Abstract
This study evaluated the pharmacological and behavioral effects of S 21357, a drug with high affinity for both 5-HT 1A and 5-HT 2A receptors. The drug behaved as antagonist at both 5-HT 1A autoreceptors and postsynaptic 5-HT 1A 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 21357 (4 and 128 mg/kg, PO) inhibited 5-HTP-induced head-twitch responses in mice, indicating that it possesses 5-HT 2A 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 21357 (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 21357 may have potential efficacy against panic attack. Finally, our results suggest that compounds sharing high affinities for both 5-HT 1A and 5-HT 2A receptors may directly or synergistically increase the range of defensive behaviors affected.
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