A mutation in CLOCK leads to altered dopamine receptor function

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Analysis of Variance
  • Animals
  • CLOCK Proteins / genetics*
  • Colforsin / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / metabolism
  • Dopamine Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Homovanillic Acid / metabolism
  • In Vitro Techniques
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Mutation / genetics*
  • Receptors, Dopamine / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Dopamine Agents
  • Receptors, Dopamine
  • 3,4-Dihydroxyphenylacetic Acid
  • Colforsin
  • CLOCK Proteins
  • Clock protein, mouse
  • Dopamine
  • Homovanillic Acid