The regulation of MPOA dopamine and copulation in male rats: The roles of gonadal steroids and nitric oxide/sGC/cGMP pathway
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Male rat copulation is regulated by a complex network of neural and endocrine pathways. Gonadal steroids play significant roles as parts of this network, although several details of their actions have not been elucidated. Previous studies have demonstrated the importance of dopamine (DA) in the medial preoptic area (MPOA), a site of sensori-motor and neural-endocrine integration during copulation. The DAergic tone in the MPOA is greatly influenced by levels of circulating gonadal steroids. Therefore, the possibility that the DA producing cells that project to this area may be directly regulated by these steroids was examined with immunocytochemical localization of nuclear steroid receptors (androgen receptors and estrogen receptor α and β) and A13 and A14 DA cells. Despite some overlap in their distributions, none of the DA cells contained the steroid receptor examined. This evidence suggests these DA cells are not directly regulated by gonadal steroids in adult male rats. Instead, the effects of gonadal steroids on MPOA DA appear to be mediated through indirect pathways. One candidate is a pathway involving nitric oxide (NO). NO not only regulates MPOA DA, but also is sensitive to gonadal steroid manipulations. One possible mechanism through which steroids can alter neuronal nitric oxide synthase (nNOS) is by altering its production. However, there was no change in nNOS protein levels with one-month castration. This suggests more subtle changes yet to be detected. Although the importance of NO for regulation of MPOA DA has been demonstrated, there was little information regarding how NO regulates DA in the MPOA. One of the most common effector pathways for NO is through the NO-cGMP pathway. The administration of a cGMP analog increased, while a soluble guanylyl cyclase (sGC) inhibitor reduced extracellular DA levels in the MPOA. Furthermore, a NO donor-induced DA release was blacked by a sGC inhibitor, while the nNOS inhibition failed to block a cGMP analog-induced DA release. Finally, a cGMP analog facilitated copulation and MPOA DA release, while a sGC inhibitor inhibited copulation and DA release. Taken together, these studies indicate that the NO-cGMP pathway mediates the effect of NO on MPOA DA, and this modulation is behaviorally relevant. These studies support the hypothesis that gonadal steroids alter copulation, at least partially, by subtly altering nNOS functions, which in turn indirectly alter DA levels. Furthermore, the effect of NO on DA in the MPOA is mediated by the NO-cGMP pathway. Given the similarity of this pathway to the clinically utilized pathway involved in erection, the results of the current studies may represent a possibility of a more effective treatment for the erectile dysfunction with a single pharmacological agent.