Pharmacological modulators of nitric oxide signaling and contextual fear conditioning in mice

Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is a retrograde neuronal messenger that participates in synaptic plasticity, including late-phase long-term potentiation (LTP) and long-term memory (LTM) formation. Our recent studies have shown that nNOS knockout (KO) mice have a severe deficit in contextual fear conditioning compared to wild type (WT) counterparts (Kelley et al. 2009). Given the role of the nNOS gene in fear conditioning, we investigated whether systemic administration of modulators of NO signaling affect the formation of contextual and cued fear memories and the effects of these modulators on cyclic 3'5'-guanosine monophosphate (cGMP) levels in the hippocampus and amygdala. The preferential nNOS inhibitor S-methyl-l-thiocitrulline (SMTC; 10-200 mg/kg) was administered (IP) to WT mice, and the NO donor molsidomine (10 mg/kg) was administered (IP) to nNOS KO mice either 30 min pretraining or immediately posttraining. Pretraining SMTC administration to WT mice impaired both short- and long-term memories of contextual (36% inhibition) but not cued fear conditioning. Pretraining molsidomine administration to nNOS KO mice improved their deficit in short- and long-term memories of contextual fear conditioning (46% increase). Posttraining drug administration had no effect on WT and nNOS KO mice. The systemic administration of SMTC dose-dependently decreased cGMP concentrations down to 25% of control, while molsidomine increased cGMP concentration (three- and five-fold) in amygdala and hippocampus, respectively. These findings suggest that neuronal NO and its downstream second messenger cGMP are important for acquisition and subsequent consolidation of LTM of contextual fear conditioning.