The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens

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.

Keywords: 5-HT2C; Hallucinogens; Kv1; addiction; cocaine.

Figure 1

Autoradiographs of brain 5-HT_2C receptors from mice that overexpress 5-HT_2C (5-HT_2C-VGV) allowing clear observations of 5-HT_2C receptor distribution in the brain. Notably, 5-HT_2C is densely expressed in the nucleus accumbens (NAc), but not in the dorsal striatum (DStr); the darker the shade, the higher the receptor binding site density. [³H]Mesulergine (3 nM for eight weeks) or [¹²⁵I]DOI (0.14 nM for 48 hours) was used in the presence of spiperone (100 nM) to label 5-HT_2C receptors. These sections were part of a set collected by Dr. Canal (Olaghere da Silva et al., 2010). All sections labeled with [³H] Mesulergine or with [¹²⁵I]DOI are from the same brain. Pictures from the latter were cropped and pasted to align them vertically.

Figure 2

Proposed 5-HT2C anti-cocaine addiction mechanism involving modulation of Kv1.x channels on GABAergic medium spiny neurons (MSN) of the NAc shell.