Sex-influence of nicotine and nitric oxide on motor coordination and anxiety-related neurophysiological responses

Rationale Nitric oxide (NO) is a messenger synthesized in both the neuronal and glial populations by nitric oxide synthase type 1 (NOS1). Nicotine regulates NO production in a sex-dependent manner, both molecules being involved in motor function. Objective The present study evaluates sex differences in motor coordination, general movement, and anxiety-related responses resulting from both constant and continuous nicotine treatment and the genetic depletion of NOS1 activity. Methods Male and female mice were analyzed with the open-field and the rotarod tests. To understand the role of NO, knockout mice for NOS1 (NOS1−/−) were analyzed. Nicotine was administered continuously at a dose of 24 mg/kg/day via osmotic mini-pumps over 14 days because the behavioral effects elicited are similar to those observed with discontinuous administration. Results Data analyses revealed noteworthy sex differences derived from NOS1 depletion. Control NOS1−/− males exhibited an exacerbated anxiety-related response in relation to control NOS1−/− females and control wild-type (WT) males; these differences disappeared in the nicotine-administered NOS1−/− males. Additionally, nicotine administration differentially affected the horizontal movements of NOS1−/− females with respect to WT animals. NO depletion affected male but not female motor coordination improvement along the test days. However, the drug affected female motor coordination only at the end of the administration period. Conclusions We show for the first time that NO affects motor and anxiety behaviors in a sex-dependent manner. Moreover, the behavioral effects of constant nicotine administration are dimorphic and dependent on NO production.