Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine.
The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine.
Caine
S B
SB
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts, USA. barak@mclean.harvard.edu
Negus
S S
SS
Mello
N K
NK
Bergman
J
J
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000517:prevention & control; D004193:Discrimination Learning / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine