Role of Serotoninergic Neurons and 5-HT Receptors in the Action of Hallucinogens

This book chapter (2000) investigates the role of psychedelics on serotonin (5-HT) receptors. The chapter leans heavily on animal research, as at the time of publishing (but still today) human research is limited in scope.

Abstract

“Brain serotonin receptors and serotoninergic pathways have received increasing attention as targets for a wide variety of therapeutic agents. Perhaps peculiar to this realm, however, are the so-called hallucinogenic drugs, which presently lack demonstrated therapeutic utility, and still remain, as they have for at least the past 50 years, pharmacological curiosities. Research into their mechanism of action is generally poorly funded, and we know relatively little about how they affect the brain, despite their continued popularity as recreational drugs among a significant proportion of the population.“

Author: David E. Nichols

Notes

A newer book chapter (or more recent papers) may provide a better overview of what we currently know.

Summary

A. Introduction

Brain serotonin receptors and serotoninergic pathways have received increasing attention as targets for a wide variety of therapeutic agents, but hallucinogenic drugs still remain a pharmacological curiosity.

Modern man is at a loss to describe the effects of hallucinogenic drugs, and even neuroscientists know very little about them. These substances are subject to strict legal controls, especially in humans.

The name “hallucinogen” is a misnomer, because these drugs do not reliably produce hallucinations. Other names for these drugs include “psychotomimetic” and “entheogen”, but there is no consensus on the best name for this class of drugs.

Naturally occurring hallucinogenic drugs have played an important role in the development of philosophy and religious thought in many cultures. In ancient Greece, a secret ceremony involved drinking a special hallucinogenic potion, and in Brazil, ayahuasca is used in religious rituals.

Psychedelics are substances that induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation. They are feared by modern man, yet revered by many ancient cultures.

The hallucinogens do not obey regular dose-response relationships, and the nature of the drug effect depends on several important variables, including the subject’s set and the environment within which the experience takes place.

Dr. Stanislov Grof has opined that LSD is a powerful unspecific amplifier of biochemical and physiological processes in the brain. This unpredictability is a primary factor in adverse reactions (“bad trips”) that occur with recreational use of these drugs.

LSD use among high school youth has continued at a relatively constant level over the past several decades, with some modest increase reported in recent years. At lower dosages, the psychological effects are generally not overwhelming.

A person with dyslexia may experience somatic, perceptual, and psychic symptoms.

One gets the clear impression that the receptors in the brain that are affected by hallucinogenic drugs are very important in defining exactly who we are in relation to the rest of the world.

Although present interest in hallucinogenic drugs is focused on purely basic science goals, one must not lose sight of the fact that these drugs only came to our attention because of their powerful and unique effects upon the psyche.

B. Chemical Classes of Hallucinogens

The chemical structures of hallucinogens can be classified into two broad categories: (1) the tryptamines, and (2) the phenethylamines. The tryptamines include simple tryptamines such as DMT and psilocin, and the ergolines, relatively rigid analogs including LSD and a few closely related compounds.

Fig. 1 shows the chemical structures of hallucinogen molecules, including (+ )-LSD, (+ )-tartaric acid, and substituted “amphetamines”, e.g., DOM.

c. Historical Relationship Between Serotonin and Hallucinogen Action

After the isolation and identification of serotonin, interest in its role as a neurotransmitter was greatly stimulated by the virtually contemporaneous discovery of LSD. The discovery of LSD led to the discovery of serotonin and the subsequent development of sensitive assays for serotonin and its metabolites.

The idea that LSD could be attributed to the blockade of central serotonin receptors was short lived, however, as a brominated derivative of LSD was found to be devoid of LSD-like effects, and morpholide analogues of LSD had only 8% of the anti serotonin activity of LSD.

Although LSD was not a central antagonist of serotonin, it did have effects on serotoninergic function in the CNS. It was also suggested that LSD might have a direct agonist effect at serotonin receptors in the eNS.

