Circadian Genes Differentially Affect Tolerance to Ethanol in Drosophila.

Background There is a strong relationship between circadian rhythms and ethanol ( Et OH) responses. EtOH consumption has been shown to disrupt physiological and behavioral circadian rhythms in mammals ( Alcohol Clin Exp Res 2005b, 29, 1550). The Drosophila central circadian pacemaker is composed of proteins encoded by the per, tim, cyc, and Clk genes. Using Drosophila mutant analysis, we asked whether these central components of the circadian clock make the equivalent contribution toward Et OH tolerance and whether rhythmicity itself is necessary for tolerance. Methods We tested flies carrying mutations in core clock genes for the capacity to acquire Et OH tolerance. Tolerance was assayed by comparing the sedation curves of populations during their first and second sedation. Animals that had acquired tolerance sedated more slowly. Movement was also monitored as the flies breathe the Et OH vapor to determine if other facets of the Et OH response were affected by the mutations. Gas chromatography was used to measure internal Et OH concentration. Constant light was used to nongenetically destabilize the PER and TIM proteins. Results A group of circadian mutations, all of which eliminate circadian rhythms, do not disrupt tolerance identically. Mutations in per, tim, and cyc completely block tolerance. However, a mutation in Clk does not interfere with tolerance. Constant light also disrupts the capacity to acquire tolerance. These lines did not differ in Et OH absorption. Conclusions Mutations affecting different parts of the intracellular circadian clock can block the capacity to acquire rapid Et OH tolerance. However, the role of circadian genes in Et OH tolerance is independent of their role in producing circadian rhythmicity. The interference in the capacity to acquire Et OH tolerance by some circadian mutations is not merely a downstream effect of a nonfunctional circadian clock; instead, these circadian genes play an independent role in Et OH tolerance. [ABSTRACT FROM AUTHOR]