Corticosteroid actions at the brain can modulate neural function and behavioral processes. Classic corticosteroid effects are mediated through intracellular receptors which act primarily by regulation of DNA transcription. However, an alternative nongenomic mechanism mediating rapid corticosteroid actions by effecting the neuronal membrane has also been proposed. We have recently described a behavioral model of rapid corticosterone effects fulfilling criteria for considering nongenomic steroid actions, such as resistance to protein synthesis inhibition and to blockage of intracellular receptors through the use of specific receptor antagonists. The model consists of a rapid increase induced by a corticosterone injection (within 7.5 min of a systemic injection) on the locomotor response displayed by rats in a novel environment. In the present study, we aimed to study whether the gas molecule nitric oxide might be included among the effector systems involved in such rapid corticosterone effect. The administration of nitric oxide synthase inhibitors, given either systemically [NG-nitro-L-arginine methyl ester (L-NAME), 30 mg/kg body weight, i.p.] or centrally [N-nitro-L-arginine (N-Arg), 10 microliters of a 10-mM solution i.c.v.], prevented the increase in locomotion induced by corticosterone (Cort, 5 mg/kg body weight i.p.). Specificity of this effect was supported by the ability of the nitric oxide precursor L-arginine (L-Arg, 350 mg/kg body weight i.p.) to inhibit L-NAME action. This effect of nitric oxide synthase inhibition on steroid effects was shown to be task-specific, since L-NAME failed to influence another rapid behavioral effect of corticosterone, the suppression of the acoustic startle response. Under our experimental conditions, corticosterone failed to affect peripheral blood pressure, discarding that the antagonistic effect of nitric oxide synthase inhibition on the corticosterone-induced effect in locomotion were related to a peripheral action at the cardiovascular level. Therefore, these data suggest a role for nitric oxide on the neurochemical mechanisms elicited by corticosterone to rapidly enhance locomotion in a novel situation.