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-HT(1A) receptor sensitivity assessed by two behavioral measures, reciprocal forepaw treading or hypothermia induced by acute injection of the 5-HT(1A) receptor agonist 8-OH-DPAT. The effectiveness of these drug treatments to downregulate 5-HT(2A) receptors was confirmed by measuring the binding of [³H]-ketanserin in cortical homogenates, because all of these drug treatments have been shown to result in the downregulation of 5-HT(2A) receptor sites. Acute or chronic treatment of rats with the 5-HT₂ receptor antagonist mianserin, or chronic administration of the 5-HT(2A) receptor antagonist ketanserin, did not alter 8-OH-DPAT-induced hypothermia or forepaw treading. These data indicate that downregulation of 5-HT(2A) receptors is not sufficient to alter these postsynaptic 5-HT(1A) receptor-mediated responses. Chronic treatment of rats with the 5-HT₂ receptor agonist DOI, however, resulted in the attenuation of both 5-HT(1A) receptor-mediated responses measured in separate experimental groups. The apparent desensitization of 5-HT(1A) receptors following chronic DOI treatment was not accompanied by a change in either the number or affinity of 5-HT(1A) receptor sites as measured by the binding of [³H]-8-OH-DPAT in hippocampal homogenates. Chronic activation of 5-HT₂ receptors may be one mechanism by which the sensitivity postsynaptic 5-HT(1A) receptors can be regulated. Copyright (C) 1998 American College of Neuropsychopharmacology.