Role of 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs II: reassessment of LSD false positives

In the context of animal studies of hallucinogens, an LSD-false positive is defined as a drug known to be devoid of hallucinogenic activity in humans but which nonetheless fully mimics LSD in animals. Quipazine, MK-212, lisuride, and yohimbine have all been reported to be LSD false positives. The present study was designed to determine whether these compounds also substitute for the stimulus effects of the more pharmacologically selective hallucinogen (–)DOM (0.56 mg/kg, 75-min pretreatment time). The LSD and (–)DOM stimuli fully generalized to quipazine (3.0 mg/kg) and lisuride (0.2 mg/kg), but only partially generalized to MK-212 (0.1–1.0 mg/kg) and yohimbine (2–20 mg/kg). In combination tests, pirenpirone (0.08 mg/kg), a compound with both D₂ and 5-HT_2A affinity, blocked the substitution of quipazine and lisuride for the (–)DOM stimulus. Ketanserin (2.5 mg/kg), an antagonist with greater than 1 order of magnitude higher affinity for 5-HT_2A receptors than either 5-HT_2C or D₂ receptors, also fully blocked the substitution of these compounds for the (–)DOM stimulus, while the selective D₂ antagonist thiothixene (0.1–1.0 mg/kg) failed to block the substitution of lisuride for the (–)DOM stimulus. These results suggest that quipazine and lisuride substitute for the stimulus properties of the phenylalkglamine hallucinogen (–)DOM via agonist activity at 5-HT_2A receptors. In addition, these results suggest that 5-HT_2A agonist activity may be required, but is not in itself sufficient, for indolamine and phenylalkglamine compounds to elicit hallucinations in humans. Finally, it is concluded that MK-212 and yohimbine are neither LSD nor (–)DOM false positives.This study was supported in part by US Public Health Service grant DA 03385 (J.C.W., R.A.R.), by National Research Service Award MH 10567 (D.F.), and by a fellowship from Schering-Plough Research Institute (D.F.). Animals used in these studies were maintained in accordance with the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council.