INVESTIGATION OF HALLUCINOGENIC AND RELATED BETA-CARBOLINES

Certain beta-carbolines are known to be hallucinogenic in humans, and several produce stimulus effects in animals similar to those of the cl assical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane ( DOM). Classical hallucinogens bind at 5-HT2 serotonin receptors and th ese receptors are thought to play a role in their mechanism of action. In the present study, we examined the binding of 15 beta-carbolines a t rat 5-HT2A and 5-HT2C receptors. Affinities (K-i values) of the beta -carbolines ranged from about 100 nM to greater than 10000 nM dependin g upon the degree of saturation of the pyridyl ring, and upon the pres ence and location of methoxy substituents in the benzenoid ring. In a further study, six rats were trained to discriminate the hallucinogeni c beta-carboline harmaline (3.0 mg/kg, i.p.) from vehicle using a VI-1 5s schedule of reinforcement. This represents the first time a halluci nogenic beta-carboline has been used as a training drug in a drug disc rimination study. Administration of DOM to the harmaline-trained anima ls resulted in 76% harmaline-appropriate responding at 1.25 mg/kg DOM and disruption of behavior at a higher dose. Taken together, the resul ts of the present investigation demonstrate that: (a) certain beta-car bolines bind at 5-HT2, receptors; (b) that harmaline serves as a train ing drug at 3.0 mg/kg in drug discrimination studies with rats as subj ects; and that (c) there is some similarity between the stimulus effec ts produced by harmaline and DOM. (C) 1998 Elsevier Science Ireland Lt d. All rights reserved.