Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles

“Following 24 h of mating, male and female prairie voles form pair bonds as indicated by subjects spending significantly more time with the familiar partner than with a conspecific stranger (partner preferences; Williams et al., 1992; Winslow et al., 1993).”

“Together, these results demonstrate that driving activity in VTA-NAc projections is sufficient to increase social interaction.”

“Wang and his colleagues have demonstrated the importance of an interaction between OT and dopamine, specifically the dopamine D2 receptor, in the nucleus accumbens for pair bond formation in female prairie voles (Aragona et al., 2003; Curtis et al., 2006; Liu and Wang, 2003).”

“…1994), the two receptors have different expression patterns in prairie voles, with Oxtr specifically relegated to the shell and core of the NAcc in prairie voles (Lim et al., 2004), where Oxt-dopamine interactions aid in partner preference formation in female prairie voles (Liu and Wang, 2003).”

“…vole is mated with a male, she forms a distinct preference for this partner; however, when a dopamine agonist is infused into the nucleus accumbens, she begins to prefer a male present at the time of infusion, even if she has not mated with this male (Gingrich et al. 2000; Liu and Wang 2003).”

“For example, the seminal work of Liu and Wang has shown that coactivation of D2 receptors and OT receptors in the nucleus accumbens is necessary for pair bond formation and maintenance (100), which recently has been suggested to be facilitated by the presence of DA D2 receptor-OT receptor (D2R-OTR) heteromers (101).”

“OT can induce dopamine release in ventromedial regions associated with reward [52] reinforcing generosity.”

“For example, partner preference formation in prairie voles is modulated by the VP system acting in the LS and ventral pallidum (Liu et al., 2001; Pitkow et al., 2001; Lim & Young, 2004) and by the OT system acting in the NAc and prefrontal cortex (Young et al., 2001; Liu and Wang, 2003).”

“Besides broad roles in motivation and reward systems (Schultz, 2006), dopamine directly modulates oxytocinergic systems in the female prairie vole nucleus accumbens that are critical for the formation of social attachment (Liu & Wang, 2003; Young, Murphy Young, & Hammock, 2005).”

“forcing value of social stimulation [81,99,144].”

“, partner preference formation) [150,244], and various studies documenting a role of NAcc OTRs in female parental behavior.”

“Concurrently, there may also be coactivation of dopamine and oxyocin in the NA as revealed in a recent study where stimulation of D2-like receptors and oxytocin receptors in the NA facilitated pair bond formation in female prairie voles [89].”

“Injection of a D2-receptor antagonist into the nucleus accumbens of female prairie voles can prevent partner preference formation induced by oxytocin and oxytocin antagonists can block partner preference formation induced by D2-receptor agonist administration (Liu and Wang, 2003).”

“Infusion of a D2 antagonist into the NA prevented OT-induced partner preferences, while infusion of an OTR antagonist prevented D2 agonist-induced partner preferences (Liu & Wang, 2003).”

“These findings in voles are paralleled in humans by functional MRI (fMRI) studies showing that viewing the face of a romantic partner while recalling experiences with them activates rewardassociated regions such as the VTA, NAcc, caudate, and lentiform nuclei (11–14).”

“Finally, it is possible that multiple neurochemical differences between the species are responsible for species differences in behavior (e.g., dopamine, corticotropin-releasing factor) (Gingrich et al., 2000; Liu and Wang, 2003; Smeltzer et al., 2006; Lim et al., 2007).”

“This mechanism also appears to mediate female attachment to adult male partners in pair-bonding voles (Liu and Wang, 2003; Young et al, 2005) and possibly humans (Bartels and Zeki, 2004; Aron et al., 2005; Fisher et al., 2005), prompting the suggestion that modification of neural systems involved…”

“Indeed, this notion was supported in two recent studies showing the role of dopamine in prairie vole partner preference formation (Aragona et al., 2006; Liu and Wang, 2003).”

“In addition , OT injected into the NAC is sufficient to induce pair bonds in female prairie voles in the absence of mating and interacts with DA D2R to do so ( Liu and Wang 2003 ) .”

“Multifactorial processes within or between neurochemical groups (e.g., the interaction among dopamine and oxytocin in regulating a number of social behaviors; Liu and Wang, 2003; Pearce et al., 2017b) add to this presently opaque picture (Hung et al., 2017; Pearce et al., 2017b).”

