Abstract
Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol, are highly sensitive to stress and stress-induced alcohol seeking. Genetic analysis showed that over-expression of the corticotropin-releasing factor (CRF) system of msP rats is correlated with the presence of two single nucleotide polymorphisms (SNPs) occurring in the promoter region (position −1836 and −2097) of the CRF1 receptor (CRF1-R) gene. Here we examined whether these point mutations were associated to the innate alcohol preference, stress-induced drinking, and seeking. We have recently re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and the point mutations (AA), respectively. The phenotypic characteristics of these two lines were compared with those of unselected Wistar rats. Both AA and GG rats showed similar patterns of voluntary alcohol intake and preference. Similarly, the pharmacological stressor yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) elicited increased operant alcohol self-administration under fixed and progressive ratio reinforcement schedules in all three lines. Following extinction, yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) significantly reinstated alcohol seeking in the three groups. However, at the highest dose this effect was no longer evident in AA rats. Treatment with the CRF1-R antagonist antalarmin (0, 5, 10, and 20 mg/kg) significantly reduced alcohol-reinforced lever pressing in the AA line (10 and 20 mg/kg) while a weaker or no effect was observed in the Wistar and the GG group, respectively. Finally, antalarmin significantly reduced yohimbine-induced increase in alcohol drinking in all three groups. In conclusion, these specific SNPs in the CRF1-R gene do not seem to play a primary role in the expression of the msP excessive drinking phenotype or stress-induced drinking but may be associated with a decreased threshold for stress-induced alcohol seeking and an increased sensitivity to the effects of pharmacological blockade of CRF1-R on alcohol drinking.
Highlights
Alcoholism is an etiologically and clinically heterogeneous disorder in which compulsive alcohol use and elevated vulnerability to relapse represent core symptoms (McLellan et al, 1992)
We found that the two Marchigian Sardinian alcohol-preferring (msP) rat lines (GG and AA) showed similar patterns of alcohol intake and preference in the 24-h access twobottle free choice drinking paradigm, which was comparable to the elevated levels of drinking previously shown by the original msP line (Ciccocioppo et al, 2006; Hansson et al, 2007; Stopponi et al, 2011)
Here we show that two previously identified point mutations at the CRF1 receptor (CRF1-R) gene locus do not seem to play a major role in the expression of the msP excessive drinking phenotype or stress-induced drinking
Summary
Alcoholism is an etiologically and clinically heterogeneous disorder in which compulsive alcohol use and elevated vulnerability to relapse represent core symptoms (McLellan et al, 1992). Environment and heritability factors play a dramatic role in controlling individual predisposition to developing alcohol abuse (Cloninger et al, 1981; Schuckit et al, 1985; Enoch and Goldman, 1999; Lovinger and Crabbe, 2005). Environmental stress has been recognized as one of the major factors for alcohol abuse and dependence (Pohorecky, 1991; Sarnyai et al, 2001; Sinha, 2001; Shaham et al, 2003; Breese et al, 2005b). The interaction between environmental stress and heritable factors in the development of alcoholism is still largely unexplored. Understanding the nature of this interaction in regulating individual risk of becoming an alcohol abuser represents a major challenge in this research field and may provide invaluable help for the development of preventive strategies or pharmacotherapeutic remedies
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