Modulation of Cellular Expression of Glucocorticoid Receptor and Glucocorticoid Response Element-DNA Binding in Rat Brain during Alcohol Drinking and Withdrawal

Abstract

To define the molecular mechanisms of abnormal hypothalamic pituitary adrenal (HPA) axis during ethanol dependence, we investigated the effect of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression of glucocorticoid receptors (GRs) and glucocorticoid response element (GRE)-DNA binding in the rat brain. The effects of chronic mianserin [serotonin (5-HT) 2A/2C antagonist] treatment on these parameters in various brain structures of control diet-fed and ethanolfed rats were also investigated. It was found that ethanol treatment and withdrawal significantly decreased the GR protein levels in cortical (cingulate gyrus, frontal, parietal, and piriform cortex) and amygdaloid (central, medial, and basolateral) structures and paraventricular nucleus (PVN) of hypothalamus of rats. It was also observed that ethanol treatment produced significant reductions in GR protein levels in various hippocampal structures (CA1, CA2, CA3, and dentate gyrus), but these changes were normalized during ethanol withdrawal. Ethanol treatment also significantly decreased GRE-DNA binding in rat cortex and hippocampus, which remained decreased in the cortex but reverted to normal in hippocampus during ethanol withdrawal. Chronic mianserin (alone) treatment had no effect on cortical GRE-DNA binding and GR protein levels in cortical, amygdaloid, or PVN structures but significantly decreased the GR protein expression in various hippocampal structures and GRE-DNA binding in whole hippocampus. However, when administered concurrently with ethanol treatment, mianserin significantly antagonized the reductions in cortical GRE-DNA binding and in GR protein expression in cortical, PVN, and central, but not medial and basolateral, amygdaloid structures during ethanol withdrawal. On the other hand, mianserin treatment along with ethanol administration significantly decreased the hippocampal GRE-DNA binding and GR protein expression in various hippocampal structures during ethanol withdrawal. Furthermore, ethanol treatment and its withdrawal or mianserin treatment had no effect on the neuron-specific nuclear protein levels in the various brain structures. Taken together, these results indicate that interaction of 5-HT 2A/2C receptors with GRs in cortical, central amygdaloid, and PVN structures may play a role in neural mechanisms of alcohol dependence. It is possible that decreased GR expression in PVN may be responsible for the abnormal HPA axis during ethanol exposure and withdrawal.

Differential Effects of Antidepressants on Glucocorticoid Receptors in Human Primary Blood Cells and Human Monocytic U-937 Cells

“…Moreover, the studies on the time course of the effects of ETH suggest that the effect occurs firstly after 4 h and is stable up to 48 h in undifferentiated U-937 cells. Other studies revealed that ETH also affected GRE binding under in vivo conditions in the rat brain, and that mianserin, another AD, interacts with the effects of ETH on the GR system (Roy et al, 2002). In conjunction with these data, we suggest that the effects of MIRFand also other ADs in our system such as DESIFmay result, to a certain extent, from an interaction with the effects of ETH.…”

Alcohol Dysregulates Corticotropin-Releasing-Hormone (CRH) Promoter Activity by Interfering with the Negative Glucocorticoid Response Element (nGRE)

“…Adult rats fed a chronic alcohol diet (Lieber-deCarli, 15 days) had decreased GRE:DNA binding, as measured by gel electromobility shift assays, that was fully restored after 72 hours of EtOH withdrawal [22]. Further, they showed an EtOH-mediated decrease in GR protein levels in the cortex and hippocampus, which was likely associated with the observed overall decrease in GR:DNA binding in those same regions [22].…”

Chronic Alcohol Consumption in Rats Leads to Desynchrony in Diurnal Rhythms and Molecular Clocks

“…The HPA axis exhibits prominent rhythms in hormone secretion and tissue responsiveness (Kalsbeek et al, 2012) and appears to be particularly susceptible to alcohol-induced disruptions (Clarke et al, 2008). Centrally, chronic alcohol can alter levels of corticotropin-releasing hormone (CRH) and vasopressin and also can reduce the expression of glucocorticoid receptors in the paraventricular nucleus of the hypothalamus (Roy et al, 2002;Silva et al, 2002). Peripherally, chronic alcohol has been shown to impair the adrenal sensitivity to adrenocorticotropin and the pituitary responsiveness to CRH (Allen et al, 2011).…”