cortisol levels rise [117]. Increased cortisol concentra-physiology [26]. Since mating and love involve pleasur- tions, however, together with lower follicle stimulatingable experiences and, therefore, release dopamine and/ hormone (FSH) and others [117], indicate the stressfulor increase sympathetic activity (at least in the begin- and arousing conditions associated with the initiationning: Figure 1), this act is a substantially rewarding of social contact. Furthermore, oxytocin plays a crucialexperience, yet facilitating appetitive motivation and role in parturition and lactation, i.e., postpartum periodarousal, which may increase the level of sexual stimula- in mammals, which is characterized by milk productiontion (positive feedback). All these physiological features [26]. A pulsatile release of oxytocin not only inducesof the sexual component of love, mentioned above, myoepithelial tissue contractions necessary for themay finally enhance sexual stimulation, testosterone, act of giving birth but also contractions of cells in theoxytocin, and vasopressin release until relief is found breast that produce milk flow [26]. Indeed, oxytocin is[26]. Furthermore, vasopressin may account for a fluc- a key player in sexual behavior, since it is involved fromtuating postcopulatory aggression that has been dem- its start – the process of falling in love – to subsequentonstrated, for example, in male prairie voles [26], which outcomes, i.e., offspring. Also, oxytocin ensures trust,indicates territorial behaviors. Thus, the physiological loyalty, and devotion, which seems to be important for182 Neuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X
  9. 9. The Neurobiology of Love Figure . Love physiology: Oxytocin and vasopressin effects. Oxytocin and vasopressin are small peptides that have similar structures. They may have evolved from the same ancestral peptide [] and thus are functionally and structurally interrelated. Both are involved in social attachment formation, prosocial and reproductive behaviors, including sexual and parental. They play a role in reward processes and may therefore be associated with endogenous opioid and opiate signaling, i.e., morphine, since this autoregulatory signaling system is crucial for attachment, pleasure induction, response to separation and stress reduction [,]. Further references see text.intact or beneficial and lasting relationships [117,118]. functions [26]. However, the distributions of theseTogether with vasopressin, prolactin, and endogenous receptors within the CNS vary across development andopioids, oxytocin reduces HPA axis (re)activity (Fig- among mammalian species [9,88,93,110,142,166,202,ures 1 and 2), and it further reinforces the attachment 214]. The specific patterns and densities of oxytocinbetween mother and child, e.g., by changing olfactory binding sites may also be influenced by steroid hor-characteristics and preferences to parents’/mother’s mones, including estrogen, progesterone, androgens,odors [26]. Interestingly, milk contains high levels of and glucocorticoids (Figure 1). Moreover, develop-oxytocin and prolactin, thereby additionally facilitat- mental hormonal experiences may alter adult geneing infant-mother attachment and bonding, as well as expression for both oxytocin and vasopressin receptorsinfant’s nervous system development and the structural [26,138]. The capacity of peptides to respond to devel-tuning of stress response mechanisms [26]. opmental processes may thus provide a mechanism Findings related to oxytocin and vasopres- through which individual ontogenetic experiencessin research, and connected neurobiological aspects can influence adult social behavior. However, oxytocinincluding the role of monoamines and other peptides and vasopressin are capable of binding to each other’slike endogenous opioids, suggest a tight coupling receptors [9], a fact that is further complicating analy-between attachment processes, love phenomena, and ses of pathways through which oxytocin and vasopres-reward pathways, i.e., lust, happiness, pleasure, pas- sin affect social attachment behaviors [26]. In addition,sion and desire [10,57,89,98,117]. In fact, most regions catecholamines, endogenous opioids, and prolactincharted to contain vasopressin and oxytocin receptors influence parental behavior as well, either by modulat-in the human brain are activated by both maternal and ing the rewarding aspects of this behavior [140,141],romantic love [10,92,111]. Interestingly, the same neu- pacing mother-infant interactions [19], or throughrohormones are involved in the