Involvement of raphe-hippocampal serotonergic and septo-hippocampal cholinergic mechanisms in the penile erection induced by FR121196, a putative cognitive enhancer.

FR121196 (N-[4-acetyl-1-piperazinyl]-4-fluorobenzenesulfonamide), a putative cognitive enhancer, induced penile erection in naive rats; the dose-response curve was bell-shaped with the maximum response obtained at the dose of 3.2 mg/kg. The response to FR121196 was abolished in rats treated with intra-raphe injections of 5,7-dihydroxytryptamine or systemic injections of p-chlorphenylalanine (150 mg/kg, i.p. for three consecutive days) as well as in rats with electrolytic medial-septum lesion or surgical fimbria-fornix lesion. In addition, the penile erection induced by FR121196 (3.2 mg/kg) was dose-dependently attenuated by pindolol (0.1-3.2 mg/kg), a serotonin (5-HT)1 antagonist with beta-antagonistic activity, but not by metoprolol, a selective beta=antagonist. The inhibitory activity was shared by ICS205-930, a 5-HT3 antagonist, but not by ketanserin, a 5-HT2 antagonist, or sulpiride, a dopamine D2 antagonist. Scopolamine (0.032-1 mg/kg), but not methyl-scopolamine (0.032-1 mg/kg), also attenuated the penile erection induced by FR121196. Neurochemical analysis revealed that intraperitoneal injection of FR121196 significantly elevated the levels of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and that raphe-lesion significantly reduced both 5-HT and 5-HIAA levels without affecting choline-acetyltransferase activity in all cortical and subcortical regions examined. It is thus postulated that FR121196 facilitates the raphe-hippocampal serotonergic pathway resulting in an activation of the septo-hippocampal cholinergic pathway and finally induces the penile erectile response.