A mutation in CLOCK leads to altered dopamine receptor function
Article first published online: 27 JUL 2012
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry
Journal of Neurochemistry
Volume 123, Issue 1, pages 124–134, October 2012
How to Cite
Spencer, S., Torres-Altoro, M. I., Falcon, E., Arey, R., Marvin, M., Goldberg, M., Bibb, J. A. and McClung, C. A. (2012), A mutation in CLOCK leads to altered dopamine receptor function. Journal of Neurochemistry, 123: 124–134. doi: 10.1111/j.1471-4159.2012.07857.x
- Issue published online: 10 SEP 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 3 JUL 2012 09:11AM EST
- Received April 23, 2012; revised manuscript received June 25, 2012; accepted June 29, 2012.
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.