Elsevier

Biological Psychiatry

Volume 44, Issue 11, 1 December 1998, Pages 1099-1117
Biological Psychiatry

A Decade of Serotonin Research: Role of Serotonin in Treatment of Psychosis
Serotonergic basis of antipsychotic drug effects in schizophrenia

https://doi.org/10.1016/S0006-3223(98)00187-5Get rights and content

Abstract

Recent attention has been focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. There are two reasons for the new emphasis: the tremendous success of the so-called “atypical” antipsychotic drugs (a common feature of which is their high affinity for specific 5-HT receptor subtypes); and the elucidation of a complex family of 5-HT receptors whose function and pharmacology is only beginning to be understood. This paper will review the evidence that pertains to the role of 5-HT in mediating antipsychotic drug effects. The interaction of dopamine and 5-HT systems will be reviewed, and the mechanisms of action of atypical antipsychotic drugs will be evaluated in this context. The impact of serotonin on neurodevelopment, and the involvement of serotonin in the psychotomimetic and psychotogenic properties of hallucinogens, will be discussed. Together, these facts will be placed into the context of changes in serotonergic function in schizophrenia.

Introduction

Since the advent of chlorpromazine and elucidation of its mechanisms of action, there has been a focus on dopamine (DA) neurotransmission both in formulating pathophysiological theories of schizophrenia and in developing new therapeutic agents Randrup and Munkvad 1965, Carlsson 1974, Snyder et al 1974, Creese et al 1976, Seeman et al 1976, Davis et al 1991. Recently, considerable attention has been focused on the potential involvement of serotonin (5-HT) in both the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. One reason for this has been the tremendous success of the so-called “atypical” antipsychotic drugs that have as a common feature high affinity for one or more 5-HT receptor subtypes (e.g., 5-HT2A). In fact, it is now known that there is a large family of 5-HT receptors whose function and pharmacology are only beginning to be understood. The molecular biology of serotonin receptors, and the therapeutic implications of drugs acting at these receptors is reviewed in the article by Kroeze and Roth (this issue).

This paper will review evidence linking 5-HT systems to the mediation of antipsychotic drug effects, and also to the possible etiology of the disorder. We shall address the role of serotonin in neurodevelopment, and the functional interactions of DA and 5-HT systems. By examining the psychotomimetic and psychotogenic properties of hallucinogens, and changes in serotonergic function in schizophrenia, we hope to provide insight into how 5-HT systems may play a role in the clinical action of atypical antipsychotic drugs, and to highlight many of the remaining unanswered questions.

Section snippets

Functional interactions of DA and 5-HT systems

A major line of evidence supporting a potential role of serotonin in mediating antipsychotic drug effects involves the anatomical and functional interactions of DA and 5-HT. DA and 5-HT neurotransmission interact at different anatomical levels, are mediated by different 5-HT receptor subtypes, and affect different aspects of DA function. Generally speaking, the reduction of 5-HT activity is associated with an enhancement of DA. This interaction has been suggested to account for the beneficial

5-HT2a receptor antagonist properties of atypical antipsychotics

Meltzer et al (1989) formalized and popularized a concept that had been previously suggested in a report by Ceulemans et al (1985), to wit, that the ratio of 5-HT2A to D2 affinities was the key pharmacologic property of atypical antipsychotic drugs. Meltzer et al (1989) suggested that typical and atypical antipsychotics can be distinguished on the basis of lower D2 and higher 5-HT2A pKI values (a logarithmic measure of the affinity of a drug for its receptor), parameters derived from in vitro

Psychotomimetic and psychotogenic properties of hallucinogens

Another line of evidence linking serotonin to schizophrenia and, by extension, antipsychotic drug activity is the research on hallucinogenic drugs. Several terms are often used for such drugs, including hallucinogen and psychotomimetic. It should be recognized that both terms are misnomers, because not all such drugs reliably produce hallucinations, nor do they usually produce a state that mimics psychosis. As such, despite the differences between the effects of “hallucinogens” and the symptoms

