Decreased ethanol preference and wheel running in Nurr1-deficient mice.
Nurr1 (Nr4a2) is a transcription factor expressed in dopamine cells from early development and throughout life. Null mutants for Nurr1 lack the ventral midbrain dopamine neurons and die soon after birth. Animals with a heterozygous deletion are viable and display no apparent abnormality. We have investigated the impact of heterozygous deletion of Nurr1 on ethanol consumption in adult mice as a model for drug-induced reward and on wheel running as a model for natural reward. Interestingly, Nurr1 heterozygous mice never developed high ethanol consumption nor did they develop as much running behaviour as did the wild-type animals. Thus, Nurr1 appears to have a key role for the reinforcing properties of ethanol and running that underlies the development of excessive reward-seeking behaviours characteristic for addiction. Quantitative trait loci mapping using C57Bl/6 and DBA/2 mice describe a locus for ethanol preference on chromosome 2, wherein Nurr1 is located. We found two dinucleotide repeats in the Nurr1 promoter that were longer in mice with low preference for ethanol (DBA/2 and 129/Sv) than in mice with high preference for ethanol (C57Bl/6J and C57Bl/6NIH). These sequential data are compatible with Nurr1 as a candidate gene responsible for the quantitative trait loci for ethanol preference on mouse chromosome 2. Together, our data thus imply involvement of Nurr1 in the transition to a state of high ethanol consumption as well as in the development of a high amount of wheel running in mice.
Werme
Martin
M
Department of Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Hermanson
Elisabet
E
Carmine
Andrea
A
Buervenich
Silvia
S
Zetterström
Rolf H
RH
Thorén
Peter
P
Ogren
Sven Ove
SO
Olson
Lars
L
Perlmann
Thomas
T
Brené
Stefan
S
D000428:Alcohol Drinking / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018900:Dinucleotide Repeats / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage; D005518:Food Preferences / Q000502:physiology; D006579:Heterozygote; D017403:In Situ Hybridization / Q000379:methods; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants / Q000502:physiology*; D009043:Motor Activity; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011401:Promoter Regions, Genetic; D011803:Quinine; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012420:Running / Q000502:physiology*; D012439:Saccharin; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000523:psychology*; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D004268:DNA-Binding Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D014157:Transcription Factors; D000431:Ethanol; D011803:Quinine; D012439:Saccharin