Role of Adrenal Glucocorticoid Signaling in Prefrontal Cortex Gene Expression and Acute Behavioral Responses to Ethanol

Abstract

Background Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. There is growing evidence that glucocorticoids might also modulate behavioral responses to ethanol. Acute ethanol activates the HPA axis, causing release of adrenal glucocorticoid hormones. Our prior genomic studies suggest glucocorticoids play a role in regulating gene expression in the prefrontal cortex (PFC) of DBA2/J (D2) mice following acute ethanol administration. However, few studies have analyzed the role of glucocorticoid signaling in behavioral responses to acute ethanol. Such work could be significant, given the predictive value for level of response to acute ethanol in the risk for alcoholism. Methods We studied whether the glucocorticoid receptor (GR) antagonist, RU-486, or adrenalectomy (ADX) altered male D2 mouse behavioral responses to acute (locomotor activation, anxiolysis or loss-of-righting reflex (LORR)) or repeated (sensitization) ethanol treatment. Whole genome microarray analysis and bioinformatics approaches were used to identify PFC candidate genes possibly responsible for altered behavioral responses to ethanol following ADX. Results ADX and RU-486 both impaired acute ethanol (2 g/kg) induced locomotor activation in D2 mice without affecting basal locomotor activity. However, neither ADX nor RU-486 altered initiation of ethanol sensitization (locomotor activation or jump counts), ethanol-induced anxiolysis or LORR. ADX mice showed microarray gene expression changes in PFC that significantly overlapped with acute ethanol-responsive gene sets derived by our prior microarray studies. Q-rtPCR analysis verified that ADX decreased PFC expression of Fkbp5 while significantly increasing Gpr6 expression. In addition, high dose RU-486 pre-treatment blunted ethanol-induced Fkbp5 expression. Conclusions Our studies suggest that ethanol’s activation of adrenal glucocorticoid release and subsequent GR activation may partially modulate ethanol’s acute locomotor activation in male D2 mice. Furthermore, since adrenal glucocorticoid basal tone regulated PFC gene expression, including a significant set of acute ethanol-responsive genes, this suggests that glucocorticoid regulated PFC gene expression may be an important factor modulating acute behavioral responses to ethanol.

Effects of ceftriaxone on GLT1 isoforms, xCT and associated signaling pathways in P rats exposed to ethanol

“…The inputs received by the ventral tegmental area (VTA) from the PFC play a critical role in the development of addiction, and disruption of these inputs arising from the PFC interfere with the development of addiction (Chen et al 2011; Dong et al 2005; Kalivas 1993; Li et al 1999; Tong et al 1995). Moreover, results from several studies highlight the critical role played by the PFC in the development of ethanol dependence (Barker et al 2012; Costin et al 2013; Echeverry-Alzate et al 2012; Kerns et al 2005; Seo et al 2013; Vetreno et al 2013). Interestingly, results of the present work indicate that ceftriaxone treatment-induced changes in the expression of GLT1 and xCT are evident in the PFC as early as 24h after two daily doses, compared to the saline-treated group, in contrast to its effects in the NAc.…”

The Role of the Glucocorticoids in Developing Resilience to Stress and Addiction

“…Deficiencies in the GR gene in mice specifically in dopaminergic neurons expressing dopamine D1 receptors that receive dopaminergic input had decreased cocaine self-administration and dopamine cell firing (61). Acute exposure or binge-like ethanol exposure alter GC levels and promote PFC GC-regulated gene expression (62) and neurodegeneration that is dependent on type II GRs (63). GCs induce ethanol associated plasticity of glutamatergic synapses that have been proposed to underlie the development of ethanol dependence, reviewed in (64).…”

The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort

“…Changes in stress reactivity, gene expression, and neuronal signaling all accompany acute ethanol exposure and have been postulated to lead to chronic adaptations–essentially an allostatic imprint on the CNS (Costin, Wolen, Fitting, Shelton, & Miles, 2013; McBride et al, 2005). Proving causality between molecular changes and long-lasting behaviors has not yet been achieved (Heilig & Egli, 2006; Higley, Koob, & Mason, 2012).…”