The neuronal selective nitric oxide inhibitor AR-R 17477, blocks some effects of phencyclidine, while having no observable behavioural effects when given alone

We have previously shown that the non-specific nitric oxide synthase inhibi tor L-NAME blocks the behavioural effects of phencyclidine, but not d-amphe tamine. To characterise the specificity of these effects, we used the speci fic neuronal nitric oxide synthase inhibitor AR-R 17477 in two rat models o f psychosis: the prepulse inhibition of the acoustic startle response and l ocomotor activity. In biochemical assays, AR-R 17477 was shown to be select ive for the neuronal nitric oxide synthase isoform. Test drugs were given s ubcutaneously. AR-R 17477 (0.5, 1 and 5 mg/kg) antagonised phencyclidine-in duced hyperlocomotion, while higher doses (10 and 20 mg/kg) were less effic aceous. AR-R 17477 (1 mg/kg) antagonised phencyclidine-induced deficit in p repulse inhibition of the acoustic startle response, while a higher dose (1 5 mg/kg) was less active. AR-R 17477 did not affect startle amplitude or pr epulse inhibition of the acoustic startle response, did not effect locomoti on and did not induce any changes in gross behaviour (sniffing, rearing, et c.) as determined in a subjective observation study. AR-R 17477 (1 mg/kg) d id not alter the effect of d-amphetamine in prepulse inhibition of the acou stic startle response. Using radiotelemetry in rats, L-NAME (ID mg/kg subcu taneously) increased blood pressure and decreased heart rate while AR-R 174 77 (10 mg/kg) did not have any significant effect on these parameters. The results show that a neuronal nitric oxide synthase inhibitor antagonises th e effects of phencyclidine on prepulse inhibition of the acoustic startle r esponse and locomotor activity, without exhibiting significant behavioural effects of its own and suggest that our earlier results with L-NAME depende d upon an inhibition of neuronal nitric oxide synthase and not on an inhibi tion of endothelial nitric oxide synthase or inducible nitric oxide synthas e. The observed effects are unlikely to be related to an effect on cardiova scular function.