Doctor of Philosophy
Pharmacology & Toxicology
Phencyclidine (PCP) belongs to a class of drugs with a unique and characteristic spectra of pharmacological activity. PCP has recently become a major drug of abuse. Structural analogues of PCP have also been reported in street use. The following experiments explore the behavioral pharmacology of PCP and several compounds with PCP-like activity.
In Experiment I the effects of PCP were compared to three structural analogues in rhesus monkeys trained to lever press on a fixed-interval 5 min schedule of food presentation. Dose-response curves and potency estimates were determined for PCP, N-ethyl-1-phenylcyclohexylamine (PCE), 1-(1-(2-thienyl) cyclohexyl) piperidine (TCP) and ketamine.The effects of all four drugs on response rates were dependent on the baseline rate of responding. High doses of all four drugs decreased overall response rates. Onset and duration of drug effects were also determined and compared.
In Experiments II through VI the drug discrimination paradigm was used. Animals were trained to discriminate PCP (rats, 3.0 mg/kg i.p.; monkeys, 0.16 mg/kg i.m.) from saline in a two-lever drug discrimination task on a fixed-ratio 32 (FR 32) schedule of food presentation. After reliable discrimination control of lever choice was established, generalization tests were conducted every third day. Test periods consisted of a 2-min period during which responding on either lever was reinforced (rats) or responding was recorded but not reinforced (monkeys). The PCP dose-response determination preceded generalization testing with other compounds. Dose-effect curves for each drug for percent drug-lever appropriate responding and for suppression of operant responding during sessions were analyzed by linear regression.
In Experiment II the discriminative stimulus properties of PCP and five other arylcycloalkylamines were investigated in squirrel monkeys .Generalization testing was conducted with PCP, PCE, TCP, 1-(1-phenylcyclohexyl) morpholine (PCM), 1-(1-phenylcyclohexyl) pyrroldine (PHP), and ketamine. All drugs produced dose-dependent PCP-appropriate responding. The dose necessary to suppress operant responding to fifty percent of vehicle rates was 3 to 8 times larger than the ED50 for drug-lever appropriate responding.
Experiments III, IV and VI were designed to explore similarities between the discriminative stimulus properties of PCP and a series of structurally dissimilar compounds. In Experiment III the discriminative stimulus properties of dexoxadrol and etoxadrol, both 2-(2,2-substituted 1,3 dioxolan-4-yl) piperdines, were studied in squirrel monkeys. Both compounds generalized to PCP in a dose-dependent manner. The dose necessary to suppress operant responding to fifty percent of vehicle rates was 3 to 8 times larger than the ED5O dose · for drug-lever appropriate responding.
In Experiment IV the discriminative stimulus properties of stereoisomers of N-allylnormetazocine, a benzomorphan opioid with psychotomimetic properties, were investigated in squirrel monkeys and rats. In both species, the (+) isomer and the racemic mixture produced dose dependent PCP-appropriate responding. The (-) isomer did not produce PCP-appropriate responding, however it was more potent than the (+) isomer in overall response rate suppression. High doses of naloxone (rats, 30 mg/kg;monkeys, 1.0 and 3.0 mg/kg) did not block the drug lever appropriate responding or response rate suppression produced by either isomer of N -allynormetazocine.
In Experiment V the discriminative stimulus properties of ketamine stereoisomers were investigated in rats. Both isomers and the racemic form of ketamine produced drug-lever appropriate responding and decreased response rate in a dose-dependent manner. There was no significant potency difference between (±)-ketamine and either of the isomers for either of these measures.
The stereoselectivity of the discriminative stimulus properties of cyclazocine, another opioid of the benzomorphan series, in squirrel monkeys was explored in Experiment VI. The (+) isomer produced dose dependent PCP-appropriate responding . The (-) isomer and the racemic mixture did not produce PCP-appropriate responding at any of the doses tested. The (-) isomer was 300 times more potent than the (+) isomer in overall response rate suppression.
The work presented in this thesis suggests that PCP belongs to a unique class of drugs which can have a wide variety of chemical structures. The overalp in the behavioral pharmacology of PCP and the psychotomimetic opioids of the benzomorphan series is probably due to the activity of the (+) isomers of these compounds.
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