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J Neurochem. 2012 Oct;123(1):124-34. doi: 10.1111/j.1471-4159.2012.07857.x. Epub 2012 Jul 27.

A mutation in CLOCK leads to altered dopamine receptor function.

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  • 1Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.

Abstract

Mice with a mutation in the Clock gene (ClockΔ19) have a number of behavioral phenotypes that suggest alterations in dopaminergic transmission. These include hyperactivity, increased exploratory behavior, and increased reward value for drugs of abuse. However, the complex changes in dopaminergic transmission that underlie the behavioral abnormalities in these mice remain unclear. Here we find that a loss of CLOCK function increases dopamine release and turnover in striatum as indicated by increased levels of metabolites HVA and DOPAC, and enhances sensitivity to dopamine receptor antagonists. Interestingly, this enlarged dopaminergic tone results in downstream changes in dopamine receptor (DR) levels with a surprising augmentation of both D1- and D2-type DR protein, but a significant shift in the ratio of D1 : D2 receptors in favor of D2 receptor signaling. These effects have functional consequences for both behavior and intracellular signaling, with alterations in locomotor responses to both D1-type and D2-type specific agonists and a blunted response to cAMP activation in the ClockΔ19 mutants. Taken together, these studies further elucidate the abnormalities in dopaminergic transmission that underlie mood, activity, and addictive behaviors.

© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

PMID:
22757753
[PubMed - indexed for MEDLINE]
PMCID:
PMC3438377
Free PMC Article

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