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 important component underlying the addictive process in humans [1] [2] [3] [4]. In all vertebrate animal models, including humans [5], and even in fruit flies, sensitization 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 serotonin neurons plays an essential role in cocaine sensitization. Targeted expression of either a stimulatory (Galpha(s)) or inhibitory (Galpha(i)) Galpha subunit, or tetanus toxin light chain (TNT) in dopamine and serotonin neurons of living flies blocked behavioral sensitization to repeated cocaine exposures. These flies showed alterations in their initial cocaine responsiveness that correlated with compensatory adaptations of postsynaptic receptor sensitivity. Finally, repeated drug stimulation of a nerve cord preparation that is postsynaptic to the brain amine cells failed to induce sensitization, further showing the importance of presynaptic modulation in sensitization.
Li
H
H
Department of Biology, Gilmer Hall, University of Virginia, Charlottesville, Virginia 22903, USA.
Chaney
S
S
Roberts
I J
IJ
Forte
M
M
Hirsh
J
J
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004331:Drosophila melanogaster; D004361:Drug Tolerance; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D013744:Tetanus Toxin / Q000378:metabolism / Q000494:pharmacology
D013744:Tetanus Toxin; D012701:Serotonin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D003042:Cocaine; D004298:Dopamine