In mice, the circadian gene
A link between circadian rhythms and behavioral response to cocaine has been suggested by previous work, lead author Colleen McClung, of the University of Texas Southwestern Medical Center, told
She and her colleagues examined the effect of cocaine in mice that did not make the CLOCK protein, which is a transcription factor with a central role in the body's suprachiasmatic nucleus circadian clock.
The investigators found that
The mice without
The researchers next examined the
They found CLOCK protein expressed in all of the VTA's dopaminergic neurons, which they identified by the presence of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis.
VTA dopaminergic neurons were also more excitable in
Finally, using a DNA microarray of VTA tissue, the authors found several genes differentially regulated in the mutants that are known to be involved in dopamine transmission, including several glutamate receptors, a GABA receptor, and an ion channel.
It's nice that the researchers "looked for the neurochemical and anatomical substrates for the effect of the
McClung and her colleagues suspect that regulation of these genes, in addition to regulation of TH, could contribute to elevated dopamine activity in the mutant mice. But they don't yet know if these gene expression changes are a direct result of CLOCK transcriptional regulation, McClung said.
McClung's results hint at how "the circadian system controls reward and motivation generally," according to Michael Lehman of the University of Cincinnati School of Medicine, who was not involved in the study. It makes sense if animals respond to rewarding stimuli in the environment differently at different times of the day, Lehman said.
It's becoming clear that circadian genes influence many phenotypes "beyond what...we normally thought of as being under circadian regulation," Lehman said. "This is an extension of that."