Carnosine is co-localized in glutamergic terminals and may be released together with glutamate. Carnosine is a selective inhibitor of NO-dependent activation of guanylate cyclase (GC). Nitric oxide (NO) is known to affect the synaptic plasticity in the brain via the cGMP-dependent protein kinase pathway. Nitric oxide can be released from its donor sodium nitroprusside (SNP), and GC activity might be stimulated by SNP in a concentration-dependent manner. In our previous study, we found that microinfusions of 10 mg carnosine decreased long-term potentiation (LTP) in the rat dentate gyrus in vivo; it was supposed that carnosine decreased LTP via inhibition of soluble GC. We aimed at examination of interaction between SNP and carnosine in the course of hippocampal-dependent learning in rats. Effects of infusions of artificial cerebrospinal fluid (aCSF), 0.9 mu g SNP, 10 mu g carnosine, and 10 mu g carnosine + 0.9 mu g SNP into the dentate gyrus of rats were compared. The medial perforant path was subjected to high-frequency stimulation (HFS, 100 sec(-1), 1 sec). While the SNP-infused group of animals demonstrated higher population spike (PS) amplitudes than the carnosine and carnosine + SNP groups, there was no significant difference between the SNP and aCSF (control) groups. Thus, SNP induced more intense LTP, while carnosine reduced this process. When these drugs were administered in combination, PS amplitudes reduced with carnosine were partly increased with SNP. This increment was insignificant at the SNP dose used. Therefore, SNP did not prevent an inhibitory effect of carnosine on LTP. We consider that the inhibitory effect of carnosine in relatively low doses cannot be explained by its inhibitory influence on soluble GC.