Abstract

Repeated intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking, there has been great interest in elucidating the mechanisms underlying both the development and expression of behavioral sensitization. An accumulation of data from studies of stimulant-induced locomotor activity and stereotypy has implicated excitory amino acids and nitric oxide(NO) in the development and expression of behavioral sensitization. The present study examined the effects of non-competitive NMDA receptor antagonist, MK-801 and nitric oxide synthase inhibitor, N^(G)-nitro-L-arginine methyl ester(L-NAME) on behavioral sensitization induced by repeated administration of nicotine. Repeated administration of nicotine(0.4mg/kg, s.c.) twice daily for consecutive days result in an augmentation of the locomotor and stereotypy activating effect of nicotine(0.4mg/kg, s.c.) challenged 3 days after last injection. Administration of the NMDA receptor antagonist, MK-801(0.3mg/kg, i.p.) and nitric oxide inhibitor, L-NAME(75mg/kg, i.p.), before daily nicotine injections attenuated the development of behavioral sensitization to subsequent nicotine challenge. Whereas, administration of MK-801(0.3mg/kg, i.p.) and L-NAME (75mg/kg, i.p.) twice daily for withdrawal periods of 3 days ensuing after chronic nicotine treatment periods of 7 days results in different consequences. MK-801 attenuated the expression of behavioral sensitization to nicotine, but L-NAME did not significantly reduce activity scores. These results suggest that NMDA receptor is involved in the expression as well as development of behavioral sensitization to nicotine, and that nitric oxide synthesis is involved in the development of behavioral sensitization to nicotine but not critically involved in expression of behavioral sensitization to nicotine. However, nitric oxide synthesis may have a modulatory role in expression of behavioral sensitization to nicotine. In addition, behavioral sensitization is thought to be mediated by changes in central dopaminergic systems. Accordingly, NMDA receptor and nitric oxide may influence on these changes similar to proposed role of nitric oxide and NMDA receptor in cellular adaptation and learning.