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The Journal of Neuroscience, January 28, 2009, 29(4):1087-1092; doi:10.1523/JNEUROSCI.4037-08.2009

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

Morgane Thomsen,¹ F. Scott Hall,² George R. Uhl,² and S. Barak Caine¹

¹Alcohol and Drug Abuse Research Center, McLean Hospital–Harvard Medical School, Belmont, Massachusetts 02478, and ²Molecular Neurobiology Branch, National Institute on Drug Abuse–Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224

Correspondence should be addressed to Dr. Morgane Thomsen, Alcohol and Drug Abuse Research Center, McLean Hospital–Harvard Medical School, 115 Mill Street, Belmont, MA 02478. Email: mthomsen{at}mclean.harvard.edu

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.

Key words: cocaine; drug abuse; DAT; SERT; knock-out mouse; progressive ratio

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Received Aug. 24, 2008; revised Nov. 4, 2008; accepted Dec. 22, 2008.

Correspondence should be addressed to Dr. Morgane Thomsen, Alcohol and Drug Abuse Research Center, McLean Hospital–Harvard Medical School, 115 Mill Street, Belmont, MA 02478. Email: mthomsen{at}mclean.harvard.edu

This article has been cited by other articles:

				M. Thomsen, D. D. Han, H. H. Gu, and S. B. Caine Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 204 - 211. [Abstract] [Full Text] [PDF]

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