tropisetron and 4-chlorophenylalanine-methyl-ester

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.

Topics: Animals; Cholinergic Antagonists; Dopamine Antagonists; Fenclonine; Hippocampus; Indoles; Ketanserin; Male; Nootropic Agents; Penile Erection; Pindolol; Piperazines; Raphe Nuclei; Rats; Rats, Inbred F344; Receptors, Cholinergic; Septum Pellucidum; Serotonin; Serotonin Antagonists; Sulfonamides; Tropisetron

Tiapride dose-dependently attenuated the biphasic nociceptive responses induced by s.c. injection of formalin to the hindpaw of mice, and its activity on the first (ED50 = 110 mg/kg p.o.) and the second (ED50 = 32.0 mg/kg p.o.) phases paralleled that on the nociceptive response to intrathecal injection of substance P (ED50 = 190 mg/kg p.o.) and somatostatin (ED50 = 56.0 mg/kg p.o.), respectively. Moreover, a similar antinociceptive activity was observed in streptozotocin-induced diabetic or genetically diabetic (db/db) mice. The effects of tiapride (100 mg/kg p.o.) on both phases of the formalin test in normal mice were abolished by pretreatment with p-chlorophenylalanine (800 x 2 mg/kg p.o.), a 5-hydroxytryptamine (5-HT) depletor, or pindolol (1 mg/kg i.p.), a 5-HT1 antagonist, but were scarcely affected by 3-tropanyl-indole-3-carboxylate, a 5-HT3 antagonist. Ketanserin (1 mg/kg i.p.), a 5-HT2 antagonist, attenuated the effect of tiapride on the second phase but not on the first phase. This study on the antinociceptive mechanism of action of tiapride (that blocks painful neuropathy in diabetic patients) has led us to hypothesize that the drug attenuates pain transmission through an indirect activation of central 5-HT1 and 5-HT2 receptors.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dopamine Antagonists; Female; Fenclonine; Indoles; Injections, Spinal; Ketanserin; Male; Mice; Nociceptors; Pain; Pain Measurement; Pindolol; Serotonin; Serotonin Antagonists; Somatostatin; Substance P; Synaptic Transmission; Tiapamil Hydrochloride; Tropisetron