D. Early Hypothesis for a Presynaptic Agonist Mechanism of Action

LSD, DMT, psilocin and 5-methoxy-DMT have been found to inhibit the firing of cells in the dorsal raphe nucleus. This might be the underlying basis for the action of hallucinogens.

The rate suppressant effect of phenethylamine hallucinogens on raphe cell firing was soon established to be mediated by stimulation of 5-HT 1A somatodendritic receptors. However, 5-HT 1A agonists that suppressed raphe cell firing were identified that were not hallucinogenic.

E. Evidence for Agonist Activity at the 5-HT2A Serotonin Receptor Subtype

The vast majority of mechanistic studies have been carried out in rodents, and the two-lever drug discrimination procedure appears to be the most useful model for studying hallucinogenic drugs.

Although the model cannot be certain that studies carried out with this paradigm actually reflect what would happen in humans if similar experiments were performed, it has shown the best correlation with extant human data.

Hallucinogenic drugs act at 5-HT2 receptor subtypes, and the most potent substituted phenethylamine hallucinogen analogue, DOTFM, has 5-HT2A/2C affinity and is a full agonist at the cloned 5-HTzA and 5-HTzc receptors.

There has been some uncertainty as to which of the two 5-HT2A and 5-HT2C receptor subtypes is more important to the mechanism of action of hallucinogens. However, a highly selective 5-HT2A receptor antagonist was able to abolish the discriminative cue of the hallucinogenic amphetamine derivative DOl.

FIORELLA et al. (1995b) found that the ability of 5-HT2A receptor antagonists to block the discriminative stimulus properties of (-)-DOM was correlated with their affinity for 5-HT2A sites.

Rat head twitches are mediated by 5-HT2A receptors, and can be abolished by the 5-HT2A selective antagonist MDL 100.907.

Although the preponderance of evidence suggests that hallucinogens are agonists, some studies have shown that LSD may be a partial agonist or even an antagonist at the 5-HT2A receptor. Some caution must still remain regarding the extrapolation of rat drug discrimination data to humans.

I. Mechanistic Basis for Rapid Tolerance to the Hallucinogens

The administration of hallucinogens to humans results in the development of tolerance, which is of great interest because it could help understand the mechanism of action of hallucinogens.

Repeated treatment of rats with DOM leads to desensitization and downregulation of central 5-HTz receptors, and the number of receptors recovers only very slowly after four injections in 24 h.

II. Possible Species Differences?

Although the interoceptive cue produced by hallucinogens may be mediated by 5-HTzA receptor stimulation, the effects of hallucinogens on rat behavior may not be strictly analogous to those in humans.

The serine/alanine residue 242 in transmembrane helix 5 of the human 5-HTzA receptor can explain the different binding affinities of the two receptors for mesulergine.

Following a similar line of inquiry, JOHNSON et al. (1994) and NELSON et al. (1993) showed that the difference in the amino acid Ser242 between the rat and human 5-HT2A receptors is responsible for the difference in affinity of ergolines and their N(l)-alkyl derivatives.

The human 5-HTzA receptor may bind psilocin in a different orientation than N,N-dimethyltryptamine, serotonin, or bufotenin (5-hydroxy-N,N-methyltryptamine), and this may be due to a hydrogen bond with Ser242 in the psilocin moiety.

F. Evidence for Involvement of the 5-HT2C Receptor Subtype

Lisuride, a nonhallucinogenic analogue of LSD, is able to produce hallucinogenic effects in rats by activating 5-HT2A receptors. However, lisuride is not an agonist at 5-HT2C receptors and can actually block the agonist actions of 5-HT at this receptor.

Additional animal data suggests that serotonin depletion may be a necessary but not sufficient condition for hallucinogenesis. This issue cannot be resolved until an analogue is tested in man that possesses selective 5-HTzA agonist effects but lacks any action at the 5-HTc receptor.

The 5-HT2C receptor subtype is a principal 5-HT receptor in the rat brain, and is expressed at high levels in many brain regions other than the choroid plexus.

