The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens.
Clinton E. Canal, Kevin S. Murnane
Journal of Psychopharmacology November 15, 2016 DOI: 10.1177/0269881116677104 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Addiction Serotonin |
| Keywords | Ventral tegmental area Nucleus accumbens Animals Humans Cocaine Receptor, serotonin, 5-ht2a Receptor, serotonin, 5-ht2c Hallucinogens Behavior, addictive Kv1 |
| Key findings | Classic hallucinogens may counteract addiction through 5-HT 2C receptor activation that inhibits Kv1.x channels in nucleus accumbens shell GABAergic neurons, enhancing inhibitory activity. |
Abstract
Classic hallucinogens share pharmacology as serotonin 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT 2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT 2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area—nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT 2C receptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT 2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.
Comparable studies
Other narrative reviews on serotonin, most cited first.
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