“A key example is Oxt release into the vStr, which promotes affiliative social behavior (Liu and Wang, 2003; Shahrokh et al., 2010; Young and Wang, 2004).”

“Animal research has shown a great degree of overlap in OT and dopamine receptor binding sites (Baskerville et al., 2009; Liu and Wang, 2003; Smeltzer et al., 2006 As OT was originally associated with induction of labour, it is not surprising to find interactions with gonadal or sex steroid hormones.”

“Concurrent activation of D2 dopamine and OTRs in the NAcc are necessary for partner preference formation in female prairie voles (Liu & Wang 2003).”

“…injection of a dopamine agonist into the nucleus accumbens can promote prairie vole pair bonding even without mating, but this effect can be reversed with administration of an oxytocin antagonist, suggesting that the pair-bonding process involves oxytocindopamine interaction (Liu & Wang, 2003).”

“…that studies on prairie voles investigating the synaptic plasticity changes that underlie the formation of longlasting social attachments between mates has also emphasized the positive involvement of DA action on D2 receptors in NAs (Gingrich, Liu, Cascio, Wang, & Insel, 2000; Liu & Wang, 2003).”

“Administration of OT induces central dopamine release and vice versa, and their coaction appears to be critical for partner preference (Edwards & Self, 2006; Liu & Wang, 2003; Young & Wang, 2004).”

“So while dopamine (through D2 receptors) and oxytocin work together in the ventral striatum to “cement” partner preferences in monogamous species (Liu and Wang, 2003), oxytocin may inhibit dopamine in the same region to diminish drug reward.”

“…voles, mice and primates) point toward two brain areas as being relevant for monogamous pair bonding — the nucleus accumbens in the case of OXT receptors, and the ventral pallidum in the case of AVP V1a receptors (Wang et al., 1997; Young et al., 1999; Liu and Wang, 2003; Lim et al., 2004a).”

“The same effect can be observed when blocking dopamine during mating (22).”

“Indeed, there is ample research to suggest to that common genetic variation in the receptor structure for these molecules may impact on some aspects of social functioning in humans; additionally, central administration of oxytocin seems to encourage certain social behaviors and cognitive capacities (Meyer-Lindenberg e…”

“…other studies indicate that while OTR activation in the NAc is necessary for male-female attachments in female prairie voles (Young et al., 2001; Liu and Wang, 2003), it is not sufficient to induce such attachments in other species; there must be other circuitry that further determines how…”

“OT receptors are particularly notable in both the shell and the core of the NAcc and have been implicated, together with DA release, in pair bond formation in the monogamous female vole [17 ,32].”

“In the case of partner preference, mating-induced OT release may link sexual arousal and bonding by activating the mesolimbic dopamine circuit and causing release of DA from the NAcc (Aragona et al., 2003; Insel, 2003; Liu and Wang, 2003; Wang et al., 1999; Young and Wang, 2004).”

“Bonding and affiliation in monogamous mammals Although OT-based affiliative bonding is likely to have evolved in mammals to activate maternal care and reinforce the mother–infant bond, other female affiliative interactions in rodents are also regulated by OT. In the monogamous prairie vole Microtus ochrogaster, female…”

“Antipsychotics are not known to alter oxytocin function, though dopamine and oxytocin may work together to facilitate social behaviors modulated by the nucleus accumbens (Liu and Wang, 2003).”

“Endogenous OT acting via OT receptors (OTRs) in the nucleus accumbens is necessary for pair bonding in female prairie voles (Young et al., 2001; Liu and Wang, 2003); exogenous OT promotes pair bonding in the absence of mating (Liu and Wang, 2003); and viral vector-mediated upregulation of OTR expression in the nucleus…”

“These neurotransmitter systems likely interact with MOR and oxytocin processing in key brain regions involved in social and emotional processing (Hagelberg et al., 2002; Liu and Wang, 2003; Depue and Morrone-Strupinsky, 2005a; Lintas et al., 2011; Colasanti et al., 2012; Tops et al., 2014).”

“OT may be particularly related to pair-bond formation and parenting behavior in female voles (Liu and Wang, 2003; Olazabal and Young, 2006) and is also associated with mating (Carter, 1992).”

