ROLE OF NITRIC-OXIDE IN THE DEVELOPMENT OF TOLERANCE AND SENSITIZATION TO BEHAVIORAL-EFFECTS OF PHENCYCLIDINE IN MICE

1 To determine whether nitric oxide (NO) was involved in tolerance and sensitization to the effects of phencyclidine (PCP), we examined NO s ynthase activity and the number of NADPH-diaphorase (NADPH-d)-positive cells in discrete brain regions of saline-, acute PCP- and repeated P CP-treated mice. We also investigated the effects of a NO synthase inh ibitor, N-G-nitro-L-arginine methyl ester (L-NAME), on the behavioural changes induced by repeated PCP treatment in mice. 2 Acute PCP (1, 3, and 10 mg kg(-1), s.c.) treatment induced dose-dependent hyperlocomot ion, motor incoordination and stereotyped behaviours, consisting of sn iffing, head movement and ataxia in mice. 3 In mice treated repeatedly with PCP (1, 3, and 10 mg kg(-1) day(-1)), s.c., once a dal for 14 da ys), the sniffing, head movement. ataxia and motor incoordination indu ced by PCP were attenuated (indicating the development of tolerance to these behaviours), whereas the hyperlocomotion induced by PCP was pot entiated (indicating the development of sensitization to hyperlocomoti on). The development of tolerance and sensitization to PCP-induced beh aviours in the repeated PCP-treated mice was more marked at the dose o f 10 mg kg(-1) day(-1)) than at other doses. 4 NO synthase activity in the cerebral cortex and cerebellum, but not in the striatum and hippo campus, was significantly decreased by acute PCP (10 mg kg(-1)) treatm ent in comparison with saline treatment, and such changes in activity in the cerebral cortex and cerebellum were reversed by repeated PCP tr eatment (10 mg kg(-1) day(-1)). 5 The number of neurones containing NA DPH-d reactivity in the cerebral cortex, nucleus accumbens, and striat um of acute and repealed PCP-treated mice showed no change in comparis on with saline treated mice. 6 Tolerance to PCP (10 mg kg(-1) day(-1)) -induced ataxia and motor incoordination was significantly attenuated by combined treatment with L-NAME (50 mg kg(-1) day(-1) i.p.). 7 Sensi tization to PCP-induced hyperlocomotion was further enhanced by combin ed treatment with L-NAME (50 mg kg(-1) day(-1)). However, N-G-nitro-D- arginine methyl ester (D-NAME. 50 mg kg(-1) day(-1), i.p.), a less act ive enantiomer of L-NAME, had no effect, suggesting a stereospecific m echanism. 8 The PCP-induced behaviours in animals that had exhibited t olerance and sensitization to PCP (10 mg kg(-1) day(-1)) were not infl uenced by acute L-NAME (5 and 50 mg kg(-1), i.p.) or D-NAME (50 mg kg( -1), i.p.) treatment. 9 These results suggest that NO may play an impo rtant role in the development, but nor in the maintenance, of toleranc e and sensitization to the effects of PCP in mice.