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

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The reward value of reinforcing actions, such as sexual behavior and pair bonding, is regulated by dopamine (DA) cell firing in the ventral tegmental area (VTA) and increased DA release in the nucleus accumbens (NAc) (see Gordon et al., 2011). Oxytocin (OT) neurons in the hypothalamic paraventricular and supraoptic nuclei send projections to the VTA and NAc (Sonfroniew, 1983; Otero‐Garcia et al., 2015) and OT has been implicated as a mediator of socially rewarding behaviors and activity within mesolimbic circuitry (see Kovacs et al., 1998; Love, 2013; Sarnyai and Kovacs, 2014, for review). Receptor autoradiography in rats (Dumais et al., 2013) and other species (see Gimpl and Fahrenholz, 2001) has localized OT receptors (OTR) to both the VTA and NAc, and injection of OT into the VTA of rats increases DA release in NAc (Melis et al., 2007; Shahrokh et al., 2010). Although these findings imply that OTR functionally stimulate DA firing in mesolimbic pathways, the exact circuitry involved in OTR regulation of neuronal activity in these regions is not yet known.
The VTA is comprised of seven subregions containing DA neurons that were originally known as the A10 cell group (Fu et al., 2012). At the lateral extent are the parabrachial pigmented nucleus and the rostral VTA subregions (Fu et al., 2012). The parabrachial pigmented nucleus extends the full rostral‐caudal length of the VTA, while the rostral VTA gives way to the medial parainterfascicular and paranigral nuclei in the posterior VTA (Fu et al., 2012; Sanchez‐Catalan et al., 2014). Other subregions of the VTA cell group are the midline interfascicular, rostral linear, and caudal linear nuclei (Fu et al., 2012; Sanchez‐Catalan et al., 2014). DA neurons in these midline areas project to different parts of the forebrain. DA neurons in the medial parabrachial pigmented and paranigral nuclei project to the medial prefrontal cortex (PFC), the medial shell of the NAc, and the basolateral amygdala (see Ikemoto, 2007; Lammel et al., 2014), whereas more lateral neurons in the parabrachial pigmented nucleus project to the lateral shell of the NAc (see Ikemoto, 2007; Lammel et al., 2014). This heterogeneity between anterior and posterior, lateral and medial DA neurons is thought to mediate different effects on reward and reinforcement‐dependent learning (Schultz, 2010; Lammel et al., 2011; Sanchez‐Catalan et al., 2014). Characterization of OTR activation of subpopulations of VTA neurons may lead to a better understanding of OT regulation of both natural and drug‐related reward and reinforcement‐dependent behaviors.
A significant proportion of VTA neurons use GABA or glutamate (GLU) as neurotransmitters instead of DA (see Yetnikoff et al., 2014). The GABA and GLU neurons within the VTA can be interneurons that make local connections with DA neurons (Omelchenko and Sesack, 2009; Dobi et al., 2010; Taylor et al., 2014), as well as projection neurons with efferent fibers terminating in distal brain nuclei, including the medial PFC, NAc, amygdala, lateral habenula, and ventral pallidum (Yamaguchi et al., 2011; Morales and Root, 2014; Taylor et al., 2014). GABA neurons tend to be concentrated in the lateral VTA subregions, while GLU neurons are concentrated in the medial nuclei (Yamaguchi et al., 2011; Taylor et al., 2014). Additionally, evidence from both immunolabeling and optogenetic experiments suggest that VTA neurons can express genetic markers for multiple neurotransmitters and regulate striatal pathways through the possible corelease of DA, GLU, and/or GABA (Yamaguchi et al., 2007; Stuber et al., 2010; Tecuapetla et al., 2010; Tritsch et al., 2012; Stuber et al., 2015).
OT regulation of VTA neurons and associated behavioral processes could occur via a direct effect at either the cell body or the terminal portions of these varied projection pathways.
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