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BEHAVIORAL PHARMACOLOGY

Discriminative Stimulus Effects of 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane in Rhesus Monkeys

Departments of Pharmacology (J.-X.L., C.P.F.) and Psychiatry (C.P.F.), the University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Chemical Biology Research Laboratory (K.C.R.), National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland

Discriminative stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and related drugs have been studied extensively in rodents, although the generality of those findings across species is not known. The goals of this study were to see whether monkeys could discriminate DOM and to characterize the DOM discriminative stimulus by studying a variety of drugs, including those with hallucinogenic activity in humans. Four rhesus monkeys discriminated between 0.32 mg/kg s.c. DOM and vehicle after an average of 116 (range = 85–166) sessions while responding under a fixed ratio 5 schedule of stimulus shock termination. Increasing doses of DOM occasioned increased responding on the drug lever with the training dose occasioning DOM-lever responding for up to 2 h. The serotonin (5-HT)_2A/2C receptor antagonists ritanserin and ketanserin, the 5-HT_2A receptor antagonist (+)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL100907), and its (-)stereoisomer MDL100009 [(-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol], but not haloperidol, completely blocked the discriminative stimulus effects of DOM. Quipazine as well as several drugs with hallucinogenic activity in humans, including (+)lysergic acid diethylamide, (-)DOM, and 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), occasioned DOM-lever responding. The -opioid receptor agonists U-50488 and salvinorin A (a hallucinogen) did not exert DOM-like effects and neither did ketamine, phencyclidine, amphetamine, methamphetamine, cocaine, morphine, yohimbine, fenfluramine, 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), or (±)-2-(N-phenethyl-N-1'-propyl)amino-5-hydroxytetralin hydrochloride (N-0434). These data confirm in nonhuman primates a prominent role for 5-HT_2A receptors in the discriminative stimulus effects of some drugs with hallucinogenic activity in humans. The failure of another drug with hallucinogenic activity (salvinorin A) to substitute for DOM indicates that different classes of hallucinogens exert qualitatively different discriminative stimulus effects in nonhumans.

Address correspondence to: Dr. Charles P. France, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail france{at}uthscsa.edu