Self-administration of cocaine derivatives by squirrel monkeys

Lever pressing by squirrel monkeys was maintained under a 5-min fixed-interval schedule of drug self-administration; the first response after 5 min elapsed produced an i.v. injection of cocaine (2.7-267.7 micrograms/kg), the phenyltropane analog of cocaine, WIN 35,065-2 (0.6-64.3 micrograms/kg) or their respective N-demethylated derivatives, norcocaine (3.0-1,000.0 micrograms/kg) and WIN 35,981 (0.8-245.5 micrograms/kg). As the dose per injection was increased, responding maintained by each drug first increased and then decreased. When saline was substituted for the drugs, responding occurred irregularly and at low rates. The drugs were equally effective in maintaining responding, but WIN 35,065-2 was 3 to 10 times more potent than cocaine; cocaine and WIN 35,065-2 were each 3 to 10 times more potent than their N-demethylated derivatives, norcocaine and WIN 35,981. There was a high degree of stereoselectivity in the effects of the phenyltropane analogs; the (-)-isomer, WIN 35,065-2, was the most potent drug studied, yet its enantiomer, WIN 35,065-3, did not maintain responding at any dose tested (0.6-6427.7 micrograms/kg/injection). These structure-activity relations correspond to those observed previously for the effects of cocaine derivatives on schedule-controlled responding by pigeons and squirrel monkeys, suggesting that the reinforcing and other behavioral effects of these drugs reflect common pharmacological actions.