Evidence for 5-HT dysfunction in schizophrenia

There is sparse evidence for 5-HT involvement in the pathophysiology of schizophrenia. Direct evidence for abnormal 5-HT2A-mediated neurotransmission in schizophrenia comes primarily from cerebral spinal fluid (CSF) studies of 5-HT metabolites and postmortem ligand binding studies of 5-HT, 5-HT metabolites, 5-HT transporters, and 5-HT receptors. Indirect evidence comes from pharmacologic challenges probing the 5-HT system, the observed effects of antipsychotic drugs with clinical efficacy in

Serotonin and neurodevelopment: implications for atypical antipsychotics

Serotonin plays a role in the development of multiple tissues and organs, including the fertilized ovum, the heart, the intestines, craniofacial structures, and the central nervous system from the earliest stages of gastrulation through adulthood (Lauder 1990). Within the brain, serotonin influences neuronal and glial morphology, connectivity, and function (Azmitia and Whitaker-Azmitia 1991). Some of these effects are direct, some are mediated by growth factors (the best characterized of which

Conclusions

In summary, a broad array of evidence (both direct and indirect) implicates 5-HT in the pathophysiology of schizophrenia, and as a key substrate mediating atypical antipsychotic drug effects Kapur and Remington 1996, Kapur 1996. Moreover, in view of the role of serotonin in neurodevelopment and neuronal plasticity, there is a strong rationale for the potential involvement of serotonin in the pathogenesis and neurodevelopmental diathesis of schizophrenia. This evidence, however suggestive of and

Acknowledgements

This work was supported, in part, by US Public Health Service research grants MH00537, MH-40537, and MH-42705, and Center grants MH33127 and HD03310.

This work was presented at the Neuroscience Discussion Forum “A Decade of Serotonin Research” held at Amelia Island, Florida in November, 1997. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

References (210)

  • M.B Bowers et al.

    Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in psychiatric patients

    Int J Neuropharmacol

    (1969)
  • A Breier et al.

    Clozapine attenuates metachlorophenylpiperazine (mCPP)-induced plasma cortisol increases in schizophrenia

    Biol Psychiatry

    (1993)
  • D.L Cameron et al.

    A subset of ventral tegmental area neurons is inhibited by dopamine, 5-hydroxytryptamine and opioids

    Neuroscience

    (1997)
  • A.J Carlsson

    Antipsychotic drugs and catecholamine synapses

    Psychiatry Res

    (1974)
  • J Chen et al.

    Activation of 5-HT3 receptor by 1-phenylbiguanide increases dopamine release in the rat nucleus accumbens

    Brain Res

    (1991)
  • A.R Chubakov et al.

    The effects of serotonin on the morpho functional development of rat cerebral neocortex in tissue culture

    Brain Res

    (1986)
  • M.L De Ceballos et al.

    Prenatal exposure of rats to antidepressant drugs down-regulates beta-adrenoreceptors and 5-HT2 receptors in cerebral cortex

    Neuropharmacology

    (1985)
  • A Dray et al.

    Evidence for the existence of a raphe projection to the substantia nigra in rat

    Brain Res

    (1976)
  • A Dray et al.

    The dorsal and median raphe projections to the substantia nigra in the ratElectrophysiological, biochemical and behavioral observations

    Brain Res

    (1978)
  • H.C Fibiger et al.

    An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat

    Neuroscience

    (1977)
  • D.X Freedman et al.

    Psychotomimetic drugs and brain 5-hydroxytryptamine metabolism

    Biochem Pharmacol

    (1970)
  • K Fuxe et al.

    Effects of 5-methoxy-N,N-dimethyltryptamine on central monoamine neurons

    Eur J Pharmacol

    (1972)
  • J Gelernter et al.

    Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome

    Genomics

    (1995)
  • D.M Gillies et al.

    Effects of 5-HT3 receptor-selective agents on locomotor activity in rats following injection into the nucleus accumbens and the ventral tegmental area

    Eur J Pharmacol

    (1996)
  • R.A Glennon et al.

