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The Journal of Neuroscience, November 28, 2007, 27(48):13140-13150; doi:10.1523/JNEUROSCI.2284-07.2007

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Behavioral/Systems/Cognitive
Lack of Self-Administration of Cocaine in Dopamine D₁ Receptor Knock-Out Mice

S. Barak Caine,¹ Morgane Thomsen,¹ Kara I. Gabriel,¹ Jill S. Berkowitz,¹ Lisa H. Gold,² George F. Koob,² Susumu Tonegawa,³ Jianhua Zhang,⁴ and Ming Xu⁵

¹Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, ²Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, ³The Picower Center for Learning and Memory and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, ⁴Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, and ⁵The University of Chicago, Department of Anesthesia and Critical Care, Chicago, Illinois 60637

Correspondence should be addressed to Dr. S. Barak Caine, McLean Hospital, Alcohol and Drug Abuse Research Center, 115 Mill Street, Belmont, MA 02478. Email: barak{at}mclean.harvard.edu

Evidence suggests a critical role for dopamine in the reinforcing effects of cocaine in rats and primates. However, self-administration has been less often studied in the mouse species, and, to date, "knock-out" of individual dopamine-related genes in mice has not been reported to reduce the reinforcing effects of cocaine. We studied the dopamine D₁ receptor and cocaine self-administration in mice using a combination of gene-targeted mutation and pharmacological tools. Two cohorts with varied breeding and experimental histories were tested, and, in both cohorts, there was a significant decrease in the number of D₁ receptor knock-out mice that met criteria for acquisition of cocaine self-administration (2 of 23) relative to wild-type mice (27 of 32). After extinction of responding with saline self-administration, dose–response studies showed that cocaine reliably and dose dependently maintained responding greater than saline in all wild-type mice but in none of the D₁ receptor knock-out mice. The D₁-like agonist SKF 82958 (2,3,4,5,-tetrahydro-6-chloro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrobromide) and the D₂-like agonist quinelorane both functioned as positive reinforcers in wild-type mice but not in D₁ receptor mutant mice, whereas food and intravenous injections of the opioid agonist remifentanil functioned as positive reinforcers in both genotypes. Finally, pretreatment with the D₁-like antagonist SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-01] produced surmountable antagonism of the reinforcing effects of cocaine in the commonly used strain C57BL/6J. We conclude that D₁ receptor knock-out mice do not reliably self-administer cocaine and that the D₁ receptor is critical for the reinforcing effects of cocaine and other dopamine agonists, but not food or opioids, in mice.

Key words: dopamine; cocaine; D₁; self-administration; knock-out; mouse

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Received May 18, 2007; revised Sept. 27, 2007; accepted Oct. 14, 2007.

Correspondence should be addressed to Dr. S. Barak Caine, McLean Hospital, Alcohol and Drug Abuse Research Center, 115 Mill Street, Belmont, MA 02478. Email: barak{at}mclean.harvard.edu

This article has been cited by other articles:

				M. Thomsen, F. S. Hall, G. R. Uhl, and S. B. Caine Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice J. Neurosci., January 28, 2009; 29(4): 1087 - 1092. [Abstract] [Full Text] [PDF]

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