Estradiol in the Preoptic Area Regulates the Dopaminergic Response to Cocaine in the Nucleus Accumbens

Abstract

The sex-steroid hormone estradiol (E2) enhances the psychoactive effects of cocaine, as evidenced by clinical and preclinical studies. The medial preoptic area (mPOA), a region in the hypothalamus, is a primary neural locus for neuroendocrine integration, containing one of the richest concentrations of estrogen receptors in the CNS and also has a key role in the regulation of naturally rewarding behaviors. However, whether estradiol enhances the neurochemical response to cocaine by acting in the mPOA is still unclear. Using neurotoxic lesions and microdialysis, we examined whether the mPOA modulates cocaine-induced neurochemical activity in the nucleus accumbens. Tract tracing and immunohistochemical staining were used to determine whether projections from the mPOA to the ventral tegmental area (VTA) are sensitive to estrogen signaling. Finally, estradiol microinjections followed by microdialysis were used to determine whether estrogenic signaling in the mPOA modulates cocaine-induced changes of dopamine in the nucleus accumbens. Results showed that lesions of the mPOA or microinjections of estradiol directly into the mPOA increased cocaine-induced release of dopamine in the nucleus accumbens. Immunohistochemical analyses revealed that the mPOA modulates cocaine responsiveness via projections to both dopaminergic and GABAergic neurons in the VTA, and that these projections are sensitive to estrogenic stimulation. Taken together, these findings point to a novel estradiol-dependent pathway that modulates cocaine-induced neurochemical activity in the mesolimbic system.

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.…”

“…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].…”

“…Therefore, in addition to direct interactions with the VTA, removal of the mPOA might impact cocaine-induced mesolimbic activity and locomotion as a result of changes in other regions interacting with the mesolimbic system. We should also like to note that while our previous study [9] examined a role for the mPOA in cocaine-induced response of only females and the present study examined only males, it is still probable that mPOA-mesolimbic connections mediate gender differences resulting from cocaine administration, this is the focus of future and ongoing studies in our lab.…”

“…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]. 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].…”

Use of fast-scan cyclic voltammetry to assess phasic dopamine release in rat models of early postpartum maternal behavior and neglect

“…Moreover, disruption of mesolimbic dopamine transmission disrupts MB (Numan et al, 2005; Numan et al, 2009 Pereira and Morrell 2011). The ventral tegmental area (VTA) contains mesolimbic dopamine cell bodies and receives reciprocal innervation from the medial preoptic area and the paraventricular nucleus of the hypothalamus, which regulate MB (Numan et al, 2009; Simerly and Swanson 1988; Tobiansky et al, 2016). Therefore, by acting on the GABA and dopaminergic neurons in the VTA, hypothalamic nuclei engaged in MB may trigger dopamine release in VTA projection targets such as the nucleus accumbens (NAc) to produce motivated behavior directed toward the infant.…”