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 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.
Johansson
C
C
Preclinical Research and Development, Astra Arcus AB, Södertälje, Sweden.
Deveney
A M
AM
Reif
D
D
Jackson
D M
DM
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006213:Hallucinogens / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects
C102136:ARL 17477; D000578:Amidines; D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D019001:Nitric Oxide Synthase; D010622:Phencyclidine; D019331:NG-Nitroarginine Methyl Ester