SuppReading3 - REPORTS References and Notes Fig. 4....

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product is required for this regulated release. Similar to inactive ( 25 ), tyramine increas- es initial cocaine responsiveness in per o flies. Exposure of tyramine-fed per o flies to 35 m g of cocaine induced behaviors normally seen in control flies exposed to 75 m g (Fig. 4). Thus, although long-term increase of tyra- mine levels can affect initial cocaine respon- siveness, it is not sufficient for sensitization in flies lacking normal per function. A unifying feature of most genes that regulate circadian rhythmicity in Drosophila and vertebrates is the PAS dimerization do- main, common to a subset of basic helix- loop-helix transcription factors ( 26 , 27 ). Within the circadian cycle, CLOCK/CYCLE heterodimers activate per transcription, whereas PER/TIM heterodimers inhibit the activity of CLOCK/CYCLE ( 28 30 ). We find that mutations in per , clock , and cycle share the same cocaine phenotype: a deficien- cy in the ability to sensitize after one or more drug exposures. This similarity leads us to suspect that as in circadian behaviors, these genes are functioning in a common pathway. In contrast to the above mentioned genes, the tim o mutant showed normal cocaine re- sponses. The implication of this finding is two- fold. First, there must be an as yet unidentified PER binding partner that is specifically in- volved in regulation of drug responsiveness. Second, drug responsiveness is likely regulated by per expression in a set of cells distinct from those involved in circadian function. In tim o mutants, PER levels are constitutively low ( 19 , 20 ); if the same TIM-containing cells were involved in circadian and cocaine responses, tim o flies should not sensitize. References and Notes 1. C. McClung and J. Hirsh, Curr. Biol. 8 , 109 (1998). 2. A. C. Morse, V. G. Erwin, B. C. Jones, Physiol. Behav. 58 , 891 (1995). 3. B. K. Tolliver, J. K. Belknap, W. E. Woods, J. M. Carney, J. Pharmacol. Exp. Ther. 270 , 1230 (1994). 4. A. Goodman, and A. Gilman, in The Pharmalcological Basis of Therapeutics , A. Gilman, T. Rall, A. Nies, P. Taylor, Eds. (McGraw-Hill, New York, 1990), p. 417. 5. T. E. Robinson and K. C. Berridge, Brain Res. Brain Res. Rev. 18 , 247 (1993). 6. S. M. Strakowski, K. W. Sax, M. J. Setters, P. E. Keck Jr., Biol. Psychiatry 40 , 872 (1996). 7. R. Andretic and J. Hirsh, in preparation. 8. M. W. Young, Annu. Rev. Biochem. 67 , 135 (1998). 9. R. J. Konopka, and S. Benzer, Proc. Natl. Acad. Sci. U.S.A. 68 , 2112 (1971). 10. D. J. Henry and F. J. White, J. Neurosci. 15 , 6287 (1995). 11. E. J. Nestler and G. K. Aghajanian, Science 278 ,58 (1997). 12. F. J. White, X.-T. Hu, D. J. Henry, S.-F. Zhang, in The Neurobiology of Cocaine: Cellular and Molecular Mechanisms , R. P. Hammer, Ed. (CRC, Boca Raton, FL, 1995), p. 81.
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SuppReading3 - REPORTS References and Notes Fig. 4....

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