attachment between their documented abilities to affect the release andmother and child (in both directions, see above) and in actions of other peptides, including oxytocin [26,101].the long-term pair bonding between adults, although Finally, release patterns of both neuropeptides varyeach neurohormone may have distinct binding sites since oxytocin appears to act faster and with more dra-and may be gender-specific [10,32]. matic pulses, as compared to vasopressin [40]. Oxytocin and vasopressin receptors have been Hormones generally act on the ANS to integratefound, for example, in the olfactory and limbic-hypo- attention, emotional states, motivation and social com-thalamic systems, as well as in brainstem and spinal munication with behavioral, physiological, or envi-cord areas that regulate reproductive and autonomic ronmental demands [55,58,60]. The ANS thereforeNeuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X 183
  10. 10. Tobias Esch and George B. Stefanois essential for social attachment and love, and it also CNS serotonin contents apparently increases aggressivecontains receptors for oxytocin and vasopressin [26]. behaviors both in animals and humans [66]. Moreover,Clearly, catecholamines, and other ANS signaling mol- testosterone further enhances vasopressin levels in theecules, play a role in love phenomena, and love, on the medial amygdala, lateral hypothalamus, and the preop-other side, acts on autonomic functions and states, tical medial area, involved in aggressive behaviors [66].i.e., stress and stress reduction (see above). Falling or Thus, gonadal, or sex, hormones are involved in the neu-being in love makes us feel good and, at times, “out of rophysiology of love, not surprisingly: Gonadal steroids,this world.” In fact, love produces states that resemble including androgens and estrogen, may exert develop-obsessive behaviors or disorders; while, in the case of mental effects on neural systems that have been impli-love, thoughts much more than behaviors characterize cated in social attachment, and they may mediate boththe actual obsession, i.e., thinking about the object of genetic and environmental influences on the propen-love “all the time” [117,118]. Recently, researchers spec- sity to love and form attachments [26]. These hormonesified molecules inducing such mental states: Vasopres- may further regulate oxytocinergic or vasopressinergicsin and oxytocin, the stress hormones norepineph- functions, as well as the expression of other peptidesrine and cortisol, as well as “pleasure molecules” like and neurotransmitters, which in turn can also modu-dopamine, endocannabinoids and endorphins – possi- late oxytocin and vasopressin, i.e., feedback [26]. How-bly together with endogenous morphine – have already ever, social attachment apparently occurs even in thebeen mentioned and will be further investigated in the absence of gonadal steroids, pointing out their ques-following text. In addition, blood drawn from individ- tionable role within the framework of love and socialuals currently in love also revealed lower levels of sero- attachment. Again, we see the complex interrelationstonin, comparable to that of patients suffering compul- of molecular signaling processes underlying love phe-sive-obsessive disorders [118]. This finding appears to nomena and sex-related contradictory at first, since serotonin is known for Dopamine has recently received special attentionits mood enhancing effects for which it is sometimes from psychopharmacologists and neurobiologists, duecalled a “pleasure hormone” as well. However, sero- to its obvious role in mood, affect, and motivation reg-tonin induces mental calmness, something that indi- ulation [15,17,36,57]. Clearly, dopamine plays a sig-viduals who have just made an attractive social con- nificant role in love phenomena and related physiol-tact (i.e., first approach), yet started to fall in love and ogy, especially in the beginning, and even some of thewant to overcome neophobia, don’t want to experience peripheral aspects or symptoms associated with love[117,118]. Thus, the early phase of love and attachment – e.g., increased intestinal peristalsis and diarrhea, asreminds us of a “roller-coaster,” that is, hormones of the described – may represent consequences of intenseANS and related neuropeptides are climbing-up and fall dopamine signaling involved in the love physiology.down again in a short period of time, thereby inducing However, with this report we primarily focus upondifferent states that are necessary for a good relation- the neurobiological features