Sexual dimorphism and diergism of the mammalian central nitric oxide producing systems

Nitric oxide-producing neurons, identified by the presence of neuronal nitric oxyde synthase (nNOS), are widely distributed within the CNS, including regions involved in the control of reproduction and sexual behavior (like the bed nucleus of the stria terminalis (BST), the amygdala, the medial preoptic area (MPA), the mediobasal hypothalamus, or the magnocellular nuclei), where the distribution of nNOS overlaps that of gonadal hormones' receptors [i.e., estrogen receptors (ERalpha and ERbeta), androgen receptors (AR), and progesterone receptors (PR)]. However, only a few studies have detailed the co-expression of nNOS (or the corresponding NADPH-diaphorase activity) with these receptors, and have revealed species-specific and region-specific differences in the proportion of the colocalization. Overall, these data suggest the existence of significant neuroendocrine relationships among gonadal hormones and nNOS system. Experimental studies have, therefore, been performed. In mammals, sex steroids control the expression of nNOS in the preoptic-hypothalamic region. In the male, castration decreases the number of nNOS-IR neurons in the rat and the hamster MPA. In the female, estradiol (E2) increases, the NADPH–diaphorase staining in the guinea pig ventrolateral nucleus and in the rat paraventricular nucleus (PVN), and MPA. It increases also the nNOS mRNA in the ventrolateral subdivision of the rat ventromedial nucleus (VMH). However, contrasting data were also collected (i.e. no effects of castration or an increase of mRNA for nNOS in the hypothalamus of male rat). These discrepancies in the effects of gonadal hormones on the nNOS could be due to a combination of several factors: differences between species, methodology used, parameter studied or even a regional specificity. In addition, the presence of NOS-IR cells is not always reflecting the same amount of NADPH-diaphorase positive elements as recently demonstrated for the mouse basal forebrain. Differential expression of specific nNOS inhibitors should also be considered in the future to better clarify these relationships. Estrogen receptors seem to be important also for the differentiation of the limbic-hypothalamic nNOS system. A first study on the distribution of nNOS in male mice knockout for ERalpha (ERaKO) demonstrated significant changes in the limbic-hypothalamic region, when compared to that observed in wild-type mice. However, what we have observed was a nucleus-specific decrease rather than a total disappearance of the system. In particular, a significant decrease in NOS-IR cell number has been observed in PVN and arcuate nucleus (ARC), as well as a significant decrease in the density of NOS immunostained fibres in MPA. Other regions that are …