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

A selective inhibitor of neuronal nitric oxide synthase, AR-R 17477, counteracts behavioral effects of the psychosis-inducing drug phencyclidine in rats. AR-R 17477 (0.5, 1, and 5 mg/kg) reduced phencyclidine-induced hyperactivity, and 1 mg/kg reversed phencyclidine-induced deficits in prepulse inhibition of the startle response, a measure of sensorimotor gating. Higher doses were less effective. The compound did not alter normal behavior or affect the actions of d-amphetamine. Unlike the non-specific inhibitor L-NAME, AR-R 17477 did not change blood pressure or heart rate. The findings indicate that blocking the neuronal isoform of nitric oxide synthase specifically counteracts phencyclidine's effects, likely without cardiovascular side effects.

Study at a glance

Abstract

We have previously shown that the non-specific nitric oxide synthase inhibitor L-NAME blocks the behavioural effects of phencyclidine, but not d-amphetamine. To characterise the specificity of these effects, we used the specific neuronal nitric oxide synthase inhibitor AR-R 17477 in two rat models of psychosis: the prepulse inhibition of the acoustic startle response and locomotor activity. In biochemical assays, AR-R 17477 was shown to be selective for the neuronal nitric oxide synthase isoform. Test drugs were given subcutaneously. AR-R 17477 (0.5, 1 and 5 mg/kg) antagonised phencyclidine-induced hyperlocomotion, while higher doses (10 and 20 mg/kg) were less efficaceous. AR-R 17477 (1 mg/kg) antagonised phencyclidine-induced deficit in prepulse inhibition of the acoustic startle response, while a higher dose (15 mg/kg) was less active. AR-R 17477 did not affect startle amplitude or prepulse inhibition of the acoustic startle response, did not affect locomotion and did not induce any changes in gross behaviour (sniffing, rearing, etc.) as determined in a subjective observation study. AR-R 17477 (1 mg/kg) did not alter the effect of d-amphetamine in prepulse inhibition of the acoustic startle response. Using radiotelemetry in rats, L-NAME (10 mg/kg subcutaneously) increased blood pressure and decreased heart rate while AR-R 17477 (10 mg/kg) did not have any significant effect on these parameters. The results show that a neuronal nitric oxide synthase inhibitor antagonises the effects of phencyclidine on prepulse inhibition of the acoustic startle response and locomotor activity, without exhibiting significant behavioural effects of its own and suggest that our earlier results with L-NAME depended upon an inhibition of neuronal nitric oxide synthase and not on an inhibition of endothelial nitric oxide synthase or inducible nitric oxide synthase. The observed effects are unlikely to be related to an effect on cardiovascular function.