Regulation of cortical and hippocampal 5-HT1A receptor function by corticosterone in GR+/− mice

SummaryOur objective in the present study was to examine 5-HT1A receptor function in prefrontal cortex and hippocampus of GR+/− mice, which appear to be an appropriate murine model of depression. 5-HT1A receptor function was determined by measuring [35S]GTPγS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT (1 μM), an indication of the capacity of the receptor to activate G proteins. 5-HT1A receptor expression was determined by measuring the binding of [3H]8-OH-DPAT (2 nM). We observed no effect of the constitutive reduction in GR on 5-HT1A receptor-stimulated [35S]GTPγS binding or 5-HT1A receptor binding sites. Corticosterone treatment (10 mg/kg, sc once daily for 21 days) of wild-type mice resulted in a decrease in 5-HT1A 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-HT1A receptor function in frontal cortex by chronic corticosterone administration. In contrast, corticosterone treatment of GR+/− mice resulted in an increase in 5-HT1A 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-HT1A receptor function in prefrontal cortex and hippocampus.