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 cocai ne-induced ambulation-accelerating activity and the L-NNA administered before and during the chronic injection of cocaine in mice blocked th e development of reverse tolerance to the ambulation-accelerating effe ct of cocaine (15 mg/kg). Mice were rendered reverse tolerant to cocai ne by a s.c. injection of cocaine (15 mg/kg) once daily for 6 days. Th e development of reverse tolerance was evidenced by an increased respo nse to cocaine, and the inhibition of reverse tolerance was evidenced by a lesser ambulatory response. L-NNA (5 and 10 mg/kg) administered b efore and during cocaine conditioning inhibited the development of coc aine-induced conditioned place preference (CPP). Cocaine-induced CPP w as developed by an injection of cocaine (15 mg/kg) once every other da y 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 evidence d by an enhanced ambulatory activity to apomorphine (2 mg/kg). Therefo re, the present results suggest that these dopaminergic behaviors of c ocaine may be mediated partially via the activation of the nitric oxid e system and that the enhancement of postsynaptic dopamine receptor se nsitivity may be an underlying common mechanism that mediates the coca ine-induced dopaminergic behaviors such as reverse tolerance and CPP.