Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice

作者：Thomsen Morgane^*; Hall F Scott; Uhl George R; Caine S Barak

来源：Journal of Neuroscience, 2009, 29(4): 1087-1092.

DOI：10.1523/JNEUROSCI.4037-08.2009

• cocaine
• drug abuse
• DAT
• SERT
• knock-out mouse
• progressive ratio

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.

• 出版日期2009-1-28