Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene.
Behavioral and biochemical studies suggest that dopamine (DA) plays a role in the reinforcing and addictive properties of drugs of abuse. Recently, this hypothesis has been challenged on the basis of the observation that, in mice genetically lacking the plasma membrane dopamine transporter [DAT-knock out (DAT-KO)], cocaine maintained its reinforcing properties of being self-administered and inducing place preference, despite the failure to increase extracellular dopamine in the dorsal striatum. Here we report that, in DAT-KO mice, cocaine and amphetamine increase dialysate dopamine in the medial part of the nucleus accumbens. Moreover, reboxetine, a specific blocker of the noradrenaline transporter, increased DA in the nucleus accumbens of DAT-KO but not of wild-type mice; in contrast, GBR 12909, a specific blocker of the dopamine transporter, increased dialysate dopamine in the nucleus accumbens of wild-type but not of DAT-KO mice. These observations provide an explanation for the persistence of cocaine reinforcement in DAT-KO mice and support the hypothesis of a primary role of nucleus accumbens dopamine in drug reinforcement.
Carboni
E
E
Department of Toxicology and Consiglio Nazionale delle Ricerche Center for Neuropharmacology, University of Cagliari, 09126 Cagliari, Italy.
Spielewoy
C
C
Vacca
C
C
Nosten-Bertrand
M
M
Giros
B
B
Di Chiara
G
G
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D000077593:Reboxetine; D012054:Reinforcement, Psychology
D018759:Adrenergic Uptake Inhibitors; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493215:Slc6a3 protein, mouse; C043425:vanoxerine; D000077593:Reboxetine; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine