S B Caine1, S S Negus, N K Mello. 1. Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. barak@mclean.harvard.edu
Abstract
RATIONALE: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent studies suggest that D(1-like )and D(2-like )agonists have differing profiles of cocaine-related actions. OBJECTIVE: To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine self-administration using this procedure. METHODS: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. RESULTS: Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose- effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2-like) agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. CONCLUSIONS: The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.
RATIONALE: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent studies suggest that D(1-like )and D(2-like )agonists have differing profiles of cocaine-related actions. OBJECTIVE: To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine self-administration using this procedure. METHODS: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. RESULTS: Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose- effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2-like) agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. CONCLUSIONS: The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.
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