of love-related dopamineship to begin and, later on, stabilize. release, especially within the CNS: Although several dis- Another important hormone showing changes tinct dopamine systems (i.e., receptors and their sub-under love, and a somewhat surprising pattern of types) exist in the brain, the mesolimbic dopaminerelease, is testosterone since its concentrations vary in system appears to be the most important for motiva-opposite directions in the two sexes: Men in love dem- tional processes [17,216]. Accordingly, dopamine, inter-onstrate decreasing testosterone levels, whereas women preted here as a crucial part of the biologically impor-in the same condition produce more testosterone [117]. tant reward process, is a central instrument for theIt has been suggested that falling in love may therefore neurobiology of love. This seems to be particularly trueinclude the tendency to temporarily eliminate some of with regard to the stimulating and pleasurable aspectsthe biological differences between the sexes, or to soften of dopamine signaling [57]. It is important to note that,some male features in men and, in parallel, to increase based on new knowledge, there is a potential for endog-them in women, including a more “outgoing” or aggres- enous morphine signaling to be part of this process [64,sive behavior style [117,220]. However, this speculative 65,73,175,185,219].aspect has to be thoroughly examined further before Enkephalin inhibits the release of oxytocin and vaso-specific conclusions should be drawn. pressin in the posterior pituitary gland, i.e., neurohy- The early phase of love may represent a rather pophysis (as opposed to the anterior adenohypophy-extreme neurobiological state, even physiologically con- sis where the stress-related HPA axis is going through),tradictory to subsequent phases and states. Within the and by doing so, opioid peptides may decrease vaso-brain, testosterone receptors are distributed, for exam- pressin- (and oxytocin-) related memory and learn-ple, around hypothalamic regions where testosterone ing stimulation as well as oxytocin-associated breedingeventually is aromatized – i.e., processed – into estro- behaviors [20,126]. However, opioid peptides are a sub-gens, which then appear to determine an actual increase stantial and innate part of the love and reward/pleasurein aggressiveness [66]. However, the specific pathways physiology, as are presumably the endogenous opiates,involved as well as the significance of related estro- e.g., morphine [54,57]. In fact, recent information sug-gen signaling still are speculative. A behavioral corre- gests that morphinergic signaling should also be partlation between testosterone and serotonin levels has of the love-pleasure-reward hypothesis described ear-also been demonstrated: In fact, a lack or diminution of lier [64,65,73,175,185,219].184 Neuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X
  11. 11. The Neurobiology of Love Endogenous morphine, both biochemically and ized by deficits in attachment performance or behavior,immunocytochemically, has been found in various neu- such as autism, may be related to a malfunction in thisral tissues, including within the limbic structures [12,13, signaling system [129].24,44,45,68,74,103,104,187,218]. These same structures,interestingly, exhibit vasopressinergic or oxytocinergicsignaling, i.e., amygdala, nucleus accumbens, periaq- DISCUSSIONueductal grey, raphe nucleus, VTA, hippocampus, etc.,which, again, indicates a close relationship of bothsignaling systems with the limbic reward concept Common CNS pathways:[20,117,118]. Additionally, reports demonstrate the Love and other rewarding experiencespresence of morphine precursors in various mamma-lian tissues, including brain [54]. Furthermore, an opi- The profound neurophysiological and neurobiolog-ate receptor subtype, designated mu3, has been cloned, ical connection between love and reward has becomewhich is opiate alkaloid selective and opioid peptide obvious. Hence, the limbic reward and motivation sys-insensitive [21], strongly supporting the hypothesis of tem is involved in many other biological and physi-an endogenous morphinergic signaling system [54,57, ological phenomena, including medicine [53,54,178,148,159,217]. The psychiatric implications of this sys- 182]. Accordingly, we find common pathways, analo-tem have been examined, including brain reward cir- gous brain structures and regions repeatedly activatedcuitry [64]. Morphine, given its reported effects and in pleasure-related rewarding activities.those exerted via constitutive