PRECLINICAL PROFILE OF THE MIXED 5-HT1A 5-HT2A RECEPTOR ANTAGONIST S21357/

This study evaluated the pharmacological and behavioral effects of S 2 1357, a drug with high affinity for both 5-HT1A and 5-HT2A receptors. The drug behaved as antagonist at both 5-HT1A autoreceptors and postsy naptic 5-HT1A receptors, as it prevented the inhibitory effect of leso pitron on the electrical discharge of the dorsal raphe nucleus (DRN) 5 -HT neurons and the activity of forskolin-stimulated adenylate cyclase in hippocampal homogenates. In addition, S 21357 (4 and 128 mg/kg, PO ) inhibited 5-HTP-induced head-twitch responses in mice. indicating th at it possesses 5-HT2A antagonistic properties. In a test battery desi gned to assess defensive behaviors of Swiss-Webster mice to the presen ce of, or situations associated with, a natural threat stimulus (i.e., rat), S 21357 (0.12-2 mg/kg, IP) reduced contextual defense reactions after the rat was removed, risk assessment activities when the subjec t 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 21357 may have potential efficacy aga inst 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.