Regulation of cortical and hippocampal 5-HT_1A receptor function by corticosterone in GR+/- mice

Our objective in the present study was to examine 5-HT_1A receptor function in prefrontal cortex and hippocampus of GR+/- mice, which appear to be an appropriate murine model of depression. 5-HT_1A receptor function was determined by measuring [³⁵S]GTPγS binding stimulated by the 5-HT_1A receptor agonist 8-OH-DPAT (1μM), an indication of the capacity of the receptor to activate G proteins. 5-HT_1A receptor expression was determined by measuring the binding of [³H]8-OH-DPAT (2nM). We observed no effect of the constitutive reduction in GR on 5-HT_1A receptor-stimulated [³⁵S]GTPγS binding or 5-HT_1A receptor binding sites. Corticosterone treatment (10mg/kg, sc once daily for 21 days) of wild-type mice resulted in a decrease in 5-HT_1A receptor function in prefrontal cortex [8-OH-DPAT-stimulated [³⁵S]GTPγS binding (% above basal), vehicle-treated: 39±4.9; corticosterone-treated: 17±2.8], but not in hippocampus. The constitutive reduction in GR expression prevented the down-regulation of 5-HT_1A receptor function in frontal cortex by chronic corticosterone administration. In contrast, corticosterone treatment of GR+/- mice resulted in an increase in 5-HT_1A receptor function in hippocampus which reached statistical significance in CA2/3 region [8-OH-DPAT-stimulated [³⁵S]GTPγS binding (% above basal), vehicle-treated: 41±9.7; corticosterone-treated: 94±23]. These changes seem to be evoked by a combined effect of high corticosterone levels and GR deficiency. Although GR+/- mice do not exhibit changes in baseline corticosterone, the constitutive deficiency in GR appears to have unmasked regulatory effects of elevated corticosterone in the maintenance of 5-HT_1A receptor function in prefrontal cortex and hippocampus.