NO release [57,159,217], Activations in lateral frontal or prefrontal corti-may thus form the foundation of a common signaling ces, as demonstrated for love [10], can also be indica-among love and pleasure phenomena, including attach- tive of more generally positive mental states, i.e., posi-ment behaviors [10,54,57,127]. tive affect, as seen in relaxation techniques, listening to In general, morphine exerts immune, vascular, and music, or meditation [35,49,50,54,57]. When teenagersneural down regulating activities, and endogenous opi- listen to music of their choice, parts of the frontal (andate compounds are involved, as described, in the plea- temporal) lobe in the left hemisphere get activated [6,7].sure-reward system [57,181,189,190]. Indeed, morphine In contrast, when they listen to music they dislike, anal-may allow one to make rational short cuts since being ogous areas on the other side are active [54]. Pleasur-rationale, or dwelling upon single aspects in/of love, able music, however, also stimulates deeper structures,may sometimes not be appropriate, that is, too time- i.e., limbic, again showing a left-right asymmetry withconsuming or biologically dangerous [54,183]. In addi- the more negative perceptions following activations intion, mu receptors are critical to lust and reward and right hemispheric structures, e.g., parahippocampusthey may trigger feelings of wellness, which are essen- and amygdala, related to anxiety or fear [6,7,54,160].tial for positive motivation, lasting relationships, and Furthermore, meditation has been shown to increaseattachment [57,129]. These same pleasurable feelings left-sided anterior activation of the brain, as measur-are further involved in other biologically critical pro- able by various EEG techniques [35,54]. Davidson etcedures, e.g., food intake [129], again demonstrating the al. recently suggested that this particular brain activ-core role of the love-pleasure-reward system in the sur- ity pattern is associated with faster recovery and morevival of an organism and its species (see below). Inter- adaptive responding to negative and/or stressful eventsestingly, mice lacking mu receptors have been shown – i.e., higher flexibility, stress reduction [33,35,51,52].to be more susceptible to noxious stimuli – that is, they Clearly, love could account for such phenomena asexperience more pain – and, in contrast, to become well (see above). Taken together, CNS activation pat-less prone to addiction and addictive behaviors [129]. terns related to positive effects and love are not equallyMoreover, stress perception and attachment forma- shared between the two hemispheres. Deactivationstion are related to mu opioid receptor signaling: This are also of interest, since emotions are likely to be theopioid receptor system of the brain, for example, serves product of both increases and decreases of activities into associate the warmth and odor of a mother with her specialized regions [10]. An overall but slight decreaseinfant’s feelings or memories of relaxation and wellness, in right hemisphere activity, i.e., asymmetry, particu-i.e., remembered wellness, thereby essentially support- larly in prefrontal and limbic regions (including amyg-ing infant-mother bonding [57,129]. Separation cries of dala), can be stated for love [10]. However, these resultsinfants upon separation from their mothers – causing may be due to different neuroimaging techniques uti-high levels of stress, i.e., increased corticosterone con- lized and they should be interpreted with great care.centrations – can be diminished by experimental stim- Further research is necessary. In addition, brain activ-ulation of mu receptors, as well as oxytocin or prolactin ity can exhibit highly fluctuating patterns, i.e., unstableinjections [80,140,210]. Also, opiate signaling seems to or dynamic, with reference to varying psychological,modulate memory in a way that negative memories are physiological, and environmental factors. Nonethe-erased, possibly enhancing more positive recollections less, CNS commonalities seem to exist and these espe-or feelings of wellness [10,72]. Taken together, endog- cially concern (pre)frontal and limbic “shares” in theenous opioid/opiate binding mediates natural rewards neurobiology of love.and has been proposed to be the basis of infant attach- Researchers have hypothesized that pleasurablement behaviors [129]. Furthermore, diseases character- experiences like various complementary medicalNeuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X 185
