This review (2016) investigates and proposes a model how psychedelics work in the brain, specifically with regards to the 5-HT (serotonin) 2C receptor. The authors also explain how this mechanism may work to treat addiction.
Abstract
“Classic hallucinogens share pharmacology as serotonin 5-HT2A, 5-HT2B, and 5-HT2C 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-HT2C 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-HT2C 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-HT2C 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-HT2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.“
Authors: Clinton E. Canal & Kevin S. Murnane
Summary
Classic hallucinogens are serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonists that counteract the addictive effects of drugs from several classes. This review builds rationale for the hypothesis that 5-HT2C receptors on NAc shell, GABAergic, medium spiny neurons inhibit potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms.
Classic hallucinogens are serotonin 5-HT2 receptor agonists
Several types of hallucinogens are classified as CH, including psilocybin, lysergic acid diethylamide, mescaline, and 2,5-dimethoxy-4-bromoamphetamine. These drugs have been characterized extensively in both nonhuman animals and in humans.
All CH have high affinity for serotonin 5-HT2 G protein-coupled receptors, and most stimulate 5-HT2 receptors at low nanomolar concentrations. However, some CH also stimulate 5-HT1 receptors, and some have been reported to stimulate adrenergic GPCRs, but using traditional radioligand competition binding assays we did not replicate the observed effects.
CH’s psychoactive effects are blocked by 5-HT2 receptors in both rodents and humans. 5-HT2A, 5-HT2B, and/or 5-HT2C receptors may be the elemental GPCRs that underlie CH’s non-addictive nature.
Results from preclinical studies and reports from experienced hallucinogen users show that classic hallucinogens have low addiction liability
CH are relatively non-addictive compared to other psychoactive drugs scheduled by federal governments in the most restrictive classes, including heroin in Schedule 1 and cocaine in Schedule 2. Experienced drug users report that CH do not produce drug craving or an impulse to re-dose after psychoactive effects have peaked.
CH’s non-addictive characteristics are recapitulated in well-controlled, preclinical animal studies, which demonstrate a strong correlation between drugs that produce dependence in humans and those that are voluntarily consumed by laboratory animals.
In one of the earliest studies on the reinforcing effects of drugs, no animal initiated self-administration of mescaline either spontaneously or after one month of programmed administration.
Administration of morphine, codeine, cocaine, amphetamine, pentobarbital, ethanol, and caffeine to rhesus monkeys provided similar results as the mescaline study. In one example, extreme environmental conditions were required to elicit self-administration of DMT in monkeys. After several days of sensory deprivation, two of the three monkeys consistently self-administered DMT for up to 20 days. In a second example, psilocybin, mescaline, and DMT were substituted in monkeys that were maintained on a baseline of ()-MDMA self-administration. Although these subjects transiently and sporadically self-administered these hallucinogens, these effects were weak and clearly unlike those seen across a broad range of other psychoactive drugs.
Despite the relative absence of addictive properties, CH can elevate mood and produce a strong sense of well-being, but they also produce profound alterations in cognition and sensory perception and can produce emotional lability, fear, anxiety, and/or panic.
Why are classic hallucinogens non-addictive? Focus on serotonin
There are several biological possibilities to explore why CH are relatively non-addictive, including long durations of action and 5-HT2A receptor desensitizaton, which causes rapid, prolonged, and profound tolerance to their psychoactive effects. LSD’s psychedelic effects are greatly attenuated with repeated dosing, but DMT’s effects persist with repeated administration in a single drug-taking session. Despite their differerent durations of action and capacities to induce tolerance, none of the CH mentioned above are known to produce drug craving in human users.
Psychoactive drugs increase dopamine release in the nucleus accumbens, which in turn increases dopamine release in the ventral tegmental area (VTA), prefrontal cortex (PFC), amygdala, hippocampus, dorsal striatum, and NAc. Serotonin plays a modulatory role in the behavioral effects of many psychoactive drugs.
Many studies demonstrate that enhancing central serotonin release attenuates addictive behaviors. For example, using designer receptors exclusively activated by designer drugs (DREADDs) abolishes cocaine-elicited conditioned place preference and reduces the potency of several cocaine- and amphetamine-like analogs in self-administration studies. Studies in rodents and nonhuman primates show that selective SERT inhibitors decrease cocaine self-administration, cocaine-induced increases in extracellular dopamine, and cocaine-induced activation of the PFC. Furthermore, serotonin attenuates the abuse-related and addictive effects of psychoactive drugs.
