engleski

Circadian genes have phenotype-specific roles in psychostimulant-induced neuronal plasticity in Drosophila

Addictive drugs engage mechanisms of neural plasticity by changing the function and structure of the brain resulting in addiction. In both vertebrates and invertebrates subset of circadian genes regulates different forms of drug-induced neuronal plasticity. However, description of genetic mechanisms through which circadian genes modulate different drug-induced behaviors is limited, in part due to inadequate behavioral test that can be used in genetic screens in genetically tractable model organisms. To address these issues, we developed new behavioral assays for measuring motor activating and rewarding effects of psychostimulants cocaine (COC) and methamphetamine (METH) in Drosophila melanogaster. Our new assay for measuring locomotor activity after volatilized exposure to psychostimulants (FlyBong) is: high throughput, objective, reproducible and allows analyzing data either on population or individual fly level. FlyBong was validated showing different locomotor sensitization to volatilized COC in circadian mutants per01, ClkJrk and cyc01 ; ry compared to , tim01 or wild type. We show that flies can develop locomotor sensitization to volatilized METH, and response of circadian mutants to METH is distinct from those to COC. We modified two- choice Capillary Feeder (CAFE) assay to test rewarding effect of COC and METH. In assay flies can self-administer food from capillaries that contain sugar solution with or without drug (COC or METH). We show that flies self- administer COC and METH in spite of inherently aversive bitter taste. Preference for COC is higher and longer-lasting compared to METH, which is mostly aversive. COC self- administration is under modulation of gene cyc, while self-administration of METH in addition is modulated by Clk and per. Our results suggest that different circadian genes modulate motor-inducing and rewarding aspects of COC and METH. Different behavioral phenotypes in different circadian mutants to COC and METH can be used for investigation of neural mechanisms and genetic contribution to endophenotypes related to addiction in humans.

Psychostimulants, circadian genes, rewarding effect, locomotor sensitization, Drosophila melanogaster

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