Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats

Abstract

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 thehypothalamic-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-sweetenedwater.AcutealcoholwithdrawalwasaccompaniedbydownregulatedGRmRNAinvariousstress/reward-relatedbrainregions [i.e., prefrontalcortex, nucleusaccumbens(NAc), and bed nucleus of the stria terminalis (BNST)],whereas protracted alcohol abstinence was accompanied by up regulated GRmRNA in theNAccore, ventral BNST,and central nucleus of the amygdala. Nosignificant 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. ©2012 the authors.