Serotonin and serotonin receptors in hallucinogen action

This book chapter (2010) reviews the effects of psychedelics on the brain, specifically looking at the serotonin (5HT) receptors.

Abstract

“Hallucinogens are a class of substances that induce profound changes in perception and cognition. A closely related drug, 3,4-methylenedioxymethamphetamine (MDMA), produces euphoria and a feeling of empathy, with minimal sensory distortion. Both of these classes of substances produce their effects by interacting with the serotonergic system. This chapter will review the receptor interactions that contribute to the behavioral effects of serotonergic hallucinogens and MDMA. In rodents, the behavioral effects of hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and mescaline are primarily mediated by activation of 5-HT2A receptors. There is evidence, however, that 5-HT1A receptors, 5-HT2C receptors and dopamine receptors may play a secondary role. The molecular requirements for interaction of hallucinogens with the 5-HT2A receptor are well-defined on the basis of structure-activity relationships. By contrast with the hallucinogens, MDMA is a potent releaser of monoamines that has complex effects on serotonergic, dopaminergic and noradrenergic systems. In recent years, psilocybin and MDMA have been administered to human volunteers in controlled clinical trials. Human studies confirm that the 5-HT2A receptor plays a primary role in mediating the subjective effects of psilocybin, whereas the effects of MDMA are largely attributable to carrier-mediated release of serotonin. These findings emphasize the importance of clinical investigation of hallucinogenic drugs. Additionally, there is a growing consensus that these drugs are likely to show therapeutic efficacy in the treatment of certain psychiatric disorders.”

Authors: Adam L. Halberstadt & David E. Nichols

Summary

Introduction

Hallucinogenic drugs have been used by humans for thousands of years to diagnose and cure disease, induce mystical and spiritual states, and produce euphoria and inebriation. Modern scientific investigation of hallucinogens began with the identification of mescaline as the active principal of peyote by Arthur Heffter in 1897.

The first description of LSD’s hallucinogenic effects coincided with the isolation and characterization of serotonin (5-HT). It was soon recognized that LSD acts as a 5-HT agonist in some assay systems.

Serotonergic hallucinogens produce subjective psychological effects such as changes in thought and mood, depersonalization, and perceptual alterations.

Soon after the discovery of LSD, it was recognized that hallucinogens have similarities to the symptomatology of schizophrenia. Psilocybin and MDMA have been used experimentally to produce a model psychosis, and it has been claimed that MDMA has value as an adjunct to psychotherapy.

5-HT 2A receptor

The 5-HT 2A receptor is a G q/11-coupled receptor that is linked to the phosphoinositide hydrolysis signaling cascade. Phenylalkylamine hallucinogens bind to 5-HT 2A receptors with high affinity.

Drug discrimination

Much of what is known about hallucinogenic drugs has been derived from drug discrimination studies. These studies show that hallucinogens produce similar interoceptive stimulus effects.

Head-twitch response

Hallucinogens induce stereotypical motor responses in laboratory animals, including ear scratching in mice, head twitching in mice and rats, reciprocal hindleg body scratch in gerbils, limb flicks and abortive grooming in cats, and limb jerks in primates. There is extensive evidence that the 5-HT 2A receptor mediates the hallucinogen-induced HTR. This evidence was provided by the finding that the ability of hallucinogens to induce the HTR is abolished in 5-HT 2A / knockout mice.

Exploratory and investigatory behavior

Open-field measures of unconditioned locomotor activity are often used to assess compounds for stimulant or depressant effects. The Behavioral Pattern Monitor (BPM) provides both quantitative and qualitative measures of unconditioned locomotor and investigatory activity in rats.

Hallucinogens decrease locomotor activity and investigatory behaviors, increase avoidance of the center of the chamber, and are associated with exacerbation of the neophobia and agoraphobia normally exhibited by rats.

The effects of DOI and 5-MeO-DMT in the BPM paradigm are mediated by activation of 5-HT 2A receptors, but the effects of LSD and 5-MeO-DMT in the BPM paradigm are mediated by activation of both 5-HT 1A and 5-HT 2A receptors.

