Discriminative stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane in rhesus monkeys.

In rhesus monkeys trained to distinguish the hallucinogen DOM from a placebo, the drug's effects lasted up to two hours and were blocked by serotonin 5-HT2A receptor antagonists but not by the dopamine antagonist haloperidol. Other hallucinogens such as LSD and 2C-T-7 produced DOM-like effects, but the kappa-opioid hallucinogen salvinorin A did not, nor did several other psychoactive drugs. These results confirm that 5-HT2A receptors play a key role in the discriminative stimulus effects of certain hallucinogens in nonhuman primates, and they reveal that different classes of hallucinogens produce qualitatively distinct effects.

Study at a glance

Abstract

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 kappa-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.