Associative learning is enhanced by selective neuronal nitric oxide synthase inhibitors and retarded by a nitric oxide donor in the rabbit

Abstract.

Rationale: Previous studies had reported that the nitric oxide (NO) donor, sodium nitroprusside (SNP), retarded and the non-specific NO synthase (NOS) inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME), enhanced acquisition of classically conditioned responses (CRs). These effects of IV SNP and IP l-NAME on CR acquisition occurred in the absence of any effect on non-associative processes or performance variables and at a time when there were no alterations in blood pressure or heart rate. Objectives: In this study, we examined whether the changes in associative learning produced by l-NAME and SNP were due to their central effects on NO content of brain. To this end, we examined the effects of the selective neuronal NOS inhibitors 7-nitroindazole (7-NI) and AR-R 17477 and the effects of central (ICV) administration of the NO donor SNP on learning. Methods: Effects of drugs on CR acquisition were determined during classical conditioning of the rabbit's nictitating membrane (NM) response. Explicitly unpaired presentations of conditioned stimuli (CSs) and unconditioned stimuli (USs) were employed to measure non-associative levels of responding and unconditioned response (UR) topography. Results: The SC injection of 7-NI and AR-R 17477 significantly enhanced associative learning while ICV administration of SNP significantly retarded learning. Conclusion: Production of NO within the brain by neuronal NOS normally acts to retard associative learning presumably by decreasing excitability within neuronal circuits involved in the acquisition of the classically conditioned NM reflex.