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Circadian Genes and Redox Regulate Neuroplasticity to Psychostimulants in Drosophila

Addiction to psychostimulants (PS), cocaine (COC) and methamphetamine (METH), can be studied in model organisms by analyzing endophenotypes relevant for addiction, such as behavioral sensitization (BS). A group of circadian genes were previously identified as required for development of BS, but their mechanism of action on PS-induced neuronal plasticity is not known. We hypothesize that a potential mechanism involves interaction between PAS domain contained in circadian proteins and elevated levels of reactive oxygen species (ROS). PS increase ROS through oxidation of PS-induced monoamine relase while PAS domain is sensitive to redox potential. Here we present evidence for circadian and redox modulation of BS in Drosophila. We are using BS phenotype to investigate interaction between drug-induced ROS levels and modulation by circadian genes. BS is measured using new high throughput test that allows administration of volatilized PS to a population of individually housed Drosophila and quantification of locomotor activity before and after drug exposure. Repeated administration of the same dose of PS leads to increased locomotor response (BS), but with different time interval between doses for COC or METH. We have confirmed the importance of circadian genes period, Clock and cycle, and we show the requirement for functional dopamine transporter and D1-type dopamine receptor in BS to COC and METH. Size of senzitized response depends on time of the day, indicating circadian modulation of the drug induced response. Single administration of COC or METH increase catalase (CAT), while decrease superoxide-dismutase (SOD), two enzymes responsible for regulating redox state of the cell. Exogenous suppression or induction of oxidative stress abolished BS to COC and METH, indicating that redox status interferes with neuronal plasticity. Our data shows that Drosophila can develop BS to either COC or METH, and that BS is controlled and modulated by functional circadian genes, involves dopaminergic system and is influenced by the redox status. By combining different manipulations in the same animal, such as PS and exogenous pro- and anti- oxidant administration in transgenic animals that allows for spatial and temporal control of relevant genes, we plan to define the interaction between circadian genes and redox state on neuronal plasticity.

neuroplasticity, circadian genes, oxidative stress, Drosophila melanogaster

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