Effects of nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats

Rationale: Nitric oxide synthase (NOS) inhibitors may modulate the discriminative stimulus effects of cocaine because they alter dopamine (DA) release. Objectives: The effects of the NOS inhibitors N(G)nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) were examined in experiments designed to better understand the mechanisms that may underlie the interactions between NOS inhibitors and cocaine. Methods: Rats were trained to discriminate 10 mg/kg cocaine from saline, and then substitution and pretreatment tests with L-NAME and 7-NI were conducted. To determine if the combined effects of NOS inhibitors and cocaine might be related to DA mechanisms and/or to N-methyl-D-aspartate (NMDA) receptor mechanisms, substitution tests with other indirect DA agonists and NMDA antagonists were carried out in the presence and absence of L-NAME. In addition, the roles of the D-1 and D-2 families of DA receptors in mediating the cocaine-altering effects of L-NAME and 7-NI were examined in antagonism tests using SCH 23390 and haloperidol, respectively. Results: The results demonstrated that neither NOS inhibitor alone substituted for the 10 mg/kg cocaine training dose, but when given as a pretreatment, 100 mg/kg L-NAME as well as 10 mg/kg 7-NI enhanced the discriminative stimulus and rate-decreasing effects of cocaine. L-NAME pretreatment also enhanced the potency of (+)-amphetamine and GBR 12909, but not MK-801, phencyclidine, or NPC 17742, for producing discriminative stimulus and rate-decreasing effects in substitution tests. Further testing showed that the cocaine-enhancing effects of L-NAME and 7-NI were attenuated by doses of haloperidol and SCH 23390 that minimally altered the effects of cocaine alone. Conclusions: These findings suggest that L-NAME and 7-NI may increase the potency of cocaine and other indirect DA agonists through a central mechanism whereby DA neurotransmission is directly enhanced by NOS inhibition.