Requirement of Circadian Genes for Cocaine Sensitization in Drosophila

Abstract

The circadian clock consists of a feedback loop in which clock genes are rhythmically expressed, giving rise to cycling levels of RNA and proteins. Four of the five circadian genes identified to date influence responsiveness to freebase cocaine in the fruit fly, Drosophila melanogaster. Sensitization to repeated cocaine exposures, a phenomenon also seen in humans and animal models and associated with enhanced drug craving, is eliminated in flies mutant for period, clock, cycle, and doubletime, but not in flies lacking the gene timeless. Flies that do not sensitize owing to lack of these genes do not show the induction of tyrosine decarboxylase normally seen after cocaine exposure. These findings indicate unexpected roles for these genes in regulating cocaine sensitization and indicate that they function as regulators of tyrosine decarboxylase.

The Pineal Gland is Critical for Circadian Period1 Expression in the Striatum and for Circadian Cocaine Sensitization in Mice

“…Cocaineinduced behavioral sensitization has been commonly used as an experimental model across the species (Prinssen et al, 1996;Andretic et al, 1999;Sircar, 2000), since it replicates repetitive drug taking in humans and also promotes the drug cravings and further addictive behaviors seen in drug dependence (Robinson and Berridge, 1993;Sax and Strakowski, 2001).…”

“…The importance of the Per pathway is suggested by the finding that for cocaine sensitization to occur in different species, Per expression is obligatory. Thus, fruit flies mutant for clock genes, including Per, failed to develop behavioral cocaine sensitization (Andretic et al, 1999).…”

“…Behavioral sensitization is a process in which repeated exposure to a drug results in increased behavioral responses and that is common across the species; that is, from fruit flies (Drosophila) to humans (Robinson and Berridge, 1993;Prinssen et al, 1996;Andretic et al, 1999;Sax and Strakowski, 2001). Recent work using Drosophila has identified a family of circadian 'clock genes' as an important contributor to the development of cocaine sensitization (for a review, see Wolf, 1999;Hirsh, 2001).…”

“…Recent work using Drosophila has identified a family of circadian 'clock genes' as an important contributor to the development of cocaine sensitization (for a review, see Wolf, 1999;Hirsh, 2001). Thus, flies mutant for these genes, including Period (Per), do not sensitize to cocaine (Andretic et al, 1999).…”

“…In the mouse circadian clock, Clock and Bmal1 are two transcription factors critical for the regulation of expression of three period genes (Per1, Per2, and Per3) and two cryptochrome genes (Cry1 and Cry2) (Etchegaray et al, 2003;Morse and Sassone-Corsi, 2002). In a follow-up on Drosophila work (Andretic et al, 1999), it was found that mice deficient (ie 'knockout') for Per1, but not Per2, do not develop behavioral sensitization to cocaine (Abarca et al, 2002).…”