  12. 12. Tobias Esch and George B. Stefanotreatments (e.g., therapies that elicit pleasurable sen- both the immune and the vascular trauma associatedsations such as massage or acupuncture) may exert with cyclic reproductive activities, such as endometrialcalming effects via release of gamma-aminobutyric build-up, when a high degree of vascular and immuneacid (GABA) in the amygdala and other limbic areas activities occurs [159]. Given the extent of proliferative[23,54]. This speculative aspect may be supported by growth capacity during peak estrogen levels in the cycle,the findings that link endogenous morphine produc- NO may function to enhance down regulation of thetion to limbic structures and complementary medicine immune system to allow for these changes [159]. Also,[54]. Thus, on the neurochemical level, love and plea- enhanced constitutive NO activity may exert beneficialsure may involve substances that possess calming and effects on mental states, since it helps to keep or facili-anxiolytic capacities, including oxytocin, thereby facil- tate a state of calmness and contentment, again resem-itating feelings of well-being and relaxation [54,57,159, bling morphine signaling [54,57,59]. Taken together,197, 217]. In addition, the pleasure of love may possess a these love-related signaling molecules have the poten-co-ordinating influence on a network of cortical or sub- tial to make one feel ‘good and relaxed’ by releasing NOcortical limbic and paralimbic structures, regions that [159,188]. However, NO autoregulatory signaling is aare intimately involved in the regulation of cognition, crucial and common pathway in a multitude of physi-emotion, and autonomic, endocrine or vegetative func- ological processes, including stress and placebo, as welltions [54]. Modulation of this neuronal network could as relaxation response [52,55,58,59,60,186]. Clearly, NOinitiate a sequence of effects through which pleasur- signaling is a physiologically complex phenomenon andable activities regulate multisystem functions [54,57]. its involvement in love and related states, as discussedMoreover, NO, endocannabinoid or endorphin, and here, has to be examined further.even endogenous morphine autoregulatory signaling Recent studies revealed a pathway for ‘limbic touch’have been demonstrated or discussed in association [10] that bypasses somatosensory cortices and directlywith pleasure-related experiences or therapies [52,54, activates parts of the insula, thereby evoking pleas-90,95,114,115,122, 147,182,186,215]. These molecules ant feelings related to touch and regulating emotional,that possess a strong CNS affinity and are further capa- hormonal, and affiliative responses to caress-like, skin-ble of reducing stress may also be involved in the pla- to-skin contact between individuals [134]. The dem-cebo response, thus promoting beneficial effects associ- onstrated CNS activity pattern involved in such phe-ated with love[179]. nomena overlaps with what has been described for Both the amygdala and the hippocampus contain maternal and romantic love and may thus reflect the sen-numerous receptors for varying neurotransmitters. sory-emotive component that is common to and crucialNuclei of the amygdala, for example, are strongly mod- for caring relationships [10,76]. However, romantic andulated by dopamine, norepinephrine, and serotonin, maternal love are not all the same: Besides data indicat-each of which have been demonstrated to exert their ing specific as well as overlapping CNS activity (the lat-effects via NO [22,57,94,174]. Clearly, the amygdala is ter represents the primary focus of this work), resultsintimately involved in sex and sexuality, as described obtained for romantic love were generally more signifi-[159]. The medial part of the female amygdala plays an cant in an attempt to examine these different conditionsimportant role in pregnancy and related coordination by modern neuroimaging means [10]. These results alsoof the endocrine system [159]. Stimulation of the cor- pointed towards a more pronounced (‘acute’) physiol-ticomedial amygdala has been shown to induce ovula- ogy in romantic love, as compared to maternal, therebytion in the female, and cutting the limbic stria termina- demonstrating the stressful conditions involved whenlis abolishes this effect [159]. The introduction of tract falling in love, i.e., arousal (see above). Thus, not alllesions to the rat amygdala can eliminate male libido, forms of positive social contact that possibly inducebut not female [120,150,174]. In general, stimulation pleasure or well-being are automatically and neurobi-of the amygdala