RGD Reference Report - Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats. - Rat Genome Database

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Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats.

Authors: Yong, W  Spence, JP  Eskay, R  Fitz, SD  Damadzic, R  Lai, D  Foroud, T  Carr, LG  Shekhar, A  Chester, JA  Heilig, M  Liang, T 
Citation: Yong W, etal., Alcohol Clin Exp Res. 2014 May;38(5):1275-83. doi: 10.1111/acer.12379. Epub 2014 Mar 10.
RGD ID: 8662401
Pubmed: PMID:24611993   (View Abstract at PubMed)
PMCID: PMC4015136   (View Article at PubMed Central)
DOI: DOI:10.1111/acer.12379   (Journal Full-text)

BACKGROUND: Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats. METHODS: Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats. DNA sequence analysis was then performed to screen for polymorphism in Crhr2 in order to identify genetic variation, and luciferase reporter assays were then applied to test their functional significance. Next, binding assays were used to determine whether this polymorphism affected CRF2 receptor binding affinity as well as CRF2 receptor density in the CNS. Finally, social interaction and corticosterone levels were measured in the P and NP rats before and after 30-minute restraint stress. RESULTS: Crhr2 mRNA expression studies found lower levels of Crhr2 mRNA in iP rats compared to iNP rats. In addition, DNA sequencing identified polymorphisms in the promoter region, coding region, and 3'-untranslated region between the iP and iNP rats. A 7 bp insertion in the Crhr2 promoter of iP rats altered expression in vitro as measured by reporter assays, and we found that CRF2 receptor density was lower in the amygdala of iP as compared to iNP rats. Male P rats displayed decreased social interaction and significantly higher corticosterone levels directly following 30-minute restraint when compared to male NP rats. CONCLUSIONS: This study identified Crhr2 as a candidate gene of interest underlying the chromosome 4 QTL for alcohol consumption that was previously identified in the P and NP model. Crhr2 promoter polymorphism is associated with reduced mRNA expression in certain brain regions, particularly the amygdala, and lowered the density of CRF2 receptor in the amygdala of iP compared to iNP rats. Together, these differences between the animals may contribute to the drinking disparity as well as the anxiety differences of the P and NP rats.



Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Crhr2Ratalcohol preference  IAGP DNA:polymorphism more ...RGD 
Iusm:PRatincreased circulating corticosterone level  IAGP compared to NP/IusmRGD 
Objects Annotated

Genes (Rattus norvegicus)
Crhr2  (corticotropin releasing hormone receptor 2)

Strains
Iusm:P  (alcohol-preferring)

Objects referenced in this article
QTL Alc18 Alcohol consumption QTL 18 Rattus norvegicus
QTL Alc21 Alcohol consumption QTL 21 Rattus norvegicus
QTL Alc22 Alcohol consumption QTL 22 Rattus norvegicus

Additional Information