Reinforcing properties of stereoisomers of the putative sigma agonists N-allylnormetazocine and cyclazocine in rhesus monkeys.
There are many similarities in the effects of phencyclidine (PCP) and opioids with sigma agonist activity such as N-allylnormetazocine (SKF-10,047) and cyclazocine. Yet PCP and sigma agonists differ in reinforcing properties. PCP is reliably self-administered in animal models and has abuse liability in humans, whereas (+/-)-N-allylnormetazocine and (+/-)-cyclazocine are not self-administered or abused. Inasmuch as other research has demonstrated differences in the selectivity of PCP-like effects of the stereoisomers of opioids, this study compared the reinforcing properties of PCP to the reinforcing properties of isomers of N-allylnormetazocine and cyclazocine. Rhesus monkeys were trained to lever-press on a fixed-ratio 10 schedule for i.v. cocaine (50 micrograms/kg/injection). During substitution tests, cocaine was replaced with various doses of test drugs or vehicle. The drugs tested were PCP, (+/-)-N-allylnormetazocine, (-)-N-allylnormetazocine, (+)-N-allylnormetazocine, (+/-)-cyclazocine, (-)-cyclazocine and (+)-cyclazocine. PCP and the (+)-isomers of both benzomorphans, at one or more doses, were self-administered at rates which exceeded rates maintained by vehicle and which equaled or exceeded cocaine-maintained base-line rates. Neither the racemates nor the (-)-isomers of N-allylnormetazocine or cyclazocine were self-administered by the monkeys at rates which were greater than vehicle control levels of responding. Reinforcing doses of the three compounds resulted in injections evenly distributed across the 60-min session in a pattern similar to cocaine self-administration, whereas the racemic mixtures and the (-)-isomers produced negatively accelerated patterns of injections which resembled typical saline patterns of extinction responding. These data provide further evidence that the (+)-isomers of sigma agonists are more selective for PCP-like effects than the (-)-isomers in monkeys.
D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003496:Cyclazocine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D010620:Phenazocine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology*; D017480:Receptors, sigma; D012054:Reinforcement, Psychology; D012653:Self Stimulation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011957:Receptors, Opioid; D017480:Receptors, sigma; C012134:SK&F 10047; D003042:Cocaine; D010620:Phenazocine; D003496:Cyclazocine