| Summary: | The salience of natural or drug-associated reward is mediated by phasic dopamine (DA) release in the nucleus accumbens (NAc) arising from DAergic cells in the ventral tegmental area (VTA). Circulating sex steroid hormones can modulate reward associated with drugs of abuse; yet, it still remains unclear which brain regions are responsible for this modulation. The medial preoptic area (mPOA) is a hypothalamic brain area involved in the expression of naturally rewarding behaviors as well as the regulation and reception of circulating sex steroid hormones in female rats. Considering its role in regulating naturally rewarding behaviors, its well-established anatomical connectivity with the VTA, and its responsiveness to circulating sex steroid hormones, the mPOA is an ideal neural node through which hormones could modulate the rewarding facets of drugs of abuse. Here I show that preoptotegmental efferents to the VTA are primarily GABAergic, that they appose putative DAergic cell bodies in the VTA that project to the NAc, and that they are capable of responding to sex steroid hormones and changes in DA release. Furthermore, cocaine influences neural activity in mPOA efferents that project to the VTA. Removal of the mPOA also enhanced cocaine-induced locomotion, Fos-immunoreactivity in the mesolimbic reward system, DA release in the NAc, and augmented conditioned place preference. Together these findings suggest that the mPOA modulates the release of DA in the mesolimbic reward circuitry via inhibitory connections with DA neurons residing in the VTA, and sex steroid hormones, in turn, may act in the mPOA to modulate response to cocaine. === text
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