The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis.
David Fiorella, R A Rabin, Jerrold C Winter
Psychopharmacology October 1995 DOI: 10.1007/bf02246074 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical behavioral pharmacology study Peer reviewed |
|---|---|
| Population | Rats trained to discriminate LSD from saline |
| Interventions | LSD (-)DOM risperidone pirenpirone metergoline ketanserin loxapine LY53857 pizotyline spiperone cyprohepatadine mesulergine promethazine thioridazine |
| Dose | 0.1 mg/kg LSD (15-min pretreatment time), 0.4 mg/kg (-)DOM (75-min pretreatment) |
| Topics | Serotonin |
| Key points | The potency of a series of serotonergic antagonists in blocking LSD-appropriate responding correlated significantly with their 5-HT2A receptor affinity for both LSD (r = +0.75) and (-)DOM (r = +0.95) stimuli, but not with 5-HT2C affinity. The authors conclude that the stimulus effects of LSD and the substitution of (-)DOM for LSD are mediated by agonist activity at 5-HT2A receptors. |
Abstract
Investigations conducted over the past 3 decades have demonstrated that serotonergic receptors, specifically the 5-HT2A and 5-HT2C subtypes, play an important role in the behavioral effects of hallucinogenic compounds. The present study was designed to determine the respective significance of these two receptors in the stimulus effects of LSD and (-)DOM in the rat. Specifically, the interactions of a series of serotonergic antagonists (risperidone, pirenpirone, metergoline, ketanserin, loxapine, LY53857, pizotyline, spiperone, cyprohepatadine, mesulergine, promethazine, and thioridazine) with the LSD stimulus and the (-)DOM stimulus in LSD-trained subjects was defined. From these data, IC50 values were determined for the inhibition of the LSD-appropriate responding elicited by either 0.1 mg/kg LSD (15-min pretreatment time) or 0.4 mg/kg (-)DOM (75-min pretreatment). In addition, the affinities of these antagonists for 5-HT2A and 5-HT2C receptors were determined in radioligand competition studies, 5-HT2A affinity correlated significantly with IC50 values for the blockade of the LSD (r = +0.75, P < 0.05) and (-)DOM (r = +0.95, P < 0.001) stimuli in the LSD trained subjects. 5-HT2C affinity did not correlate significantly with either series of IC50 values. These data indicate that (1) the stimulus effects of LSD, and (2) the substitution of (-)DOM for the LSD stimulus are mediated by agonist activity at 5-HT2A receptors.