Selective heterologous regulation of 5-HT1A receptor-stimulated [35S]GTPγS binding in the anterior cingulate cortex as a result of 5-HT2 receptor activation

Previous studies have shown that administration of the 5-HT2 receptor agonist DOI to rats results in the heterologous desensitization of 5-HT1A receptor-mediated behavioral and neuroendocrine responses [Neuropsychopharmacology 19 (1998) 354; J. Neurosci. 21 (2001) 7919]. We hypothesized that the basis for these changes in 5-HT1A receptor function may involve changes in the capacity of the 5-HT1A receptor to activate G proteins. We examined the effect of chronic administration of DOI on the regulation of 5-HT1A receptor function at the level of receptor-G protein interaction using quantitative autoradiography of [S-35]GTPgammaS binding stimulated by the 5-HT1A receptor agonist (+/-)8-OH-DPAT (1 muM). Repeated administration of DOI (1 mg/kg, s.c. once daily for 8 days) resulted in a marked down-regulation in 5-HT2A binding sites, as labeled by the antagonist radioligand [H-3]ketanserin, throughout the cerebral. cortex. Chronic DOI treatment also resulted in a significant and selective attenuation of 5-HT1A receptor-stimulated [S-35]GTPgammaS binding in the anterior cingulate cortex (vehicle-treated: 74 +/- 7.7% above basal; DOI-treated: 43 +/- 4.6% above basal). Interestingly, 5-HT1A receptor-stimulated [S-35]GTPgammaS binding was not altered in the dorsal or median raphe, or in the limbic structures other cortical, regions examined. The decrease in 5-HT1A receptor-stimulated [S-35]GTPgammaS binding in anterior cingulate cortex was not to a decrease in 5-HT1A receptor number, indicating that the capacity of the 5-HT1A receptor to activate G proteins is attenuated in this cortical area following repeated DOI treatment. The heterologous regulation of 5-HT1A receptor function by chronic 5-HT2A receptor activation in the anterior cingulate cortex raises interesting questions as to how the regulatory interaction between these serotonin receptor subtypes influences cognition, memory and emotion. (C) 2002 Elsevier Science B.V. All rights reserved.