Modulation of voluntary ethanol consumption by beta-arrestin 2.
Beta-arrestin 2 is a multifunctional key component of the G protein-coupled receptor complex and is involved in mu-opiate and dopamine D2 receptor signaling, both of which are thought to mediate the rewarding effects of ethanol consumption. We identified elevated expression of the beta-arrestin 2 gene (Arrb2) in the striatum and the hippocampus of ethanol-preferring AA rats compared to their nonpreferring counterpart ANA line. Differential mRNA expression was accompanied by different levels of Arrb2 protein. The elevated expression was associated with a 7-marker haplotype in complete linkage disequilibrium, which segregated fully between the lines, and was unique to the preferring line. Furthermore, a single, distinct, and highly significant quantitative trait locus for Arrb2 expression in hippocampus and striatum was identified at the locus of this gene, providing evidence that genetic variation may affect a cis-regulatory mechanism for expression and regional control of Arrb2. These findings were functionally validated using mice lacking Arrb2, which displayed both reduced voluntary ethanol consumption and ethanol-induced psychomotor stimulation. Our results demonstrate that beta-arrestin 2 modulates acute responses to ethanol and is an important mediator of ethanol reward.
Björk
K
K
Laboratory of Clinical and Translational Studies, NIAAA/NIH, 10 Center Dr., Bethesda, MD 20892-1108, USA.
Rimondini
R
R
Hansson
A C
AC
Terasmaa
A
A
Hyytiä
P
P
Heilig
M
M
Sommer
W H
WH
D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D001070:Appetitive Behavior / Q000502:physiology; D019390:Arrestins / Q000172:deficiency* / Q000235:genetics*; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012201:Reward; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D012333:RNA, Messenger; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins