Circadian regulation of central ethanol sensitivity by the mPer2 gene.
The effect of alcohol is known to vary with the time of the day. Although initially it was suggested that this phenomenon may be due to diurnal differences in ethanol metabolism, more recent studies were contradicting. In the present study, we therefore first set out in assessing the diurnal variations in ethanol sensitivity in mice analysing, concurrently, ethanol elimination rates. Ethanol-induced (3.5 g/kg; intraperitoneal) loss of righting reflex (LORR) duration was thus determined at several Zeitgeber time (ZT) points (ZT5, 11, 17 and 23) in C57BL/6N mice. In parallel, the corresponding ethanol elimination rates were also assessed. The results display the existence of a distinct diurnal rhythm in LORR duration peaking at ZT11, whereas no differences could be observed regarding the elimination rates of alcohol. Successively, we checked the involvement of the clock genes mPer1 and mPer2 in conveying this rhythm in sensitivity, testing LORR and hypothermia at the peak and trough previously observed (ZT5 and ZT11). Per1(Brdm1) mice demonstrate a similar diurnal pattern as control mice, with enhanced LORR durations at ZT11. In contrast, Per2(Brdm1) mice did not exhibit a temporal variation to the depressant effects of ethanol with respect to LORR, revealing a constant high sensitivity to ethanol. The present study reveals a central role of the mPer2 gene in inhibiting alcohol sensitivity at the beginning of the inactive phase.
Perreau-Lenz
Stéphanie
S
Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, J5, Mannheim, Germany. stephanie.perreau-lenz@zi-mannheim.de
Zghoul
Tarek
T
de Fonseca
Fernando R
FR
Spanagel
Rainer
R
Bilbao
Ainhoa
A
D000435:Alcoholic Intoxication / Q000235:genetics*; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000235:genetics; D001833:Body Temperature Regulation / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D004856:Postural Balance / Q000187:drug effects / Q000235:genetics; D012018:Reflex / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D000431:Ethanol