Discriminative Stimulus Effects of 1-(2,5-Dimethoxy-4-Methylphenyl)-2-Aminopropane in Rhesus Monkeys: Antagonism and Apparent pA2 Analyses
- Departments of Pharmacology (J.-X.L., C.P.F.) and Psychiatry (C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Chemical Biology Research Laboratory, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland (K.C.R.)
- 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
Abstract
Discriminative stimulus effects of the serotonin (5-HT) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) have been studied in rats and, more recently, in rhesus monkeys. This study examined DOM, 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), and dipropyltryptamine hydrochloride (DPT) alone and in combination with three antagonists, MDL100907 [(±)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]], ketanserin [3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione], and ritanserin [6-[2-[4-[bis(4-fluorophenyl)methylidene]piperidin-1-yl]ethyl]-7-methyl-[1,3]thiazolo[2,3-b]pyrimidin-5-one], to identify the 5-HT receptor subtype(s) that mediates the discriminative stimulus effects of these 5-HT receptor agonists. Four adult rhesus monkeys discriminated between 0.32 mg/kg s.c. DOM and vehicle while responding under a fixed ratio 5 schedule of stimulus shock termination. DOM, 2C-T-7, and DPT dose-dependently increased responding on the DOM-associated lever. MDL100907 (0.001-0.01 mg/kg), ketanserin (0.01-0.1 mg/kg), and ritanserin (0.01-0.1 mg/kg) each shifted the dose-response curves of DOM, 2C-T-7, and DPT rightward in a parallel manner. Schild analysis of each drug combination was consistent with a simple, competitive, and reversible interaction. Similar apparent affinity (pA2) values were obtained for MDL100907 in combination with DOM (8.61), 2C-T-7 (8.58), or DPT (8.50), for ketanserin with DOM (7.67), 2C-T-7 (7.75), or DPT (7.71), and for ritanserin with DOM (7.65), 2C-T-7 (7.75), or DPT (7.65). Potency of antagonists in this study was correlated with binding affinity at 5-HT2A receptors and not at 5-HT2C or α1 adrenergic receptors. This study used Schild analysis to examine receptor mechanisms mediating the discriminative stimulus effects of hallucinogenic drugs acting at 5-HT receptors; results provide quantitative evidence for the predominant, if not exclusive, role of 5-HT2A receptors in the discriminative stimulus effects of DOM, 2C-T-7, and DPT in rhesus monkeys.
Footnotes
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This work was supported in part by the Intramural Research program of the National Institutes of Health National Institute on Drug Abuse and National of Institutes of Health National Institute on Alcohol Abuse and Alcoholism; and by National Institutes of Health National Institute on Drug Abuse [Grant DA17918].
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doi:10.1124/jpet.108.145458.
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ABBREVIATIONS: 5-HT, serotonin; DOM, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane; MDL100907, (±)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]; ketanserin, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione; ritanserin, 6-[2-[4-[bis(4-fluorophenyl)-methylidene]piperidin-1-yl]ethyl]-7-methyl-[1,3]thiazolo[2,3-b]pyrimidin-5-one; 2C-T-7, 2,5-dimethoxy-4-(n)-propylthiophenethylamine; DPT, dipropyltryptamine hydrochloride; FR, fixed ratio; CL, confidence limit; MK-212, 6-chloro-2(1-piperazinyl) pyrozine hydrochloride.
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- Received August 28, 2008.
- Accepted December 15, 2008.
- U.S. Government work not protected by U.S. copyright
