Effect of chronic serotonin-2 receptor agonist or antagonist administration on serotonin-1A receptor sensitivity

We have investigated the effect of 5-HT2 receptor agonist or antagonist administration on postsynaptic 5-HT1A receptor sensitivity assessed by two behavioral measures, reciprocal forepaw trending or hypothermia induced by acute injection of the 5-HT1A receptor agonist 8-OH-DPAT. The effectiveness of these drug treatments to downregulate 5-HT2A receptors was confirmed by measuring the binding of [H-3]-ketanserin in cortical homogenates, because all of these drug treatments have been shown to result in the downregulation of 5-HT2A receptor sites. Acute or chronic treatment rats with the 5-HT2 receptor antagonist mianserin, or chronic administration of the 5-HT2A receptor antagonist ketanserin, did not alter 8-OH-DPAT-induced hypothermia or forepaw treading. These data indicate that downregulation of 5-HT2A receptors is not sufficient to alter these postsynaptic 5-HT1A receptor-mediated responses. Chronic treatment of rats with the 5-HT2 receptor agonist DOI, however, resulted in the attenuation of both 5-HT1A receptor-mediated responses measured in separate experimental groups. The apparent desensitization of 5-HT1A receptors following chronic DOI treatment was not accompanied by a change in either the number or affinity of 5-HT1A receptor sites as measured by the binding of [H-3]-8-OH-DPAT in hippocampal homogenates. Chronic activation of 5-HT2 receptors may be one mechanism by which the sensitivity postsynaptic 5-HT1A receptors can be regulated. [Neuropsychopharmacology 19:354-364 1998] (C) 1998 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.