Prepulse inhibition of startle

Acoustic startle responses are attenuated when preceded by a weak prestimulus, a phenomenon known as prepulse inhibition (PPI). Hallucinogens such as LSD, DOI, DOB and 5-MeO-DMT disrupt PPI in rats.

5-HT 2C receptor

Hallucinogens bind to 5-HT 2C receptors with high affinity, and are relatively non-selective for 5-HT 2A versus 5-HT 2C receptors. The action of hallucinogens at 5-HT 2C receptors has led authors to speculate that hallucinogenesis may be mediated by interactions with both of these receptor populations.

The correlation between 5-HT 2C receptor affinity and hallucinogen potency may be due to the parallel structure – affinity relationships between 5-HT 2A and 5-HT 2C receptors. However, 5-HT 2C antagonists fail to block the behavioral effects of hallucinogens.

Although some evidence suggests that 5-HT 2C receptor interactions may contribute to or modify the effects of some hallucinogens, the vast majority of evidence demonstrates that these effects are not dependent on the 5-HT 2C receptor.

5-HT 1A receptor

LSD and other indoleamine hallucinogens inhibit the firing of serotonergic neurons in the dorsal raphe nucleus (DRN). However, the presynaptic hypothesis of hallucinogen action is flawed because phenylalkylamine hallucinogens display negligible 5-HT 1A binding affinity and do not consistently depress DRN cell firing.

The 5-HT 1A receptor is partially responsible for the effects of LSD and 5-MeO-DMT on the BPM and the discriminative stimulus effects of LSD and 5-MeO-DMT are also partially mediated by the 5-HT 1A receptor.

Animals trained with 5-MeO-DMT have a strong behavioral response to the drug, which is mediated by the 5-HT 1A receptor.

There is evidence that activation of the 5-HT 1A receptor can inhibit 5-HT 2A receptor-induced behavioral effects, and that 8-OH-DPAT and DOI can act as functional antagonists.

Dopamine receptors

Based on similar symptoms between schizophrenia and hallucinogenic drugs, it has been proposed that dopaminergic systems are involved in the mechanism of action of hallucinogens. However, it has now been established that indolealkylamine and phenylalkylamine hallucinogens lack appreciable affinity for dopamine receptors.

There is evidence that dopaminergic mechanisms play a role in the discriminative stimulus properties of LSD, and that the 5-HT 2A and D 2 receptors contribute to the interoceptive state governing LSD discrimination, whereas the 5-HT 2A receptor contributes only to DOM discrimination. Studies have shown that the dopaminergic component of the LSD discriminative stimulus is time-dependent. When a longer pretreatment time is used, the LSD cue is mediated by D 4 receptors rather than by 5-HT 2A receptors.

Chemistry and structure – activity relationships

The serotonin 5-HT 2A receptor is the key target for hallucinogens, and the structures of DMT, 5-methoxytryptamine, psilocin and LSD are similar. This explains why these molecules interact with serotonin receptors.

Recent mutagenesis studies of the 5-HT 2A receptor have revealed that the serine residue in transmembrane helix 5 interacts with the 5-hydroxy group of serotonin, as well as the 5-methoxy group of the 2,5-dimethoxy-substituted phenethylamines.

The binding site of phenethylamines must shrink or compress to accommodate the amine, and N -alkyl groups would hinder the interaction. By contrast, tertiary amines are potent because they engage the amino group through an approach more perpendicular to the plane of the molecule.

Substitution of an alpha-methyl group on the phenethylamine side-chain gives more potent compounds. This is probably due to the alpha-methyl group retarding metabolic deamination, adding significant hydrophobicity, and improving the efficacy of the compound in activating second messenger systems.

Although substitution at the 6-indole position of the tryptamines renders them inactive, substituting the phenethylamines at the 4-position provides good activity. This is likely due to the different sizes of the phenethylamines and tryptamines.

