Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice.
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.
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA. barak@mclean.harvard.edu
S Barak
SB
Caine
Morgane
M
Thomsen
Kara I
KI
Gabriel
Jill S
JS
Berkowitz
Lisa H
LH
Gold
George F
GF
Koob
Susumu
S
Tonegawa
Jianhua
J
Zhang
Ming
M
Xu
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000008:administration & dosage; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D018491:Dopamine Agonists / Q000008:administration & dosage; D018492:Dopamine Antagonists / Q000008:administration & dosage; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage; D017447:Receptors, Dopamine D1 / Q000172:deficiency*; D012054:Reinforcement, Psychology; D000077208:Remifentanil; D012646:Self Administration; D018709:Statistics, Nonparametric
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D006993:Hypnotics and Sedatives; D010880:Piperidines; D017447:Receptors, Dopamine D1; C071262:SK&F 82958; D003042:Cocaine; D000077208:Remifentanil