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.

Gonadectomy and hormone replacement affects in vivo basal extracellular dopamine levels in the prefrontal cortex but not motor cortex of adult male rats.

Gonadectomy in adult male rats is known to impair performance on dopamine (DA)-dependent prefrontal cortical tasks and selectively dysregulate end points in the mesoprefrontal DA system including axon density. In this study, in vivo microdialysis and high-pressure liquid chromatography were used to determine whether short (4 day)- and/or long-term (28 day) gonadectomy and hormone replacement might also influence the more functionally relevant metric of basal extracellular DA level/tone. Assessments in medial prefrontal cortex revealed that DA levels were significantly lower than control in 4-day gonadectomized rats and similar to control in 4-day gonadectomized animals supplemented with both testosterone and estradiol. Among the long-term treatment groups, DA levels were significantly higher than control in gonadectomized rats and gonadectomized rats given estradiol but were similar to control in rats given testosterone. In contrast, extracellular DA levels measured in motor cortex were unaffected by long- or short-term gonadectomy. The effects of gonadectomy and hormone replacement on prefrontal cortical DA levels observed here parallel previously identified effects on prefrontal DA axon density and could represent hormone actions relevant to the modulation of DA-dependent prefrontal cortical function and perhaps its dysfunction in disorders such as schizophrenia, attention deficit hyperactivity disorder, and autism where males are disproportionately affected relative to females.

Effects of gonadectomy and hormone replacement on a spontaneous novel object recognition task in adult male rats.

Recent studies in adult male rats have shown that gonadal hormones influence performance on certain working memory and other types of cognitive tasks that are sensitive to lesions of the medial and/or orbital prefrontal cortices. This study asked whether gonadal hormone modulation of prefrontal cortical function in males also extends to the perirhinal division of the rat prefrontal cortex. Specifically, sham-operated control, gonadectomized, and gonadectomized rats supplemented with testosterone propionate or estradiol were tested on a spontaneous novel object recognition task, a paradigm where performance has been shown to be impaired by perirhinal cortical lesions. Using analyses of variance, regression analyses and post-hoc testing to evaluate group differences, it was found that during both the sample and test trials of the task all four groups spent similar absolute and proportional amounts of time ambulating, rearing, stationary, and exploring the two objects present. All groups also explored each of the two identical objects present during sample trials equally. However, during the test trials, only the control and gonadectomized rats given testosterone showed the expected increase in exploration of the novel objects presented, whereas the gonadectomized and gonadectomized, estradiol-supplemental groups continued to explore the novel and familiar objects equally. That regression analyses also identified significant correlations between low bulbospongiosus muscle weight and impaired novel vs. familiar object discrimination further indicates that gonadectomy in adult male rats adversely affects spontaneous novel object recognition in an androgen-sensitive, estrogen-insensitive manner.