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 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 saccharinsweetened 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.

Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals

“…Brain tissue collection occurred during acute withdrawal (6-8 hours after removal from alcohol vapor) when brain and blood alcohol levels are negligible (13) and withdrawal symptoms -including anxiety and brain reward deficits -are manifest (10,11,14). Previous work has established that, under these conditions, nondependent rats will work to obtain and ingest 10% wt/vol alcohol, and dependent rats will escalate their intake sufficient to block withdrawal and show compulsivelike responding for alcohol (6,10,15). We found that the levels of GR phosphorylation at Ser 232 , a marker of GR nuclear localization and transactivation, were increased in the CeA (t 10 = 2.574, P = 0.0277) but not the adjacent BLA (t 10 = 0.486, P = 0.8087) in alcohol-dependent rats compared with nondependent rats (Figure 1A).…”

“…Allostatic changes in brain reward and stress systems are thought to mediate many of these symptoms. We previously reported that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the principal neuroendocrine stress system, and consequent alterations in brain glucocorticoid receptor (GR) expression accompany compulsive-like alcohol intake in rats (5,6). Despite these strong preclinical findings and evidence for dysregulation of the HPA axis in alcoholism (7,8), a role for GR signaling in humans who suffer from alcohol dependence has yet to be determined.…”

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

“…Animal studies also have shown a considerable increase in both circulating and brain corticosterone levels following alcohol withdrawal (Rose et al, 2010) and elevated blood corticosterone levels could enhance alcohol withdrawal severity (Roberts et al, 1994) through GR activation (Sharrett-Field et al, 2013). These effects may be of interest beyond the acute withdrawal period, as recent evidence suggests a role for GR-mediated plasticity in escalation of voluntary alcohol consumption in rats (Vendruscolo et al, 2012).…”

Endogenous cannabinoids in amygdala and hippocampus in post-mortem brains of Cloninger type 1 and 2 alcoholics

“…Dysfunctional stress responses, including allostatic alterations in the function of the stress-mediating amygdala and stressinhibiting hippocampus, have been hypothesized to be one of the key neural changes in the pathology of addiction, which proceeds from a negative reinforcement of learning processes (Funk et al, 2006;Koob and Le Moal, 2008;Vendruscolo et al, 2012). Alterations in the stress systems of Cloninger type 1 and type 2 alcoholics have been reported, for example, as altered metabotropic glutamate receptor 1/5 (mGluR1/5) densities in the hippocampus (Kupila et al, 2012), altered serotonin transporter (SERT) densities in the amygdala (Storvik et al, 2007) and altered ratios between SERT densities in the amygdala and hypothalamus .…”