The peptides, histogranin and [Ser1]histogranin, were recently shown to modulate NMDA receptor function. In the present study, the effects of intracerebroventricular (i.c.v.) administration of [Ser1]histogranin and of the histogranin receptor antagonist, histogranin-(1-10), were examined on step-down type passive avoidance learning in mice. [Ser1]Histogranin (30-60 nmol) impaired retention, after post-training administration, but not when it was administered just prior to the retention assay. Histogranin-(1-10) (60 nmol) facilitated learning during training, without affecting retention. Co-administration of histogranin-(1-10) with [Ser1]histogranin (60 nmol each) led to a significant prevention of [Ser1]histogranin-induced learning impairment. These results indicate that [Ser1]histogranin impairs passive avoidance learning according to the pattern of NMDA receptor antagonists and involving specific histogranin sites.