The medial preoptic area modulates cocaine-induced activity in female rats.

Abstract

Drugs of abuse exert their effects by exploiting natural neurobiological reward mechanisms, especially the mesolimbic dopamine (DA) system. However, the mesolimbic system does not operate in isolation, and input from other reward-relevant structures may play a role in cocaine’s rewarding effects. The medial preoptic area (mPOA) of the hypothalamus is involved in the regulation of two essential and naturally rewarding behaviors, sexual and maternal behaviors. It also makes strong neuroanatomical connections with areas of the mesolimbic system, particularly the ventral tegmental area (VTA). As such, the mPOA is a logical candidate for a neuroanatomical locus modulating activity in the mesolimbic system and emergent behavioral expressions of drug reward, yet the role of this structure is largely unexplored. Here, using a female rat model, we show that the mPOA innervates the VTA in a region-specific manner, lesions of the mPOA augment cocaine-induced Fos expression in the nucleus accumbens and cocaine-induced conditioned place preference. We also show that approximately 68% of mPOA-VTA efferents release γ-aminobutyric acid (GABA), over 75% are sensitive to DA as evidenced by co-localization with DA receptors, and nearly 60% of these contain both DA receptors and GABA, which suggests a novel key role for the mPOA in the inhibition of the mesolimbic DA circuit. Combined, these results reveal the mPOA as a critical modulating structure in cocaine-induced mesolimbic activity and behavioral manifestation of reward, at least in part via GABAergic output that is sensitive to DA input.

The medial preoptic area modulates cocaine-induced locomotion in male rats

“…Similarly, as the mPOA is essential for sexual [11] and maternal behaviors [12], contains one of the highest concentrations of cells expressing sex-steroid hormone receptors [13], and contains robust connections with the mesolimbic system [14], it is not surprising that it should also modulate cocaine-induced behavioral activity. Dopamine in the NAc increases locomotion [2, 3], removing a source of inhibition into the mesolimbic dopamine system, namely the mPOA [8, 9], should then facilitate locomotion, as is evidenced in our present findings. However, how the mPOA achieves this modulation is not entirely clear.…”

“…Our findings demonstrated that neurotoxic lesions of the medial preoptic area (mPOA) increased cocaine-induced dopamine release in the NAc, that many of the neurons projecting from the mPOA to the ventral tegmental area (VTA) are sensitive to estradiol, and that estradiol microinjections into the mPOA 24-hours prior to cocaine administration increased cocaine-induced dopamine release in the NAc [9]. These results are in line with additional work from our laboratory revealing that lesions of the mPOA enhanced cocaine-induced conditioned place preference (CPP) and cocaine-induced cellular activity in the NAc [8]. Together, these results point to the mPOA as an integral region in the processing of cocaine-induced response.…”

“…In the present study, removal of the mPOA increased cocaine-induced locomotion, suggesting that the mPOA inhibits dopamine activity in the NAc of male rats, as it does in females [8, 9], through its GABAergic output. As evidence of this, a substantial number of neurons within the mPOA are GABAergic [24].…”

“…We recently provided evidence describing a novel estradiol-dependent input into the mesolimbic system that modulates cocaine-induced neural, neurochemical, and behavioral activity in female rats [8, 9]. Our findings demonstrated that neurotoxic lesions of the medial preoptic area (mPOA) increased cocaine-induced dopamine release in the NAc, that many of the neurons projecting from the mPOA to the ventral tegmental area (VTA) are sensitive to estradiol, and that estradiol microinjections into the mPOA 24-hours prior to cocaine administration increased cocaine-induced dopamine release in the NAc [9].…”

“…However, anatomical studies suggest few neurons project directly from the mPOA to the NAc [14]. The VTA, which sends dopaminergic projections to the NAc [17], and modulates both CPP [18] and locomotion [19], is densely innervated by the mPOA [14], particularly the rostral end [8]. This suggests that the mPOA may modulate dopamine activity in the NAc via direct interactions with the VTA.…”