Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress

Abstract

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...

Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders

“…2 [6,23]. As predicted from the allostatic concept of addiction (Box 1) we found upregulated CRH activity in the central amygdala of postdependent animals during acute withdrawal and many weeks thereafter, contributing to increased ethanol intake, anxiety, and ethanol-seeking behavior, all of which can be alleviated by blockade of CRH 1 receptors [6,[23][24][25][26]. In fact, the excessive ethanol consumption appears to be a means to downregulate amygdala CRH 1 receptors [27].…”

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

“…A 15-min electric (1.0 mA current intensity) footshock stress was delivered via the grid floor of the chamber under a variable-interval 40-s schedule (interval range: 10-70 s). We choose 1.0 mA because in a previous study (Hansson et al 2006), we showed that in Wistar rats, the maximum level of responding is obtained at this current intensity. After termination of footshock, the levers were extended into the chambers, and responses were recorded for 30 min.…”

Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: A urocortin 1 -independent mechanism

“…For various endocrine-independent effects of chronic EtOH, more profound effects of CRF 1 receptor manipulations have been described in postdependent animals and in animals that were selectively bred for elevated EtOH preference (54,58,59). CRF 1 receptor antagonists can reduce levels of intake of postdependent animals to the levels observed in nondependent ones (54,58,59).…”

“…Given the comorbidity of drug addiction with affective disorders, CRF systems have been suggested as potential common targets for their treatment (50,53). Regarding alcoholism, human and rodent data support a genetically determined relationship between central CRF function and EtOH consumption (54)(55)(56)(57). EtOH-induced longterm neuroadaptations responsible for increased EtOH intake and stress-evoked relapse-like behavior in EtOH-dependent animals withdrawn from EtOH have also been linked to CRF function (54,58,59), and repeated EtOH exposure sensitizes the response to the activating effects of a central CRF administration (40).…”