Serotonin attenuates the reinforcing effects of a variety of psychoactive drugs through suppression of dopamine neurotransmission. There are 16 distinct serotonin receptors that can facilitate, inhibit, or have no effect on dopamine neurotransmission. 5-HT2C and 5-HT2A receptors have opposing effects on dopamine neurotransmission, which may explain why CH, which do not provide a large spread between 5-HT2C and 5-HT2A receptor activation, do not induce craving.
Considerations of 5-HT2A receptor activation to addiction liability
There is substantial evidence that the 5-HT2A receptor facilitates dopamine neurotransmission, but systemic administration of DOI in rhesus monkeys does not increase dopamine levels in the NAc. This suggests that DOI acts on additional neural systems or microcircuits.
Studies employing neuroimaging, behavioral pharmacology, and genetic tools suggest that 5-HT2A receptors may contribute to drug seeking. This is supported by observations that 5-HT2A knockout mice self-administer MDMA to a lesser degree than wild-type mice, and that 5-HT2A receptor antagonists attenuate drug-induced increases in motor activity. Systemic administration of 5-HT2A receptor antagonists does not alter dopamine neuronal firing or release, but agonist stimulation of this receptor enhances dopaminergic activity.
Studies using reinstatement procedures to model drug relapse show that 5-HT2A receptor antagonism prevents reinstatement of drug-seeking behavior, and that 5-HT2A receptor antagonism attenuates both cue- and drug-induced reinstatement of extinguished behavior in rats.
Studies suggest that selective activation of 5-HT2A receptors may induce craving and/or relapse. However, it will be critical to assess empirically the addictive or antiaddictive potential of highly selective 5-HT2A agonists.
Considerations of 5-HT2B receptor activation to addiction liability
Much less attention has been given to 5-HT2B receptors in the central nervous system, and there is not a widely accepted 5-HT2B agonist probe. Thus, there is somewhat limited data regarding the contribution of 5-HT2B receptor activation to psychoactive substances.
Studies using knockout mice and 5-HT2B ligands show that 5-HT2B receptors contribute to the psychomotor effects of MDMA, dexfenfluramine, and selective serotonin reuptake inhibitors, although different 5-HT2B antagonists may affect these effects differently.
A designer empathogen, 1-(benzofuran-6-yl)propan-2-amine (6-APB), binds to the 5-HT2B receptor with >100-fold selectivity compared to 5-HT2A or 5-HT2C receptors, and is a 5-HT2B receptor agonist. It produces subjective effects similar to MDMA, but does not produce drug craving.
Behavioral studies
Multiple lines of evidence suggest that 5-HT2C receptor activation attenuates self-administration of addictive substances and also attenuates ICSS of the brain’s primary reward circuitry. A number of selective 5-HT2C receptor agonists have been found to recapitulate the attenuating effects of indirect serotonin agonists on behavioral models of addiction.
Studies have shown that cocaine, alcohol, cannabis, and nicotine can induce reinstatement of cocaine seeking and cocaine self-administration.
Recent studies show that Ro 60-0175 and lorcaserin reduce the psychostimulant effects of cocaine and reduce cocaine self-administration and reinstatement in primates.
5-HT2C receptors inhibit a variety of abuse-related effects of drugs, including locomotor stimulant effects, discriminative stimulus effects, cocaine self-administration, and cocaine-induced reinstatement. Additionally, 5-HT2C receptors may be addictive substances themselves.
Neurochemistry studies
5-HT2C receptor activation decreases psychostimulant-elicited dopamine release in the NAc, which is the most supported mechanism for the anti-addiction effects of 5-HT2C activation.
5-HT2C receptors on GABA neurons innervating dopamine neurons inhibit dopamine neuron activity, while 5-HT2C receptors on dopamine neurons themselves stimulate dopamine neuron activity. This suggests that the emergent effects of 5-HT2C receptor activation on dopamine neurotransmission depend on the relative activation of 5-HT2C receptors on different cell types.
Other findings corroborate the view that 5-HT2C receptor activation impacts reward circuitry via multiple mechanisms, including direct modulatory effects on dopamine signaling in the NAc. 5-HT2C receptor knockout mice exhibit increased cocaine-stimulated release of dopamine in their NAc. The 5-HT2C receptors in the NAc are densely expressed, but not in the dorsal striatum. This suggests that post-synaptic 5-HT2C receptors in the NAc may be responsible for the system-specific effect of 5-HT2C agonists and antagonists on dopamine release.
