Behavioral and biochemical distinctions in the pharmacology of two common hallucinogens

Emmanuelle A. D. Schindler

doi:10.17918/00008709

Hallucinogens have undergone relatively sparse scientific exploration in the past half-century, which has limited their clinical application and left them a pharmacological mystery. Serotonin2A (5-HT2A) receptors and the frontocortical brain region have strong ties to both hallucinogenesis and psychosis, a condition that hallucinogens mimic. As a tool to study psychosis and improve therapy, the basic pharmacology of hallucinogens must first be scrutinized. This thesis addressed this need by examining both behavioral and biochemical aspects of two common hallucinogens, LSD and DOI. The behavioral measure of drug-elicited head bobs (HBs) was used for its strong relationship to frontocortical 5HT2A receptors. The biochemical measure of PI hydrolysis, a major second messenger signal resulting from 5-HT2A receptor activation, was also analyzed. Rabbits were injected with either LSD or DOI and observed for HBs. Frontocortical tissue of naive rabbits was used to determine receptor binding affinities, study the effects of acute in vivo drug injection, and measure hallucinogen-induced PI hydrolysis. Some rabbits were treated chronically with DOI and various measures taken at different time points during recovery. Finally, hallucinogens were infused directly into the medial prefrontal cortex to study the role of this brain area in mediating HBs. Whereas HBs elicited by systemic DOI are mediated by several receptors, including 5-HT2A, 5-HT1A, dopaminel (D1), and D2 receptors, HBs produced by systemic LSD are only mediated by 5-HT2A and D1 receptors. In contrast to DOI, LSD demonstrated non-competitive, pseudo-irreversible binding at frontocortical 5-HT2A receptors. Both hallucinogens induced PI hydrolysis in rabbit frontocortical tissue, but the LSD and DOI signals were 5-HT2C- and 5HT2A-mediated, respectively. Finally, inhibition of the rate limiting enzyme for PI hydrolysis abolished DOI, but not LSD, HBs in the frontal cortex. In summary, DOI uses a 5-HT2A - PI hydrolysis mechanism to elicit HBs, whereas LSD uses 5-HT2A receptors independent of PI hydrolysis. Ultimately, dopaminergic receptor activation may be the final step in behavior, suggesting a role for dopamine in hallucinogenesis. The distinctions between LSD and DOI provide new insight into hallucinogen pharmacology, supporting the complex nature of human psychosis and warranting further investigation into the mechanism of action of these agents.

Behavioral and biochemical distinctions in the pharmacology of two common hallucinogens

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Behavioral and biochemical distinctions in the pharmacology of two common hallucinogens

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