Molecular and Pharmacological Evidence for the Role of Glucocorticoid Receptors in Alcohol Dependence /

Alcoholism or alcohol dependence is characterized by a compulsion to seek and ingest alcohol, uncontrolled intake, and emergence of a negative emotional state (e.g., dysphoria, anxiety) during withdrawal. Similar to stress, we hypothesize that chronic alcohol exposure and withdrawal sensitize brain stress systems. Glucocorticoid receptors (GR), activated by stress hormones (cortisol in humans; corticosterone in rodents), have been shown to be dysregulated in stress/reward-related brain regions. We report increased GR activation (indexed by GR phosphorylation) in the central amygdala (CeA), a stress- related brain region, in alcohol-dependent compared with nondependent rats. Consistently, GR antagonism with mifepristone injected directly into the CeA reduces alcohol self-administration in dependent rats compared with nondependent rats. Systemic GR antagonism with mifepristone also reduces alcohol self-administration specifically in dependent rats. Mifepristone, however, also inhibits progesterone receptors, which may participate in alcohol-related behaviors. Therefore, more selective drugs (CORT113176, CORT118335, and CORT108297) that do not block progesterone receptors but do bind GR were tested on alcohol self-administration. CORT113176 significantly reduced alcohol self-administration in dependent rats, providing unambiguous evidence for a functional role of GR in alcohol dependence. Finally, the GR antagonist CORT118335 reduced self-administration in both dependent and nondependent rats, whereas CORT108297 had no effect on alcohol self-administration in either dependent or nondependent groups. These findings suggest that behavioral outcomes depend on distinct conformational and signaling changes produced by each antagonist when associated with GR. The present results provide compelling evidence for GR dysregulation in alcohol dependence and suggest that GR constitutes a viable pharmacological target for alcohol dependenc