The data show that 5-HT2C agonists, administered systemically, have a strong effect on dopamine release in reward circuitry, and may be useful in the treatment of addiction.
The NAc is a key site for 5-HT2C receptor modulation of reward circuitry
Much of the circuitry-related data supporting 5-HT2C receptor modulation of psychostimulant effects is focused on 5-HT2C receptors expressed on GABA neurons of the VTA. However, important rationale for our focus on 5-HT2C receptors in the NAc is that they negatively modulate the effects of cocaine.
5-HT2C receptors are expressed on GABAergic MSN of the NAc, and 5-HT2C agonists suppress cocaine-stimulated dopamine release in the NAc, but not in the dorsal striatum. This suggests that 5-HT2C receptors are contributing significantly to the anti-addiction effects of 5-HT2C agonists, with special relevance to cocaine addiction.
The shell region of the NAc is associated more closely than the core with the appetitive or reinforcing effects of addictive substances, and 5-HT2C selective agonists decrease, and inverse agonists increase, dopamine release in the NAc shell. Immunohistochemistry results show that 5-HT2C receptors are expressed at higher densities in the NAc shell, relative to the core, and that they enhance D1-containing MSN activity, thereby increasing GABA release in the VTA.
Based on the literature, we hypothesize that activation of 5-HT2C receptors on GABAergic MSN in the NAc shell inhibits Kv1.x channels, leading to increased intrinsic activity, which would directly counteract the decrease in NAc shell MSN activity caused by psychostimulant exposure.
Potassium Kv1.x channels regulate the intrinsic activity of neurons, allowing potassium ions to flow from within the cell, and preventing the flow of potassium ions, causing spontaneous depolarization and increasing action potential frequency and neurotransmitter release.
Several studies have shown that 5-HT2C receptors are expressed in neural systems where Kv1.x channels are also expressed, and that 5-HT2C activation suppresses Kv1.x channel activity. The exact cell signaling pathways underlying these effects remain unclear.
Cocaine increases potassium currents in the NAc shell, which leads to a decrease in excitability and firing rate of GABAergic MSN. This decrease in excitability and firing rate leads to enhanced locomotor responses and behavioral sensitization to cocaine, and enhanced cocaine self-administration.
5-HT2C receptors modulate Kv1.x channels in several neural systems, including the frontal and cingulate cortices, and could be extended to other neural systems. However, 5-HT2A receptors also modulate Kv1.x channels, specifically Kv1.5 channels in cardiac tissue and Kv1.2 channels in cortical pyramidal neurons. The modulatory activity of 5-HT2 receptor subtypes that affects behavior is complex, and further elucidation of their individual functions will likely lead to further discovery of 5-HT2 receptor subtype expression patterns within discrete neural circuits.
Many cell types and unique afferents are found within the NAc and VTA. It would be interesting to compare the behavioral and neurochemical effects of 5-HT2C agonists to those of 5-HT2A agonists to tease apart contributions of the 5-HT2 receptor subtypes more clearly.
Classic hallucinogens treat addiction
Literature from the 1950s through the 1970s shows that CH are non-addictive and can reverse the addictive effects of other psychoactive drugs. They have also been used to alleviate neurotic symptoms by indigenous people for thousands of years. Most studies focused on the use of LSD for the treatment of alcoholism. The results of these studies demonstrated consistent treatment effects supporting the efficacy of LSD compared to current Food and Drug Administration-approved medications for alcoholism.
Work with CH largely terminated by the 1970s, but there has been a resurgence in the study of CH in the last decade, and some researchers speculate that stimulation of 5-HT2A receptors may exacerbate substance dependence.
Herein, we have proposed a hypothesis that the beneficial effects of CH for substance dependence are mediated by agonist stimulation of 5-HT2C receptors. However, if CH also downregulate 5-HT2A receptors, this may account for their purported therapeutic effects.
Despite the potential for CH to treat addiction, repeated exposure to CH could also chronically alter 5-HT2C receptor expression and/or function, potentially leading to an enhanced susceptibility to addiction.
hallucinogens
The literature suggests a number of experiments that warrant testing in future studies, including determining whether recently synthesized compounds such as 25CN-NBOH, which shows 90-fold higher selectivity for activating 5-HT2A over 5-HT2C, also show higher abuse liabilities than CH, and determining the precise localization of 5-HT2C receptors in cells of the NAc.
Figure 1.
Autoradiographs of brain 5-HT2C receptors from mice that overexpress 5-HT2C (5-HT2C-VGV) show that 5-HT2C 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.