“OT mediates its central effects by binding with high affinity to OT receptors (OTRs) and/or with lower affinity to vasopressin 1a (V1aR) receptors (Schorscher-Petcu et al., 2010; Song et al., 2014).”

“…monoamine systems, as well as with other neuropeptides, it facilitates a range of sensory and psychological processes essential for adaptive social behaviour, such as pair bonding and attachment formation (Insel and Young, 2001; Liu and Wang, 2003; Mitre et al., 2016; Yoshida et al., 2009).”

“Nonetheless, the results from early studies indicate the involvement of brain structures, such as the anterior hypothalamus (AH; Ferris and Potegal, 1988; Adams et al., 1993; Delville et al., 2000; DeLeon et al., 2002b; Albers et al., 2006) and lateral septum (Albert and Brayley, 1979; David et al., 2004; Knyshevski e…”

“In female prairie voles, activation of both D2 and OT receptors is necessary for pair bonding, since blocking either receptor disrupts pair bond formation (Liu and Wang, 2003).”

“…of OT receptor (OTR) in the NAc than do non-monogamous vole species, and several studies have characterized the role of intra-NAc OTR activation in facilitating partner preference formation in female, but not male, prairie voles (Liu and Wang 2003; Ross et al. 2009a, b; Keebaugh and Young 2011).”

“In several studies, OT release has been associated with higher ventromedial dopamine (Liu & Wang, 2003) providing a possible proximate motivation for monetary sacrifice.”

“…of the OTR in the striatum promotes partner preference formation and alloparental care in adult female prairie voles (Olazábal and Young 2006; Keebaugh et al. 2015; Ross et al. 2009; Liu and Wang 2003) and conditioned place preference for social stimuli in adult male mice (Dölen et al. 2013).”

“OXT has been shown to regulate specific brain functions by facilitating the release of other neurotransmitters, in particular dopamine and serotonin (Dluzen et al., 1998; Dluzen et al., 2000; Ross et al., 2009; Liu and Wang, 2003; Olazabal and Young, 2006; Dolen et al., 2013).”

“Dopamine has recently been identified for its crucial role both in pair-bonding (Aragona et al., 2003; Aragona et al., 2006; Liu and Wang, 2003; Wang et al., 1999) and parenting behavior (Lonstein, 2002).”

“Experimental manipulations of receptor activation and expression corroborate the importance of OT and VP signaling for the expression of social behavior (see, e.g., Liu and Wang, 2003; Lim et al., 2004c).”

“The NAS is an integral part of the pair bonding circuitry and is the site where oxytocin, CRF, and dopamine act to modulate partner preference formation (Young et al, 2005); the CP is an anatomically adjacent region of striatum that is involved in goal-directed behavior and habit formation (Balleine and O’Doherty, 201…”

“As such, this discrepancy compared with the role of OXT in prairie voles, where the peptide is necessary for the formation of new pair bonds (96), may be related to methodological differences in the assessment of pair bonding in rodents and humans or indicate a species-specific function of OXT.”

“Another, more speculative, lead for an attachment-dissolving intervention may come from Capgras’s delusion (Capgras and Reboul-Lachaux [1923] 1994).”

“…in female prairie voles, where administration of an oxytocin receptor antagonist blocks partner preference induced by D2 activation, whereas blockade of D2 receptors in the nucleus accumbens prevents partner preference formation induced by oxytocin (Young and Wang, 2004; Liu and Wang, 2003).”

“…et al., 2009; Hirosawa et al., 2012), modulates the social relevance of emotional stimuli (Kirsch et al., 2005), interacts with dopamine to regulate socio-affiliative behaviors (Liu and Wang, 2003; Zeki, 2007) and the appropriate assignment of salience to social stimuli (Skuse and Gallagher, 2009).”

“Further, facilitation of partner preference formation by activation of oxytocin receptors is not effective if D2like receptors are blocked (Liu and Wang, 2003).”

“Consistent with the methods established by previous studies (Liu and Wang, 2003; Aragona et al., 2006), subjects were implanted with 26-guage bilateral guide cannulae (Plastics One) anchored to the skull with stainless-steel screws and dental cement and aimed at the NAc shell ( 1.6 mm AP; 1 mm ML;…”

“The oxytocin system is known to interact with the dopaminergic system (Liu and Wang 2003).”