G. Evidence for 5-HT1A Receptor Involvement

The earliest hypothesis for the mechanism of action of hallucinogens was based on studies showing that LSD, psilocybin, and DMT inhibited the firing rate of cells in the dorsal raphe nucleus. This hypothesis could not be extended to the phenethylamine hallucinogens.

Hallucinogens act by activating the 5-HT1A receptor, which is located on the cell membranes of serotonin neurons. Phenethylamines do not activate the 5-HT1A receptor and thus do not suppress raphe firing.

LSD and potent tryptamine hallucinogens such as 5-methoxy-DMT and psilocin bind to 5-HT1A receptors, and DMT is equally efficacious to 8-hydroxy-2-( di-n-propylamino )tetralin (8-OH-DPAT) in inhibiting forskolin-stimulated cAMP formation.

LSD may produce 5-HT1A receptor-mediated effects, at least in some animal behavioral assays. The selective 5-HT1A receptor agonist 8-0HDPA T can mimic LSD in rats trained to discriminate the latter agent from saline.

Ketanserin and pirenperone failed to block the LSD cue in LSD-trained monkeys, and 5-methoxy-DMT substituted for LSD. These results suggest that 5-HT1A receptors may be preferentially involved in mediating the LSD stimulus effect.

Several studies have reported evidence of functional interactions between 5-HT1A and 5-HTz receptors. For example, 5-HT1A agonists may appear to be 5-HTz antagonists, and propranolol can block the disruptive behavior induced by LSD.

The 5-HT1A agonist 8-OH-DPAT inhibits the DOI-induced head twitch in rats, and the 5-HT1A antagonist (-)-tertatolol antagonizes this effect. This result is consistent with other studies suggesting functional interactions between these two serotonin receptor types in the modulation of various behaviors.

The authors suggest that 5-HT2 receptors may modulate 5-HTIA receptors, and that functional interactions exist between 5-HT1A and 5-HT2A receptors, evident not only in various behaviors, but also observable at the neuronal level.

Clinical data are lacking that might clarify the issue of 5-HT1A agonist activity in tryptamine hallucinogens. The author offers the hypothesis that compounds that are purely 5-HT2A/2C agonists may elicit a greater effect on central visual processes than compounds that are 5-HT1A agonists.

H. Potentiating Effects of Interactions at Other Receptor Subtypes

In a study by FIORELLA et al. (1995b), only 56% of the variability in the potency of a given antagonist to block the interoceptive cue produced by LSD could be accounted for by 5-HT2A affinity alone.

LSD may have potentiating effects at other monoamine receptors, besides the 5-HT2A and 5-HT2C receptors, since it binds with high affinity to a variety of receptors, including 5-HT1A and 5-HT2C receptors.

Although it is unlikely that the 5-HT1A agonist effects of LSD are responsible for its remarkable potency, it is possible that the 5-HT1A agonist effects of LSD may functionally antagonize 5-HTzA agonist actions.

LSD has modest affinity for a-adrenergic receptors, and clonidine may potentiate the stimulus properties of LSD in the two-lever drug discrimination paradigm.

LSD has high affinity for dopamine D z receptors and may also activate dopamine D2 receptors at behaviorally relevant doses. It has also been shown that stimulation of the 5-HT2A receptor can enhance dopaminergic function.

There is a large body of evidence that dopamine D2 receptor stimulation may potentiate serotonin 5-HT2A agonism, and thus be useful for investigating schizophrenia and psychosis.

I. Conclusions

The pharmacology of hallucinogens is characterized by an agonist interaction with serotonin 5-HT2A receptors, and perhaps also with serotonin 5-HT2c receptors. Tryptamine hallucinogens also potently activate serotonin 5-HT1A receptors.

LSD’s high potency cannot be explained simply by its affinity for serotonin 5-HTzA – 5-HT2e – or 5-HTli receptors, but may be due to the potentiating interaction of LSD with dopamine D2 receptors.

Animal pharmacology studies have shown that these molecules have a profound effect upon the human psyche. It is hoped that renewed interest in these molecules will lead to greater knowledge of their human pharmacology.