The role of the 5-HT_2A and 5-HT_2C receptors in the stimulus effects of hallucinogenic drugs I: Antagonist correlation analysis

Investigations conducted over the past 3 decades have demonstrated that serotonergic receptors, specifically the 5-HT_2A and 5-HT_2C 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, cyproheptadine, 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-HT_2A and 5-HT_2C receptors were determined in radioligand competition studies. 5-HT_2A 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-HT_2C 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-HT_2A receptors.