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Vol. 291, Issue 1, 353-360, October 1999
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard
Medical School, Belmont, Massachusetts
The reinforcing effects of D1-like and D2-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
D1-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
D2-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 D1-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
D2-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 D1-like and
D2-like agonists on patterns of responding maintained by
cocaine (0.32 mg i.v.) also differed: D1-like agonists
increased the latency to the first response but did not otherwise alter
patterns of cocaine self-administration, whereas D2-like
agonists increased the intervals between self-administered cocaine
injections. The results suggest that D2-like agonists, but
not D1-like agonists, have prominent reinforcing effects
and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D2 receptor-related neuronal mechanisms may be especially
important in mediating the abuse-related effects of cocaine.
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