Androgen influence on prefrontal dopamine systems in adult male rats: localization of cognate intracellular receptors in medial prefrontal projections to the ventral tegmental area and effects of gonadectomy and hormone replacement on glutamate-stimulated extracellular dopamine level.

Although androgens are known to modulate dopamine (DA) systems and DA-dependent behaviors of the male prefrontal cortex (PFC), how this occurs remains unclear. Because relatively few ventral tegmental area (VTA) mesoprefrontal DA neurons contain intracellular androgen receptors (ARs), studies presented here combined retrograde tracing and immunolabeling for AR in male rats to determine whether projections afferent to the VTA might be more AR enriched. Results revealed PFC-to-VTA projections to be substantially AR enriched. Because these projections modulate VTA DA cell firing and PFC DA levels, influence over this pathway could be means whereby androgens modulate PFC DA. To assess the hormone sensitivity of glutamate stimulation of PFC DA tone, additional studies utilized microdialysis/reverse dialysis application of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor subtype-selective antagonists which act locally within the PFC and tegmentally via inhibition or disinhibition of PFC-to-VTA afferents to modulate intracortical DA levels. Here, we compared the effects of these drug challenges in control, gonadectomized, and gonadectomized rats given testosterone or estradiol. This revealed complex effects of gonadectomy on antagonist-stimulated PFC DA levels that together with the anatomical data above suggest that androgen stimulation of PFC DA systems does engage glutamatergic circuitry and perhaps that of the AR-enriched glutamatergic projections from PFC-to-VTA specifically.