Effects of nitric oxide synthase inhibitors on cocaine sensitization.

Behavioral sensitization to cocaine was tested for in rats pretreated with a nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) or 7-nitro indazole (7-NI). A 5-day pre-exposure to once daily cocaine (15 mg/kg, i.p.) injections yielded sensitization to cocaine (15 mg/kg)-induced behavioral activation. Pretreatment injections of L-NAME (100 mg/kg) or 7-NI (30 mg/kg), administered 30 min before each cocaine pre-exposure injection, acutely inhibited cocaine-induced behavioral activation. No sensitization was found after L-NAME pretreatment in a protocol with a 3-day withdrawal between pre-exposure and test cocaine injections. With a 10-day withdrawal period, cocaine sensitization was prevented by L-NAME or 7-NI pretreatment. These results after a 10-day withdrawal are unlikely to arise from deficient brain NO synthase activity on the test day. Instead, these findings suggest a role for NO in mechanisms underlying the development of cocaine sensitization. We conclude that NO participates in both the development of sensitization as well as the expression of cocaine-induced behavior in previously drug-naive animals.