3 ,4,5-substituted phenethylamines do not bind to the receptor in the same way as 2,4,5-substituted phenethylamines, but a hydrophobic 4-alkoxy substituent gives highest activity in this series.

LSD’s rigid nature limits its conformational flexibility upon binding, and its ergoline NH hydrogen bonds to Ser242 in transmembrane helix 5. Very little structural modification can be tolerated by ergolines related to LSD.

The bulky diethylamide moiety is limited in its conformational flexibility, and any modification of the diethylamide gives about an order of magnitude decrease in potency. However, constraining the diethylamide into a 2,4-dimethylazetidide gave a compound with potency comparable to LSD.

Receptors mediating the behavioral effects of MDMA in animals

MDMA is a potent monoamine-releasing drug that binds to monoamine transporters and increases the non-exocytotic release of serotonin, dopamine and norepinephrine.

MDMA, a hallucinogenic amphetamine, has a different stereochemistry in its alpha side-chain carbon bearing the methyl group than the hallucinogenic amphetamines, and therefore belongs to a distinct class of psychoactive agents called entactogens.

Drug discrimination

Rats can be trained to discriminate MDMA from vehicle. The MDMA stimulus cue is clearly distinct from that produced by hallucinogens.

The neurochemical basis for the discriminative stimulus effects of MDMA is complex, and is incompletely characterized. It is likely that 5-HT release plays a role in the stimulus effects of MDMA, but the identity of the specific 5-HT receptor subtype(s) involved remains to be elucidated.

Prepulse inhibition of startle

MDMA and MDE attenuate PPI in rats and mice, and the effect is blocked by M100907, indicating 5-HT 2A receptor involvement. Fenfluramine also attenuates PPI.

Assessment of hallucinogen-induced altered states of consciousness

The Altered States of Consciousness (APZ) rating scale is a self-administered questionnaire that was developed by Dittrich to assess alterations of consciousness. It has been confirmed to be sensitive to the effects of hallucinogens. Dittrich has proposed that hallucinogens produce three major effects: oceanic boundlessness, anxious ego dissolution and visionary restructuralization. Psilocybin also produces auditory effects and increases cerebral glucose metabolic activity in the prefrontal cortex, anterior cingulate, temporomedial cortex and putamen.

Mechanism of hallucinogen effects in humans

Early studies used serotonin, dopamine and norepinephrine receptor antagonists to block the effects of hallucinogens, but these compounds were not selective and so the effects of hallucinogens were not linked to any particular transmitter system.

Meltzer and colleagues examined whether the moderately selective 5-HT 2A/2C antagonist cyproheptadine and the D 2 antagonist haloperidol could block the psychological effects induced by DMT in normal human volunteers. Neither drug effectively blocked the effects of DMT, and in some subjects the effects were actually intensified by pretreatment with cyproheptadine.

Psilocybin

Vollenweider and colleagues assessed the effect of pretreatment with ketanserin, risperidone and haloperidol on the effects of psilocybin in human volunteers. They found that ketanserin and risperidone blocked the effects of psilocybin on the OB, AED and VR dimensions of the APZ.

Mechanism of MDMA effect in humans

Citalopram, ketanserin, and haloperidol all reduced the subjective effects of MDMA, but none of them blocked the cardiovascular effects of MDMA or the ability of the drug to increase PPI. Pindolol did not substantially alter the subjective effects of MDMA or its effect on measures of cognitive performance. However, preclinical evidence in rodents indicates that the 5-HT 1A receptor plays a role in the behavioral effects of MDMA.

Summary

Over the past three decades, substantial progress has been made toward understanding how hallucinogens exert their complex behavioral effects. The 5-HT 2A receptor is the primary mediator of these effects in humans.

MDMA, an entactogen, has been the subject of intense study in recent years. These studies have provided insight into the pharmacology of hallucinogens.

Psilocybin was administered to normal human volunteers and showed positive effects on mood and behavior. It is anticipated that future research will yield additional insight into hallucinogens and serotonin.