Cocaine sensitization and reward are under the influence of circadian genes and rhythm.
Investigations using the fruit fly Drosophila melanogaster have shown that the circadian clock gene period (Per) can influence behavioral responses to cocaine. Here we show that the mouse homologues of the Drosophila Per gene, mPer1 and mPer2, modulate cocaine sensitization and reward, two phenomena extensively studied in humans and animals because of their importance for drug abuse. In response to an acute cocaine injection mPer1 and mPer2 mutant mice as well as wild-type mice exhibited an approximately 5-fold increase in activity compared with saline control levels, showing that there is no initial difference in sensitivity to acute cocaine administration in Per mutants. After repeated cocaine injections wild-type mice exhibited a sensitized behavioral response that was absent in mPer1 knockout mice. In contrast, mPer2 mutant mice exhibited a hypersensitized response to cocaine. Conditioned place preference experiments revealed similar behavioral reactions: mPer1 knockout mice showed a complete lack of cocaine reward whereas mPer2 mutants showed a strong cocaine-induced place preference. In another set of experiments, we tested C57/BL6J mice at different Zeitgeber times and found that cocaine-induced behavioral sensitization and place preference are under the control of the circadian clock. In conclusion, we demonstrate that processes involved in cocaine addiction depend on the circadian rhythm and are modulated in an opposing manner by mPer1 and mPer2 genes.
Abarca
Carolina
C
Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany. abarca@zi-mannheim.de
Albrecht
Urs
U
Spanagel
Rainer
R
D000818:Animals; D001522:Behavior, Animal; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D003042:Cocaine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D014157:Transcription Factors
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D003042:Cocaine