Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets

Abstract

The mesolimbic dopamine (DA) circuitry determines which behaviors are positively reinforcing and therefore should be encoded in the memory to become a part of the behavioral repertoire. Natural reinforcers, like food and sex, activate this pathway, thereby increasing the likelihood of further consummatory, social, and sexual behaviors. Oxytocin (OT) has been implicated in mediating natural reward and OT-synthesizing neurons project to the ventral tegmental area (VTA) and nucleus accumbens (NAc); however, direct neuroanatomical evidence of OT regulation of DA neurons within the VTA is sparse. To phenotype OT-receptor (OTR) expressing neurons originating within the VTA, we delivered Cre-inducible adeno-associated virus that drives the expression of fluorescent marker into the VTA of male mice that had Cre-recombinase driven by OTR gene expression. OTR-expressing VTA neurons project to NAc, prefrontal cortex, the extended amygdala, and other forebrain regions but less than 10% of these OTR-expressing neurons were identified as DA neurons (defined by tyrosine hydroxylase colocalization). Instead, almost 50% of OTR-expressing cells in the VTA were glutamate (GLU) neurons, as indicated by expression of mRNA for the vesicular GLU transporter (vGluT). About one-third of OTR-expressing VTA neurons did not colocalize with either DA or GLU phenotypic markers. Thus, OTR expression by VTA neurons implicates that OT regulation of reward circuitry is more complex than a direct action on DA neurotransmission. J. Comp. Neurol. 525:1094-1108, 2017. © 2016 Wiley Periodicals, Inc.

The effects of oxytocin on eating behaviour and metabolism in humans

“…This concept is in line with a study published in 2016 showing that a single intranasal dose of 24 IU oxytocin increased activation of brain circuitry involved in cognitive control (detected using fMRI) and, at the trend level, reduced food craving when women were asked to cognitively control the urge to eat while viewing images of palatable foods 80 . This finding is also consistent with animal studies demonstrating that administration of oxytocin to the VTA 56 or nucleus accumbens 81 , which are regions of the brain involved in reward that receive oxytocin projections from the PVN 4 and express oxytocin receptors 23-25 , inhibits sucrose intake. Further research examining the specific effects of oxytocin on caloric intake and underlying mechanisms in humans will be important (Figure 1).…”

Oxytocin receptors modulate a social salience neural network in male prairie voles

“…Similarly, in the PFC, OTRs modulate multiple forms of social learning and behavior in rodents (Brill-Maoz and Maroun, 2016; Nakajima et al, 2014), including pair bonding in prairie voles (Young et al, 2001). The VTA also modulates pair bonding in male prairie voles (Curtis and Wang, 2005); projects to, releases dopamine (DA) within, and modulates IEG expression in multiple SSN nuclei (Argiolas and Melis, 2013); and contains OTR-expressing neurons that modulate both social behavior and dopamine release into the NAc shell (Peris et al, 2016; Shahrokh et al, 2010; Song et al, 2016; Stivers et al, 1988). The AON and MeA were selected due to their role in OTR-dependent social odor processing and social recognition (Ferguson et al, 2001; Gur et al, 2014; Oettl et al, 2016; Wacker and Ludwig, 2012).…”

Oxytocin and Rodent Models of Addiction

“…In a recent study, direct (icv) administration of oxytocin reduced alcohol consumption and alcohol-induced dopamine efflux in the NAc (Peters, Bowen, Bohrer, McGregor, & Neumann, 2017). Additionally, oxytocin receptors have been identified on neurons in the ventral tegmental area projecting to the NAc (Peris et al, 2017). Thus, it is possible that oxytocin reduces alcohol self-administration by altering mesolimbic dopamine activity that ordinarily signals alcohol-related reward.…”

“…This absence has limited the use of immunohistochemistry to identify the neurochemical and projection phenotype of oxytocin sensitive cells in the brain (see Mouillac, Manning, & Durroux, 2008). Recently, through the use of genetically modified mice, progress has been made to characterize neuronal phenotypes that co-localize with oxytocin receptors in specific brain areas integral to addiction circuitry (Dolen, Darvishzadeh, Huang, & Malenka, 2013; Nakajima, Gorlich, & Heintz, 2014; Peris et al, 2017; Tan et al, 2017). Magnocellular oxytocin neurons in the PVN express high levels of corticotrophin-releasing factor (CRF) type 2 receptors and these CRF receptor positive neurons express oxytocin receptor mRNA as do CRF receptor positive neurons in the bed nucleus of the striatal terminalis (Dabrowska et al, 2011).…”

“…Magnocellular oxytocin neurons in the PVN express high levels of corticotrophin-releasing factor (CRF) type 2 receptors and these CRF receptor positive neurons express oxytocin receptor mRNA as do CRF receptor positive neurons in the bed nucleus of the striatal terminalis (Dabrowska et al, 2011). Oxytocin receptors have been identified on cortical somatostatin-containing interneurons (Li, Nakajima, Ibanez-Tallon, & Heintz, 2016; Nakajima et al, 2014), cortical glutamatergic and GABAergic neurons (Tan et al, 2017), parvalbumin positive interneurons and astrocytes in the NAcc (Dolen et al, 2013), and on glutamate, GABA and dopamine producing neurons in the VTA (Peris et al, 2017). These three brain areas are crucial to the circuitry regulating drug reward and reinforcement as well as relapse to drug use, and oxytocin in each of these areas may uniquely impact drug seeking.…”