Nitric oxide mediation of cocaine-induced dopaminergic behaviors: ambulation-accelerating activity, reverse tolerance and conditioned place preference in mice.

Intraperitoneal administration of N omega-nitro-L-arginine (L-NNA, 7.5 and 15 mg/kg), a nitric oxide synthase inhibitor, inhibited the cocaine-induced ambulation-accelerating activity and the L-NNA administered before and during the chronic injection of cocaine in mice blocked the development of reverse tolerance to the ambulation-accelerating effect of cocaine (15 mg/kg). Mice were rendered reverse tolerant to cocaine by a s.c. injection of cocaine (15 mg/kg) once daily for 6 days. The development of reverse tolerance was evidenced by an increased response to cocaine, and the inhibition of reverse tolerance was evidenced by a lesser ambulatory response. L-NNA (5 and 10 mg/kg) administered before and during cocaine conditioning inhibited the development of cocaine-induced conditioned place preference (CPP). Cocaine-induced CPP was developed by an injection of cocaine (15 mg/kg) once every other day for a 6-day period (3 times). The increase in postsynaptic dopamine receptor sensitivity was also blocked by L-NNA in both cocaine-induced reverse tolerant and CPP mice. The dopamine receptor sensitivity was increased in cocaine-induced reverse tolerant and CPP mice as evidenced by an enhanced ambulatory activity to apomorphine (2 mg/kg). Therefore, the present results suggest that these dopaminergic behaviors of cocaine may be mediated partially via the activation of the nitric oxide system and that the enhancement of postsynaptic dopamine receptor sensitivity may be an underlying common mechanism that mediates the cocaine-induced dopaminergic behaviors such as reverse tolerance and CPP.