may produce sexual arousal and erec- ologically the same, outright. For example, friendshiption, as well as representations and memories of inter- and love share common CNS features, even in physiol-course or orgasm [91,159,174,194]. Moreover, both lim- ogy. However, they are not the same: Friendship, in gen-bic tissues, amygdala and hippocampus, contain high eral, seems not to be coupled to love, that is, friendshipconcentrations of receptors for endocannabinoids and shows distinct neural and neuroanatomic activity pat-endogenous morphine [13,176]. This morphine, given terns – and vice versa [10]. However, this assumptionits endogenous synthesis in the regions of interest for is due to specific patterns emerging in both states. Theour hypothesis (see above), may activate pleasure path- neurobiological motivation-reward axis though, whichways via NO [29,38,159,192,217]. Now we better under- is a common and general feature, i.e., non-specific, isstand some of the pleasurable aspects of sexual activi- certainly involved in both phenomena.ties that may exhibit morphine-like properties and may Love activates specific regions in the reward sys-be mediated, among others, via these endocannabinoid- tem, as described above, and includes a suppressionand morphine-laden limbic pathways [54,159,182,217]. of activity in neural pathways associated with the crit-Finally, estrogen further stimulates NO release in the ical social assessment of other people and with nega-amygdala and may therefore provide an additional tive emotions [10]. In particular, love – and other statespathway by which the brain – and the body, organism that involve robust reward signaling – reduces the abil-– can down regulate immunocyte and vascular func- ity to critically judge [10], i.e., impaired emotional judg-tion in women [159,178]. This can be beneficial due to ment [5], decreases fear [10], and lessens the assessment186 Neuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X
  13. 13. The Neurobiology of Loveof social trustworthiness [211]. Additionally, love-plea- tion of neurochemical systems involved in the occur-sure-related activation/deactivation patterns of lat- rence of stress reduction and attachment behaviors [26,eral prefrontal cortices lead to reduced depression and 51,52,55,58,60].enhanced mood, i.e., ‘happiness’ [35,124]. Clearly, once Taken together, love phenomena act via commonone has become closely familiar with a person, the need neurophysiological pathways. More precisely: Besidesto assess the social validity of that person is reduced specific effects that are part of the neurobiological[10]. These findings therefore may help to explain why concept underlying love, numerous non-specific con-‘love makes blind’ [10], and in parallel, endorphin- and stituents and overlapping interrelations of love-plea-endogenous morphine-associated memory effects could sure mechanisms exist. These latter capacities that areplay a role. In fact, the neural mechanisms suppressed imbedded in the love concept thus point towards com-here might be the same that, when active, are respon- mon signaling pathways: We surmise that the sharedsible for maintaining an emotional barrier towards signaling found in love and related experiences isless familiar people, corresponding to the avoidance closely associated with CNS limbic reward and moti-behavior observed both in rats and voles against pups vation activities, which are connected to pleasure phe-or potential partners, which is reversed by administra- nomena and the well-being experience that is part oftion of oxytocin [89,144]. Taken together, a push-pull love, attachment and social bonding, as well as settingsmechanism has been suggested for attachment: Attach- that more generally involve high levels of social supportment on one hand deactivates areas mediating negative and closeness, i.e., ‘connectedness’.emotions, avoidance behavior, and critical social assess-ment, and on the other, it triggers mechanisms involvedin pleasure, reward, and appetitive motivation [10,57]. Pleasure and reward can activate behavioral pat- CONCLUSIONSterns, or they may even break up behavioral ‘torpidity’:Curiosity drives our motivation and actual behaviors Love is a complex neurobiological phenomenon,towards new goals and ‘fresh encounters’, stimulat- relying on trust and belief as well as brain rewarding a search for ‘new ways’ and solutions, or partners, activity, i.e., limbic processes. These processes criti-thereby involving spontaneity, appetence, and appeti- cally involve oxytocin, vasopressin, dopamine, andtive motivation [54,57]. Biologically beneficial and/or serotoninergic signaling. Moreover, endorphin andpleasurable events that occur on our way, driven by endogenous morphinergic mechanisms, coupled tocuriosity, involve reward signaling, as described, yet nitric oxide autoregulatory pathways, play a role. Nat-again encouraging and amplifying these new behav- urally rewarding or pleasurable activities are necessaryiors. Rewarding behaviors henceforth get memorized for survival and appetitive motivation, usually govern-for the goal of repetition and faster/better recognition ing beneficial biological behaviors like eating, sex, andlater on (i.e., behavioral-cognitive short cut, learning), reproduction. Thus, love and its rewarding pleasure areinvolving hippocampal mechanisms [57,60]. However, much needed.negative events and experiences may cause the opposite Love and social bonding employ a push-pull mech-neurophysiology to evolve, even including a physiolog- anism that activates reward and motivation path-ical deactivation of behaviors and motivation patterns ways. Simultaneously, brain circuits that facilitate criti-(i.e., aversive motivation, apathy), or memory deteri- cal social assessment and negative emotions, as well asoration [60,72]. Hence, stress is a common trigger or physical and mental stress, or “cognitive dwelling” (i.e.,cause of negative events, such as diseases, and it has a ‘cognitive constipation’ [179]), get down regulated. Thismajor yet principally preventable, i.e., reducible, impact down regulating property of love may also include fur-upon our life styles [55,56,58,59,60,182, 206]. Since love ther physiological phenomena. However, early phasesand pleasure may enhance positive or healthy behaviors of love, such as falling in love and its related arousaland beneficial motivations by their rewarding capac- and more pronounced behaviors and molecular sig-ities, love can be a tool in stress reduction (as illus- naling activities, are distinct from later stages or eventrated). Social support and bonding, as they appear in long-lasting relationships. Nonetheless, a broad basis ofthe face of stress and challenge, may thus help to pro- common signaling and beneficial neurobiological fea-mote healthy life style modifications, therefore involv- tures exist with connection to the love concept, therebying ‘positive physiology’ and ‘positive psychology’, i.e., combining physiological aspects related to maternal,feelings of wellness or well-being, yet integrating stress romantic or sexual love, and attachment, with otherresponse and other molecular pathways [54,57,159, healthy activities and neurobiological states. Medicine217]. For example, oxytocinergic pathways that origi- can make use of this concept, i.e., mind/body or inte-nate within the hypothalamus and project to the VTA grative medicine.are necessary for maternal behavior, as are mesolim- Many questions remain open. For example, wouldbic dopaminergic projections coming from the VTA acute exposure to oxytocin promote a search for social[57,133,144], again indicating a connection between contact, while chronic exposure might trigger socialattachment behaviors and pleasure pathways. Thus, satiety or safety and reduce social motivation? Whatthe association between social bonding and reproduc- about the other signaling pathways and neuropeptides?tion, as seen, e.g., in mother-infant interactions, may We attempted to answer some of theses questions onhave contributed, in an evolutionary sense, to the selec- possible solutions for related medical problems orNeuroendocrinology Letters No. June Vol.,  Copyright © Neuroendocrinology Letters ISSN –X 187
  14. 14. Tobias Esch and George B. Stefanoapplications. Undoubtedly, love, pleasure and lust, have increases in the plasma of Parkinson’s patients. Int J Mol Med ; :–.a stress-reducing and health-promoting potential.  Campbell A. The limbic system and emotion in relation to acu- puncture. Acupuncture in Medicine ; :–. Acknowledgements  Cardinale GJ, Donnerer J, Finck AD, Kantrowitz JD, Oka K, Spector S. Morphine and codeine are endogenous components of hu- man cerebrospinal fluid. Life Sci ; :–. This report was in part sponsored by MH 47392, DA  Carter CS. Oxytocin and sexual behavior. Neurosci Biobehav Rev09010 and the Kiernan Wellness Center. We are deeply ; :–.indebted to Ms. Danielle Benz for her expertise in the  Carter CS. Neuroendocrine perspectives on social attachmentpreparation of this manuscript. and love. Psychoneuroendocrinology ; :–.  Carter CS, Altemus M. 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