Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice.
There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. We tested the hypotheses that mice lacking the dopamine transporter (DAT(-/-)), the serotonin transporter (SERT(-/-)), or both (DAT(-/-)SERT(-/-)) exhibit decreased reinforcing effects of cocaine. We also assessed whether observed effects on self-administration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected. We used a broad range of experimental conditions that included acquisition without previous training, behavior established with food training and subsequent testing with food, cocaine or a direct dopamine agonist as reinforcers, fixed ratio and progressive ratio schedules of reinforcement, and a reversal procedure. Wild-type mice readily acquired cocaine self-administration and showed dose-response curves characteristic of the schedule of reinforcement that was used. While some DAT(-/-) mice appeared to acquire cocaine self-administration transiently, almost all DAT(-/-) mice failed to self-administer cocaine reliably. Food-maintained behaviors were not decreased by the DAT mutation, and IV self-administration of a direct dopamine agonist was robust in the DAT(-/-) mice. In contrast to those mice, cocaine's reinforcing effects were not diminished in SERT(-/-) mice under any of the conditions tested, except for impaired initial acquisition of both food- and cocaine-maintained behavior. These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine.
Thomsen
Morgane
M
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts 02478, USA. mthomsen@mclean.harvard.edu
Hall
F Scott
FS
Uhl
George R
GR
Caine
S Barak
SB
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D012055:Reinforcement Schedule; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency*
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins; C058081:ecopipam; C071262:SK&F 82958; D003042:Cocaine