Abstract
Alcoholism is a pervasive societal problem, yet available pharmacotherapies fail to treat most sufferers. The type 1 corticotropin-releasing factor (CRF1) receptor has received much attention for its putative role in the progression to alcohol dependence, although at present its success in clinical trials has been limited. Two single-nucleotide polymorphisms in the rat Crhr1 promoter have been identified in the Marchigian substrain of Sardinian alcohol-preferring (msP) rats. Unlike other Wistar-derived alcohol-preferring lines, nondependent msP rats reduce their alcohol self-administration in response to CRF1 antagonists and show increased brain CRF1 expression. The current study tested the hypotheses that the A alleles in the Crhr1 promoter polymorphisms are: (1) unique to msP (vs. CRF1 antagonist-insensitive) alcohol-preferring lines and (2) associate with greater alcohol preference or intake. Two related polymorphisms were observed in which both loci on a given chromosome were either mutant variant (A) or wild-type (G) alleles within the distal Crhr1 promoter of 17/25 msP rats (68%), as compared to 0/23 Indiana P rats, 0/20 Sardinian alcohol-preferring rats bred at Scripps (Scr:sP) and 0/21 outbred Wistar rats. Alcohol consumption in msP rats did not differ according to the presence of Crhr1 A alleles, but greater alcohol preference (98%) was observed in A allele homozygous msP rats (AA) compared to msP rats with wild-type (GG, 91%) or heterozygous (GA, 91%) genotypes. The greater alcohol preference reflected decreased water intake, accompanied by reduced total calories consumed by AA rats. The data show that msP rats differentially possess mutant A variant alleles in the polymorphic promoter region of the Crhr1 gene that may differentially regulate consumption.
Highlights
Alcohol abuse and dependence affect about 8% of the population worldwide [1], generating significant societal costs [2]
Our results demonstrate that the presence of the A allele is unique to the Marchigian substrain of Sardinian alcohol-preferring (msP) strain, and that homozygous expression of the A allele (AA) was not differentially associated with elevated baseline alcohol consumption in msP rats, the AA genotype may associate with a slight increase in alcohol preference, albeit over very high preference levels in all msP rats
We sought to determine whether the A alleles are a common modification within Wistar-derived alcohol-preferring rat strains or are a distinguishing feature of msP rats that may account for their unique sensitivity to CRF1 antagonists under non-dependent conditions [9, 31, 36]
Summary
Alcohol abuse and dependence affect about 8% of the population worldwide [1], generating significant societal costs [2] Despite this major public health burden, available pharmacotherapies for alcohol use disorders remain inadequate. Toward developing new therapeutic targets, rodent lines have been selectively bred for differential propensity to consume alcohol. Blockade of CRF1 does not typically alter alcohol intake in nondependent rodents consuming alcohol in non-binge-like patterns [7, 13,14,15]. The presence of heightened CRF system activity in rat lines bred for high alcohol preference may recapitulate the behaviors that result from extensive alcohol exposure, and consequent recruitment of CRF circuitry, that are seen in environmental rodent models of alcohol dependence
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