Castration increases and androgens decrease nitric oxide synthase activity in the brain: Physiologic implications

Abstract

Sex differences in nitric oxide synthase (NOS) activity in different regions of the rat brain and effects of testosterone and dihydrotestosterone (DHT) treatment in orchidectomized animals were investigated. Regional but no sex differences in NOS activity were detected in gonadectomized animals. Orchidectomy significantly increased NOS activity in the hypothalamus, ''amygdala,'' and cerebellum but not in the cortex. In the hypothalamus, the increase in NOS activity after castration and its reversal by androgen treatment was mimicked by changes in neuronal NOS mRNA level. In contrast, androgen receptor (AR) mRNA level in the hypothalamus was slightly reduced by castration and increased by treatment with DHT. Again in the hypothalamus, the increase in NOS activity in castrated rats was accompanied by an increase in the number of neuronal NOS؉ cells determined immunohistochemically, whereas androgen treatment prevented this increase. The changes in NOS؉ neurons correlated with the changes in the number of AR؉ cells to a degree. Overlap of AR in NOS؉ cells was not present in the regions of the hypothalamus analyzed. These results indicate that testosterone or, most likely, its metabolite DHT down-regulates NOS activity, mRNA expression or stabilization, and the number of neuronal NOS؉ neurons. N itric oxide (NO) synthesized by the enzyme neuronal nitric oxide synthase (nNOS) plays an important role in many brain functions. These include effects on long-term potentiation (1), gonadotropin secretion (2-10), and sexual behavior (11)(12)(13). NO functions as a neurotransmitter (2-10) and nNOS is present near gonadotropin-releasing hormone terminals (14) and in regions of the brain that appear to regulate emotional behaviors (15, 16). Estradiol (E 2 ) up-regulates endothelial NOS in endothelial cells (17,18) and nNOS in the brain (18-21), and many of the actions of E 2 on the brain have been suggested to be through a NO-mediated mechanism (2-10, 18-22). Administration of E 2 and progesterone to ovariectomized rats leads to an increase in the luteinizing hormone surge, the magnitude of which is significantly attenuated after administration of nNOS antisense oligonucleotides into the third ventricle (22), suggesting an intermediary role of NO in modulating some actions of E 2 by up-regulating nNOS activity.However, the actions of androgens on NOS activity in the brain are not clear. Male mice with targeted disruption of the nNOS gene (nNOS Ϫ ) display a great increase in aggressive behavior and excessive and inappropriate mounting behavior (11). Because androgens also promote aggressive behavior (23, 24), facilitate mounting behavior (25, 26), and decrease gonadotropin release (27, 28), we wanted to elucidate whether the androgens, testosterone (T) and its 5␣ reduced metabolite, dihydrotestosterone (DHT), modulate nNOS activity in the brain and the potential mechanism(s) by which this may occur.Therefore, sex-related and region-specific distributions of NOS in select regions of the rat brain of both sexes were assessed as ...

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

“…In female, but not male brain, loss of NO through targeted gene deletion or pharmacological inhibition increases ischemic damage and renders neurons insensitive to the neuroprotection ordinarily provided by an important female sex steroid, 17b estradiol. These observations are not explained by compensatory upregulation of other NOS isoforms as can occur with hormone exposure, (Singh et al, 2000;Hayashi et al, 1997;Garcia-Duran et al, 1999;Dimmeler et al, 2000;Grohe et al, 2004) preservation of ischemic CBF. Second, PARP-1's importance in ischemic neuronal death is also sexually dimorphic.…”

Sex differences in angiotensin II- induced hypertension

“…Many of the actions of E2 on the brain have been suggested to be through an NOmediated mechanism (54,55). Castration increases and androgen treatment decreases nNOS activity in the brain (56). Immunohistochemical studies from our laboratory also revealed co-localization of nNOS and ERα in the subfornical organ of female mice (57).…”

Gender-related differences in the effects of nitric oxide donors on neuroleptic-induced catalepsy in mice

“…However, similar studies in mice, especially involving the striatum, are lacking. It should be mentioned that the literature on this topic is rather confusing; for instance, studies focusing on the neuroendocrine system have shown that the activity of neuronal NOS is increased by estrogen (36) and decreased by androgens (37). In any case, if these influences were present at the level of the nigrostriatal system, they could possibly account for the differential sensitivity of female mice to the 'anticataleptic' effect of NO donors.…”