Alterations in brain serotonergic function have been implicated in the mechanism of action of LSD, mescaline, and other similarly acting hallucinogenic drugs of abuse such as STP (2, DOM). In order to test the hypothesis that the mechanism of action of LSD and phenylisopropylamine hallucinogens is through stimulation of a specific brain serotonin receptor sub-type, the affinities of these compounds for radiolabelled 5-HT2, 5-HT1A, 5-HT1B, and 5-HTIc receptors have been determined using recently developed in vitro radioligand binding methodologies. The 5-HT2 receptor was labelled with the agonist/hallucinogen radioligand 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine). The 5-HT1A, 5-HT1B, and 5-HTlc receptors were labelled with 3H-OH-DPAT, 3H-5-HT, and 3H-mesulergine, respectively. In general, the phenylisopropylamines displayed 10-100fold higher affinities for the 5-HT/receptor than for the 5-HTlc receptor and 100-1000 fold higher affinities for the 5-HT2 receptor than for the 5-HT~A or 5-HT~B receptor. There was a strong correlation between hallucinogenic potencies and 5-HT2 receptor affinities of the phenylisopropylamines (r=0.90); the correlation coefficients for the 5-HT~A, 5-HTzB, and 5-HTzc were 0.73, 0.85, and 0.78, respectively. Because there is no evidence that 5-HT1A-selective or 5-HTtB-selective agonists are hallucinogenic and because the phenylisopropylamines are potent hallucinogens, a 5-HT2 receptor interaction is implicated and supports our previous suggestions to this effect. A secondary role for 5-HT~c receptors cannot be discounted at this time. These results, when integrated with other receptor pharmacological information, indicate that an important component of the mechanism of action of LSD and the phenylisopropylamine hallucinogens is through stimulation of brain 5-HT 2 receptors.The mechanism of action underlying the hallucinogenic and/or psychoactive properties of LSD has been an intriguing mystery for more than 40 years. Evidence pointing to the involvement of serotonergic systems was provided by the electrophysiological studies of Aghajanian et al. (1968, Offprint requests to : M. Titeler 1970, 1972. However, the identification of a pharmacologically defined receptor as the specific site of action of LSD accounting for its potent mind-altering effects has been elusive.The phenylisopropylamine hallucinogens produce a syndrome that is apparently very similar to the spectrum of effects produced by LSD (Shulgin 1978). One strategy for uncovering a specific hallucinogenic site of action for LSD has been to identify a common site of action of the phenylisopropylamine hallucinogens and LSD. Extensive structure-activity studies (SAR) have been pursued involving testing the hallucinogenic and/or psychoactive potencies of these compounds (Nichols and Glennon 1984). Also SAR studies involving testing the potencies of the phenylisopropylamines as behavioral cues in rats trained to bar-press when administered the hallucinogenic phenylisopropylamine DOM (2,5-dimethoxyphenylisopropylamine) have...