Preclinical profile of the mixed 5-HT1A/5-HT2A receptor antagonist S 21,357.
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.
Griebel
G
G
Békésy Laboratory of Neurobiology, John A. Burns School of Medicine, University of Hawaii, Honolulu 96822, USA.
Blanchard
D C
DC
Rettori
M C
MC
Guardiola-Lemaître
B
B
Blanchard
R J
RJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D052160:Benzothiazoles; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D052160:Benzothiazoles; D010880:Piperidines; D011985:Receptors, Serotonin; C103737:S 21357; D012702:Serotonin Antagonists; D013844:Thiazoles; D000262:Adenylyl Cyclases