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Normal Responses to Restraint Stress in Mice Lacking the Gene for Neuronal Nitric Oxide Synthase

CHANTAL M. SOTTAS

MICHAEL HOLMES

PING ZHOU

COSTANTINO IADECOLA

DIANNE O. HARDY

REN-SHAN GE^,

MATTHEW P. HARDY^,||

From the ^* Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel; the Center for Biomedical Research, Population Council and the Rockefeller University, New York, New York; the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York; and the Institute of Neuroendocrinology and the 2nd Affiliated Hospital of Wenzhou Medical College, Wenzhou, People's Republic of China.

Correspondence to: Dr Ben Avi Weissman, Department of Pharmacology, IIBR, PO Box 19, Ness Ziona 74100, Israel (e-mail: aviw{at}iibr.gov.il); or Dr Ren-Shan Ge, Population Council, 1230 York Ave, New York, NY 10065 (e-mail: rge{at}popcbr.rockefeller.edu).

Abstract

The hormonal changes associated with immobilization stress (IMO) include a swift increase in corticosterone (CORT) concentration and a decrease in circulating testosterone (T) levels. There is evidence that the production of the short-lived neuromodulator nitric oxide (NO) is increased during stress in various tissues, including the brain. NO also suppresses the biosynthesis of T. Both the inducible and the neuronal isoforms of NO synthase (iNOS and nNOS, respectively) have been implicated in this suppression, but the evidence has not been conclusive. We used adult wild-type (WT) and nNOS knockout male mice (nNOS–/–) to assess the respective roles of CORT and nNOS-derived NO in stress mediated inhibition of T production. Animals were assigned to either basal control or 3-hour IMO groups. No difference in basal plasma and testicular T levels were observed between WT and nNOS–/–, although testicular weights of mutant mice were slightly lower compared to WT animals. The plasma contents of luteinizing hormone (LH) and CORT in unstressed mice of both genotypes were similar. Exposure to 3 hours of IMO increased plasma CORT and decreased T concentrations in mice of both genotypes. However, comparable levels of plasma LH and testicular nitrite and nitrate (NOx), NO stable metabolites, were detected in control and stressed WT and nNOS–/– mice. Adrenal concentrations of NOx declined after IMO, but the reduction was not statistically significant. These findings implicate CORT rather than NO generated by nNOS in the rapid stress-induced suppression of circulating T.

     Key words: nNOS-null mice, testosterone, glucocorticoid, androgen