Effect of Chronic Serotonin-2Receptor Agonist or Antagonist Administration on Serotonin-1AReceptor Sensitivity

We have investigated the effect of 5-HT2receptor agonist or antagonist administration on postsynaptic 5-HT1Areceptor sensitivity assessed by two behavioral measures, reciprocal forepaw treading or hypothermia induced by acute injection of the 5-HT1Areceptor agonist 8-OH-DPAT. The effectiveness of these drug treatments to downregulate 5-HT2Areceptors 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-HT2Areceptor sites. Acute or chronic treatment of rats with the 5-HT2receptor antagonist mianserin, or chronic administration of the 5-HT2Areceptor antagonist ketanserin, did not alter 8-OH-DPAT-induced hypothermia or forepaw treading. These data indicate that downregulation of 5-HT2Areceptors is not sufficient to alter these postsynaptic 5-HT1Areceptor-mediated responses. Chronic treatment of rats with the 5-HT2receptor agonist DOI, however, resulted in the attenuation of both 5-HT1Areceptor-mediated responses measured in separate experimental groups. The apparent desensitization of 5-HT1Areceptors following chronic DOI treatment was not accompanied by a change in either the number or affinity of 5-HT1Areceptor sites as measured by the binding of [3H]-8-OH-DPAT in hippocampal homogenates. Chronic activation of 5-HT2receptors may be one mechanism by which the sensitivity postsynaptic 5-HT1Areceptors can be regulated.