Dopamine transporter inhibition is required for cocaine-induced stereotypy.
The primary mechanism by which cocaine induces stereotypy has been difficult to discern because cocaine has three high-affinity targets: the reuptake transporters for dopamine (DAT), norepinephrine, and serotonin. To dissect out the role of DAT in cocaine effects, we generated a knock-in mouse line with a cocaine-insensitive DAT (DAT-CI mice). DAT-CI mice provide a powerful tool that can directly test whether DAT inhibition is important for cocaine-induced stereotypy. We found that acute cocaine failed to produce stereotypy in DAT-CI mice. In fact, 40 mg/kg cocaine suppressed stereotypy in DAT-CI mice but produced profound stereotypy in wild-type mice. These findings suggest that DAT inhibition is necessary for cocaine-induced stereotypy. Furthermore, mechanisms independent of DAT inhibition appear to inhibit stereotypy.
Tilley
Michael R
MR
Department of Pharmacology, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Gu
Howard H
HH
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D004298:Dopamine