Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster

Sensitization to repeated doses of psychostimulants is thought to be an imp ortant component underlying the addictive process in humans [1-4]. In all v ertebrate animal models, including humans [5], and even in fruit flies, sen sitization is observed after repeated exposure to volatilized crack cocaine [6]. In vertebrates, sensitization is thought to be initiated by processes occurring in brain regions that contain dopamine cell bodies [2,7]. Here, we show that modulated cell signaling in the Drosophila dopamine and seroto nin neurons plays an essential role in cocaine sensitization. Targeted expr ession of either a stimulatory (G alpha(s)) or inhibitory (G alpha(i)) G al pha subunit, or tetanus toxin light chain (TNT) in dopamine and serotonin n eurons of living flies blocked behavioral sensitization to repeated cocaine exposures. These flies showed alterations in their initial cocaine respons iveness that correlated with compensatory adaptations of postsynaptic recep tor sensitivity. Finally, repeated drug stimulation of a nerve cord prepara tion that is postsynaptic to the brain amine cells failed to induce sensiti zation, further showing the importance of presynaptic modulation in sensiti zation.