Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens
This paper (2011) reviews the evidence that indoleamine hallucinogens act not only on the 5-HT2 receptor group but on a variety of receptors to produce their behavioral effects.
Abstract
Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.
Research Summary of 'Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens'
Introduction
Hallucinogens are pharmacological agents that produce marked alterations of perception, mood and cognition and have been used in ritual and medicinal contexts for millennia. Classical serotonergic hallucinogens fall into two structural classes: indoleamines (for example LSD, psilocin, DMT and 5-MeO-DMT) and phenylalkylamines (for example mescaline, DOM, DOI). Despite structural differences, the two classes produce very similar subjective effects in humans and show cross-tolerance, which historically suggested a common receptor mechanism. Earlier research converged on the 5-HT2A receptor as the primary mediator of the characteristic effects of serotonergic hallucinogens, but many indoleamines are relatively non-selective and bind to a broader set of monoamine receptors, raising the possibility that non-5-HT2 receptors contribute meaningfully to their psychopharmacology. Halberstadt and colleagues set out to review and synthesise evidence from human and animal studies that address which receptor interactions mediate the behavioural effects of indoleamine hallucinogens. The review examines pharmacology (binding profiles and functional actions), electrophysiological findings (for example effects on dorsal raphe nucleus firing), and behavioural paradigms commonly used to probe hallucinogen effects in animals (drug discrimination, head twitch response, prepulse inhibition, exploratory/investigatory behaviour, 5-HT syndrome components, and species comparisons). The stated aim is to clarify the relative contributions of 5-HT2A and non-5-HT2 receptor mechanisms to the behavioural and subjective effects of indoleamine hallucinogens.
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Halberstadt, A. L., & Geyer, M. A. (2011). Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), 364-381. https://doi.org/10.1016/j.neuropharm.2011.01.017
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