Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior
This study (2007) identifies the biological reasons, the specific regulation of Gi/o proteins and Src, why psychedelics that affect the 5-HT2A receptor have hallucinogenic effects while agonists (lusuride) do not.
Authors
- Gonza ´lez-Maeso, J.
- Weisstaub, N. V.
- Zhou, M.
Published
Abstract
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT2A receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
Research Summary of 'Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior'
Introduction
Hallucinogenic compounds such as psilocybin, mescaline and LSD profoundly alter perception, emotion and cognition and share high affinity for the serotonin 5-HT2A receptor (2AR). Genetic or pharmacological blockade of 2AR prevents hallucinogen effects in multiple species, yet a key paradox remains: some compounds that are 2AR agonists, for example lisuride and ergotamine, lack hallucinogenic activity in humans. The neuronal substrates and signalling mechanisms that explain why only a subset of 2AR agonists produce hallucinogenic effects have therefore remained unclear. González-Maeso and colleagues set out to identify the cellular and molecular basis for this distinction. They compared hallucinogenic (HC) and nonhallucinogenic (NHC) 2AR agonists across behavioural, transcriptional, electrophysiological and pharmacological assays in mice, and used a genetic rescue strategy to restore 2AR expression selectively to cortical neurons of 2AR-deficient (htr2A -/-) mice. The study aims to determine whether distinct 2AR-mediated signalling pathways in cortical neurons account for hallucinogen-specific effects and whether cortical 2AR expression is sufficient to restore those effects.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- APA Citation
González-Maeso, J., Weisstaub, N. V., Zhou, M., Chan, P., Ivic, L., Ang, R., Lira, A., Bradley-Moore, M., Ge, Y., Zhou, Q., Sealfon, S. C., & Gingrich, J. A. (2007). Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron, 53(3), 439-452. https://doi.org/10.1016/j.neuron.2007.01.008
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