    Antagonism of the effects of the hallucinogen DOM and the purported 5-HT agonist quipazine by 5-HT2 antagonists

    Eur J Pharmacol

    (1983)
  • R.A Glennon et al.

    Structure activity studies on amphetamine analogues using drug discrimination methodology

    Pharmacol Biochem Behav

    (1984)
  • R.A Glennon et al.

    Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents

    Eur J Pharmacol

    (1984)
  • H.A Gromova et al.

    Serotonin as a stimulator of hippocampal cell differentiation in tissue culture

    J Dev Neurosci

    (1983)
  • X.M Guan et al.

    Serotonin microinfusion into the ventral tegmental area increases accumbens dopamine release

    Brain Res Bull

    (1989)
  • D Herve et al.

    Serotonin axon terminals in the ventral tegmental area of the ratFine structure and synaptic input to dopaminergic neurons

    Brain Res

    (1987)
  • X Huang et al.

    5-HT2 receptor-mediated potentiation of dopamine synthesis and central serotonergic deficits

    Eur J Pharmacol

    (1993)
  • N Iqbal et al.

    The mCPP challenge test in schizophreniaHormonal and behavioral responses

    Biol Psychiatry

    (1991)
  • R.S Kahn et al.

    m-Chlorophenylpiperazine as a probe of serotonin function

    Biol Psychiatry

    (1991)
  • R.S Kahn et al.

    Serotonin function in schizophreniaEffects of metachlorophenylpiperazine in schizophrenic patients and healthy subjects

    Psychiatry Res

    (1992)
  • H.-T Kao et al.

    Site-directed mutagenesis of a single residue changes the binding properties of the serotonin 5-HT2 receptor from a human to a rat pharmacology

    FEBS Lett

    (1992)
  • N.E Andén et al.

    Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide

    Br J Pharmacol Chemother

    (1968)
  • N.E Andén et al.

    Hallucinogenic drugs of the indolealkylamine type and central monoamine neurons

    J Pharmacol Exp Ther

    (1971)
  • N.C Andreasen et al.

    Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography

    Arch Gen Psychiatry

    (1992)
  • R.C Arora et al.

    Serotonin 2 (5-HT2) receptor binding in frontal cortex of schizophrenic patients

    J Neural Transm Gen Sect

    (1991)
  • M.J Arranz et al.

    Cytochrome P4502D6 genotype does not determine response to clozapine

    Br J Clin Pharmacol

    (1995)
  • E.C Azmitia et al.

    Awakening the sleeping giantAnatomy and plasticity of the brain serotonergic system

    J Clin Psychiatry

    (1991)
  • M.W Baker et al.

    Modulation of in vivo neuronal sprouting by serotonin in the adult CNS of the snail

    Cell Mol Neurobiol

    (1996)
  • S Benloucif et al.

    Serotonin-facilitated dopamine release in vivoPharmacological characterization

    J Pharmacol Exp Ther

    (1993)
  • J.P Bennett et al.

    Neurotransmitter receptors in frontal cortex of schizophrenics

    Arch Gen Psychiatry

    (1979)
  • C.A Bennett-Clark et al.

    Fenfluramine depletes serotonin from the developing cortex and alters thalamocortical organization

    Brain Res

    (1995)
  • S Blandina et al.

    Release of endogenous dopamine by stimulation of 5-hydroxytryptamine3 receptors in the striatum

    J Pharmacol Exp Ther

    (1989)
  • T Branchek et al.

    [3H]-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and [3H]ketanerin label two affinity states of the cloned human 5-hydroxytryptamine2 receptor

    Mol Pharmacol

    (1990)
  • G.R Breese et al.

    Evidence for involvement of 5-hydroxytryptamine in the actions of amphetamine

    Br J Pharmacol

    (1974)
  • M.S Brodie et al.

    Serotonin potentiates dopamine inhibition of ventral tegmental area neurons in vitro

    J Neurophysiol

    (1996)
  • K.D Burris et al.

    (+)Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist

    J Pharmacol Exp Ther

    (1991)
  • Cited by (0)

    View full text