Review
Serotonin research: contributions to understanding psychoses

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The history of serotonin research is closely related to the study of hallucinogenic drugs that function as agonists at serotonin-2A receptors. The fundamental idea that psychotic states seen in psychiatric disorders such as schizophrenia might be attributable, in part, to abnormalities in serotonergic systems began with the almost simultaneous discovery of lysergic acid diethylamide (LSD), psilocybin and serotonin. Sixty years of study have confirmed early speculations regarding the important relationship between serotonin and both drug-induced and disorder-based psychotic states. Now, modern biochemical, pharmacological, behavioral, neuroimaging, genetic and molecular biological sciences are converging to understand how serotonergic systems interact with other monoaminergic and glutamatergic systems to modulate states of consciousness and contribute to psychotic disorders such as the group of schizophrenias. This review summarizes experimental assessments of the serotonergic hallucinogen model psychosis in relation to the serotonin hypothesis of schizophrenia.

Introduction

The history of research on serotonin, or 5-hydroxytryptamine (5-HT), is closely intertwined with modern studies of the neurobiological origins of psychotic states in general and the group of schizophrenia disorders in particular. Among the defining events that led to this early association were the discoveries of the psychosis-like effects of lysergic acid diethylamide (LSD) by the late Albert Hofmann (Sandoz, www.sandoz.com) and the identification, less than a decade later, of serotonin as an endogenous neurohormone. As summarized in Table 1, the concept that the drug-induced psychotic state induced by LSD is attributable to either antagonist or agonist actions at serotonin receptors rapidly led to the suggestion that LSD provides a model psychosis. This concept prompted the fundamental hypotheses that abnormalities of serotonin function are responsible for psychiatric disorders such as the spectrum of schizophrenia disorders and, therefore, that serotonin agonists or antagonists might be useful in the treatment of schizophrenia. Experimental studies have confirmed early descriptions [1] of striking similarities between psychotic states in psychiatric disorders and the subjective reports of subjects under the influence of psychedelic drugs. Serotonergic hallucinogens such as LSD or the naturally occurring compound psilocybin produce profound changes in mood, thought, intuition, sensory perception, the experience of time and space, and even the experience of self. In these states, perceptual hypersensitivity, illusions and elementary hallucinations are common. In general, the intensity of these alterations of perception and consciousness are dose dependent, so that hallucinations involving disorientation in person, place and time rarely, if ever, occur with low-to-medium doses 2, 3. Depending upon the individual, the individual's expectations and the setting, the same hallucinogen might produce a loss of ego boundaries combined with elevated mood states ranging from pleasure to bliss and feelings of oneness, or might lead to more psychotic ego dissolution including fear and paranoid ideation associated with experiences of split ego [4]. Such experiential phenomena are otherwise rarely reported except in dreams, contemplative or religious exaltation, and acute psychoses 5, 6, 7. Thus, the discovery of the effects of LSD led rapidly to the suggestion that serotonergic hallucinogens provide model psychoses and, more generally, to the serotonin hypothesis of schizophrenia. The subsequent experimental assessment of these hypotheses and the new directions of research engendered by this line of work are discussed here.

Section snippets

Parallels between dose-related hallucinogen effects and the development of schizophrenia

Systematic comparisons of the symptom profiles associated with serotonergic hallucinogens and schizophrenia disorders have demonstrated robust qualitative similarities with the earliest phases of schizophrenic psychoses, with fewer similarities being evident in the chronic phases of the illnesses 8, 9, 10, 11, 12. The heightened awareness and euphoria reported by some healthy volunteers treated with psilocybin or the phenalkylamine hallucinogen mescaline in addition to the negative affective

Experimental studies of the model psychosis induced by serotonin agonists

A commonality among many theoretical descriptions of the neuronal basis of the symptomatology in schizophrenia and other psychotic disorders is the basic idea that deficits in early information processing engender the cognitive disturbances and even the psychotic symptoms observed in psychotic disorders in psychiatry 18, 19, 20. The notion is that an underlying dysfunction of information-processing mechanisms in the schizophrenia spectrum involves an inability of these patients to screen out,

Serotonin receptors involved in psychotomimetic effects

The initial uncertainty in the mid-1950s (Table 1) as to whether serotonergic hallucinogens such as LSD or psilocybin function primarily as serotonin agonists or antagonists 39, 40 continued well through the 1980s. As reviewed in Ref. [15], studies using different model systems indicated that LSD is an agonist, a partial agonist or even an antagonist at serotonin receptors. Suffice it to say that the accumulated evidence from biochemical, electrophysiological and behavioral studies in animals

Serotonin circuits and interactions with other systems

Early research into the effects of serotonergic hallucinogens and hallucinogenic anesthetics (e.g. phencyclidine and ketamine) on brain electrical activity in animals indicated that the key psychological effects of these drugs arise along a continuum of excitation. Specifically, after an initial excitation characterized by electro-encephalographic (EEG) desynchronization and psychomotor activation, all of these drugs induce a state with intermittent bursts of hypersynchronous 2.5-Hz EEG wave

New directions for research on serotonin and psychosis

Despite the extensive research linking serotonin and psychosis over the past six decades, exciting new findings are now prompting studies of novel mechanisms that could further our understanding of the neurobiology of drug- and disease-induced psychoses. Experimental approaches ranging from molecular biology to behavioral studies indicate that the unifying principle of 5-HT2A-agonist actions as mediating the psychedelic and psychotomimetic effects of serotonergic hallucinogens is

Future research on serotonergic contributions to psychoses

Six decades of discovery, observation and experimental study have generated compelling evidence that serotonergic systems and particularly central 5-HT2A receptors are important in the genesis of drug-induced psychotic states and in the treatment and potentially the etiology of some psychotic disorders such as schizophrenia. The chemical tools of discovery provided by the late Albert Hofmann facilitated the elucidation of this fundamental relationship between serotonin and psychosis. Research

Acknowledgements

We dedicate this work to the memory of Albert Hofmann, who passed away at the age of 102 during the preparation of this review. He was a friend and inspiration to both these and many other authors. M.A.G. was supported by the National Institute on Drug Abuse (DA02925) and the Veterans Affairs VISN 22 Mental Illness Research, Education and Clinical Center. F.X.V. was supported by the Swiss National Science Foundation, Swiss Federal Office of Health (BAG), the National Alliance for Research on

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