Abstract
Previous studies have shown that administration of the 5-HT 2 receptor agonist DOI to rats results in the heterologous desensitization of 5-HT 1A 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-HT 1A receptor function may involve changes in the capacity of the 5-HT 1A receptor to activate G proteins. We examined the effect of chronic administration of DOI on the regulation of 5-HT 1A receptor function at the level of receptor–G protein interaction using quantitative autoradiography of [ 35S]GTPγS binding stimulated by the 5-HT 1A receptor agonist (±)8-OH-DPAT (1 μM). Repeated administration of DOI (1 mg/kg, s.c. once daily for 8 days) resulted in a marked down-regulation in 5-HT 2A binding sites, as labeled by the antagonist radioligand [ 3H]ketanserin, throughout the cerebral cortex. Chronic DOI treatment also resulted in a significant and selective attenuation of 5-HT 1A receptor-stimulated [ 35S]GTPγS binding in the anterior cingulate cortex (vehicle-treated: 74±7.7% above basal; DOI-treated: 43±4.6% above basal). Interestingly, 5-HT 1A receptor-stimulated [ 35S]GTPγS binding was not altered in the dorsal or median raphe, or in the limbic structures and other cortical regions examined. The decrease in 5-HT 1A receptor-stimulated [ 35S]GTPγS binding in anterior cingulate cortex was not due to a decrease in 5-HT 1A receptor number, indicating that the capacity of the 5-HT 1A receptor to activate G proteins is attenuated in this cortical area following repeated DOI treatment. The heterologous regulation of 5-HT 1A receptor function by chronic 5-HT 2 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.
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