Alcoholism is a chronic relapsing disorder with substantial heritability. Uncovering gene-environment interactions underlying this disease process can aid identification of novel treatment targets. Here, we found a lowered threshold for stress-induced reinstatement of alcohol seeking in Marchigian-Sardinian Preferring (msP) rats genetically selected for high alcohol preference. In situ hybridization for a panel of 20 stress-related genes in 16 brain regions was used to screen for differential gene expression that may underlie this behavioral phenotype. An innate up-regulation of the Crhr1 transcript, encoding the corticotropin-releasing hormone receptor 1 (CRH-R1), was found in several limbic brain areas of msP rats genetically selected for high alcohol preference, was associated with genetic polymorphism of the Crhr1 promoter, and was accompanied by increased CRH-R1 density. A selective CRH-R1 antagonist (antalarmin, 10 -20 mg͞kg) was devoid of effects on operant alcohol self-administration in unselected Wistar rats but significantly suppressed this behavior in the msP line. Stressinduced reinstatement of alcohol seeking was not significantly affected by antalarmin in Wistar rats but was fully blocked in msP animals. These data demonstrate that Crhr1 genotype and expression interact with environmental stress to reinstate alcohol-seeking behavior.lcohol use is the number three modifiable cause of death in the United States (1). Alcohol dependence, hereafter called alcoholism, is a complex behavioral disorder in which substantial heritable susceptibility factors interact with the environment to produce and maintain the disease state (2). Alcoholism is clinically characterized by a chronic relapsing course similar to other common medical conditions (3). Relapse, i.e., return to alcohol seeking and uncontrolled drinking after varying intervals of sobriety, is a key phenomenon in this process, making relapse prevention a primary therapeutic objective.Gene-environment interactions are commonly implicated in alcoholism and propensity to relapse, but their exact nature is presently unknown. A behavioral analysis has long pointed to three broad categories of environmental stimuli with an ability to trigger relapse in susceptible individuals (4): consumption of small, ''priming'' doses of alcohol, presentation of conditioned cues associated with prior availability of alcohol, and stress. It is unclear whether, in alcohol-dependent individuals, these stimuli trigger relapse by interacting with preexisting genetic susceptibility factors, acquired CNS neuroadaptations secondary to a prolonged history of alcohol use, or both.Models in experimental animals offer tools in the search for novel alcoholism treatments (5, 6) and may be helpful in addressing this question. Genetic selection for high alcohol preference in rats has resulted in several lines with pharmacologically relevant levels of voluntary intake of alcohol, as well as other alcohol-related phenotypes (7,8), and an improved understanding of mechanisms mediating rel...

The present article provides an up-to-date review that summarize almost 18 years of research in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. The results of this work demonstrate that msP rats have natural preference for ethanol characterized by a spontaneous binge-type of drinking leading to pharmacologically significant blood ethanol levels. This rat line is highly vulnerable to relapse and presentation of stimuli predictive of alcohol availability or footshock stress can reinstate extinguished drug-seeking up to 8 months from the last alcohol experience. The msP rat is highly sensitive to stress, shows an anxious phenotype and has depressive-like symptoms that recover following ethanol drinking. Interestingly, these animals have an up-regulated corticotrophin releasing factor (CRF) receptor 1 system. From clinical studies we learned that alcoholic patients often drink ethanol in the attempt to self-medicate from negative affective states and to search anxiety relief. We propose that msP rats represent an animal model that largely mimics that human alcoholic population that due to low ability to engage in stress-coping strategies drink ethanol as a tension relief strategy and for self-medication purposes.

Rationale-Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour.Objectives-The present study, using genetically selected Marchigian Sardinian alcoholpreferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S + ) and a 1-s cue light (CS + ) or for water in the presence of anise odour (S − ) and 1-s white noise (CS − ), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated.Correspondence to: Roberto Ciccocioppo, roberto.ciccocioppo@unicam.it. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2011 February 9. Conclusions-The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.

This study examined whether nociceptin/orphanin FQ (NC), the endogenous ligand of the opioid receptor-like1 (ORL1) receptor, can block drug-seeking behavior induced by foot-shock stress. Male Wistar rats were trained to operantly self-administer ethanol or cocaine, and then subjected to daily extinction training until responding ceased. Subsequent exposure to 15 min of intermittent footshock elicited robust reinstatement of responding at the previously drug-paired lever. NC (0.1-2.0 microg; i.c.v.) significantly inhibited the effects of footshock stress on ethanol- but not cocaine-seeking behavior. The results support the hypothesis that the NC system participates in the regulation of behavioral responses to stress, and that drugs interacting with NC receptors may have therapeutic potential for the treatment of stress-induced alcohol-seeking behavior and relapse.

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