TY - JOUR T1 - Corticosteroid-Dependent Plasticity Mediates Compulsive Alcohol Drinking in Rats JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7563 LP - 7571 DO - 10.1523/JNEUROSCI.0069-12.2012 VL - 32 IS - 22 AU - Leandro F. Vendruscolo AU - Estelle Barbier AU - Joel E. Schlosburg AU - Kaushik K. Misra AU - Timothy W. Whitfield, Jr AU - Marian L. Logrip AU - Catherine Rivier AU - Vez Repunte-Canonigo AU - Eric P. Zorrilla AU - Pietro P. Sanna AU - Markus Heilig AU - George F. Koob Y1 - 2012/05/30 UR - http://www.jneurosci.org/content/32/22/7563.abstract N2 - Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism. ER -