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 [(35)S]GTPgammaS binding stimulated by the 5-HT(1A) receptor agonist 8-OH-DPAT (1 microM), an indication of the capacity of the receptor to activate G proteins. 5-HT(1A) receptor expression was determined by measuring the binding of [(3)H]8-OH-DPAT (2 nM). We observed no effect of the constitutive reduction in GR on 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS 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 [(35)S]GTPgammaS 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 [(35)S]GTPgammaS 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.
Hensler
Julie G
JG
Department of Pharmacology, MC 7764, University of Texas Health Science Center-San Antonio, San Antonio, TX 78229-3900, United States. hensler@uthscsa.edu
Vogt
Miriam A
MA
Gass
Peter
P
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D011965:Receptors, Glucocorticoid; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone