Regulation of dopaminergic transmission and cocaine reward by the Clock gene.
Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Here we establish a role for the Clock gene in regulating the brain's reward circuit. Mice lacking a functional Clock gene display an increase in cocaine reward and in the excitability of dopamine neurons in the midbrain ventral tegmental area, a key brain reward region. These phenotypes are associated with increased expression and phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), as well as changes in several genes known to regulate dopamine activity in the ventral tegmental area. These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine reward.
McClung
Colleen A
CA
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Sidiropoulou
Kyriaki
K
Vitaterna
Martha
M
Takahashi
Joseph S
JS
White
Francis J
FJ
Cooper
Donald C
DC
Nestler
Eric J
EJ
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006720:Homozygote; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010766:Phosphorylation; D017354:Point Mutation; D012201:Reward; D019966:Substance-Related Disorders; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000502:physiology*
D015534:Trans-Activators; D014446:Tyrosine 3-Monooxygenase; D056926:CLOCK Proteins; C538944:Clock protein, mouse; D003042:Cocaine; D004298:Dopamine