CRH SIGNALING AND THE DARK SIDE OF ADDICTION: LONG LASTING HYPERREACTIVITY TO STRESS IN ANIMALS WITH A HISTORY OF ALCOHOL DEPENDENCE

It is increasingly recognized that anti-reward systems are progressively recruited during the development of ethanol dependence, and may constitute a key component in maintaining the dependent phenotype. We recently demonstrated that in rodents, repeated cycles of ethanol intoxication and withdrawal for a prolonged period of time induces a phenotype of long-lasting increased ethanol drinking that models several facets of human alcoholism. Here, we found that elevated stress sensitivity parallels the high ethanol preference in this model, and contributes to the propensity to consume increased amounts of ethanol. After 7 weeks of daily cycles of intoxication and withdrawal rats were allowed to recover for 3 weeks without access to ethanol. In the first experiment we subjected rats to a punished drinking test (Vogel) w/o antagonist pretreatment with a corticotropin releasing hormone receptor 1 (CRH1R). Dependent rats showed a more pronounced behavioral suppression during the punished drinking period than controls. This suppression was alleviated by the CRH1R antagonist.exposed rats and controls were subjected to a 2-bottle freechoice, continuous access drinking paradigm. We then tested the effect of theantagonist on drinking behavior in a 2-bottle free choice, 1 hr-limited accessparadigm. No effect of the drug on ethanol consumption was found. In a second setof rats we asked whether the increased sensitivity to stress affects home cage drinking. As expected, previously exposed rats consumemarkedly higher amounts ofethanol than controls. Rats were than subjected for 3 consecutive days to sessions ofinescapable stress (forced swimming in cold water). During the week after thestressor rats with a history of dependence showed a sustained increase in drinkingfrom their previous base line, while control rats did not. A third group of animals wasanalyzed for CRH1R receptor expression and density. In conclusion, we provideevidence for an overactive CRH system in rats with a history of dependence causing hyper-emotionality and thereby contributing to relapse behavior