Preclinical profile of the mixed 5-HT1A/5-HT2A receptor antagonist S 21,357

• Published in: Pharmacology, biochemistry and behavior Vol. 54; no. 2; p. 509
• Main Authors: Griebel, G, Blanchard, D C, Rettori, M C, Guardiola-Lemaître, B, Blanchard, R J
• Format: Journal Article
• Language: English
• Published: United States 01.06.1996
• Subjects: Adenylyl Cyclases - metabolism; Animals; Anti-Anxiety Agents - pharmacology; Avoidance Learning - drug effects; Behavior, Animal - drug effects; Benzothiazoles; Brain Chemistry - drug effects; Dose-Response Relationship, Drug; Electrophysiology; In Vitro Techniques; Male; Mice; Motor Activity - drug effects; Piperidines - pharmacology; Raphe Nuclei - cytology; Raphe Nuclei - drug effects; Raphe Nuclei - physiology; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Serotonin Antagonists - pharmacology; Synaptic Transmission - drug effects; Thiazoles - pharmacology
• ISSN: 0091-3057
• DOI: 10.1016/0091-3057(95)02215-5

This study evaluated the pharmacological and behavioral effects of S 21,357, a drug with high affinity for both 5-HT1A and 5-HT2A receptors. The drug behaved as antagonist at both 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, as it prevented the inhibitory effect of lesopitron on the electrical discharge of the dorsal raphé nucleus (DRN) 5-HT neurons and the activity of forskolin-stimulated adenylate cyclase in hippocampal homogenates. In addition, S 21,357 (4 and 128 mg/kg, PO) inhibited 5-HTP-induced head-twitch responses in mice, indicating that it possesses 5-HT2A antagonistic properties. In a test battery designed to assess defensive behaviors of Swiss-Webster mice to the presence of, or situations associated with, a natural threat stimulus (i.e., rat), S 21,357 (0.12-2 mg/kg, IP) reduced contextual defense reactions after the rat was removed, risk assessment activities when the subject was chased, and finally, defensive attack behavior. These behavioral changes are consistent with fear/anxiety reduction. Furthermore, the drug strongly reduced flight reactions in response to the approaching rat. This last finding, taken together with recent results with panic-modulating drugs, suggest that S 21,357 may have potential efficacy against panic attack. Finally, our results suggest that compounds sharing high affinities for both 5-HT1A and 5-HT2A receptors may directly or synergistically increase the range of defensive behaviors affected.