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Published online before print November 2, 2007

0031-6997/07/5904-360-417$7.00
Pharmacol Rev 59:360-417, 2007

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5-HT Receptor Regulation of Neurotransmitter Release

Klaus B. Fink and Manfred Göthert

Department of Pharmacology, Bonn University Clinic, Bonn, Germany

Abstract
I. Introduction: Background, Definitions, and Scope
II. Experimental Approaches
    A. In Vitro Studies
    B. In Vivo Studies
    C. Advantages and Limitations of the Techniques Applied
III. Modulation of Cholinergic Neurotransmission
    A. General Aspects
    B. 5-Hydroxytryptamine 1A Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
    C. 5-Hydroxytryptamine 1B and 5-Hydroxytryptamine 1D Receptors
        1. Function and Location.
        2. Classification and Development of Nomenclature.
            a. 5-Hydroxytryptamine 1B/1D ligands.
            b. Rat 5-hydroxytryptamine 1B receptor.
            c. Development of guinea pig and human 5-hydroxytryptamine 1B and 5-hydroxytryptamine 1D auto- and heteroreceptor nomenclature.
            d. Guinea pig 5-hydroxytryptamine 1B receptor.
            e. Human 5-hydroxytryptamine 1B receptor?
        3. Specific Aspects.
        4. Concluding Summary Statement.
    D. 5-Hydroxytryptamine 2 Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
    E. 5-Hydroxytryptamine 3 Receptors
        1. Function and Location.
        2. Classification.
        3. Specific Aspects.
        4. Concluding Summary Statement.
    F. 5-Hydroxytryptamine 4 Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
IV. Modulation of Dopaminergic Neurotransmission
    A. General Aspects
    B. Dopamine Transporter-Mediated Dopamine Release
        1. Function, Location, and Mechanism.
        2. Concluding Summary Statement.
    C. Modulation via 5-Hydroxytryptamine Receptors Putatively Located on Interneurons
        1. 5-Hydroxytryptamine 1B Receptors on Interneurons.
            a. Function, site of action, and classification.
            b. Concluding summary statement.
        2. 5-Hydroxytryptamine 2A Receptors on Interneurons.
            a. Function, location, and mechanism.
            b. Concluding summary statement.
        3. 5-Hydroxytryptamine 2C Receptors on Interneurons.
            a. Function, location, and classification.
            b. Concluding summary statement.
    D. 5-Hydroxytryptamine 1B and 5-Hydroxytryptamine 2 Receptors Identified in Vitro or in Vivo
        1. Presynaptic 5-Hydroxytryptamine 1 and/or 5-Hydroxytryptamine 2 Receptor-Mediated Modulation?
        2. Presynaptic 5-Hydroxytryptamine 1B Receptors.
            a. Function, site of action, and classification.
            b. Concluding summary statement.
        3. Presynaptic 5-Hydroxytryptamine 2A and 5-Hydroxytryptamine 2C Receptors?
            a. Function, site of action, and classification.
            b. Concluding summary statement.
    E. 5-Hydroxytryptamine 3 Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
    F. 5-Hydroxytryptamine 4 Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
V. Modulation of Noradrenergic Neurotransmission
    A. General Aspects
    B. 5-Hydroxytryptamine 1A Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
    C. 5-Hydroxytryptamine 2 Receptors
        1. Function and Location.
        2. Concluding Summary Statement.
    D. 5-Hydroxytryptamine 3 Receptors
        1. Function and Location.
        2. Concluding Summary Statement.
VI. Modulation of GABAergic Neurotransmission
    A. General Aspects
    B. 5-Hydroxytryptamine 1A Receptors
        1. Function, Location, and Classification.
        2. Mechanism.
        3. Concluding Summary Statement.
    C. 5-Hydroxytryptamine 1B Receptors
        1. Function.
        2. Classification.
        3. Location.
        4. Concluding Summary Statement.
    D. 5-Hydroxytryptamine 2A Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
    E. 5-Hydroxytryptamine 3 Receptors
        1. Function, Location, and Classification.
        2. Mechanism.
        3. Interaction between Presynaptic 5-Hydroxytryptamine 3 and 5-Hydroxytryptamine 1A Receptors.
        4. Concluding Summary Statement.
    F. 5-Hydroxytryptamine 4 Receptors
        1. Function, Location, and Classification.
        2. Concluding Summary Statement.
VII. Synopsis
Serotoninergic neurons in the central nervous system impinge on many other neurons and modulate their neurotransmitter release. This review focuses on 1) the function of presynaptic 5-hydroxytryptamine (5-HT) heteroreceptors on axon terminals of central cholinergic, dopaminergic, noradrenergic, or GABAergic neurons and 2) the role of GABAergic interneurons expressing 5-HT heteroreceptors in the regulation of acetylcholine, dopamine, or noradrenaline release. In vitro studies on slices or synaptosomes and in vivo microdialysis experiments have shown that 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3, and/or 5-HT4 heteroreceptors mediate this modulation. 5-HT1B receptors on neocortical cholinergic, striatal dopaminergic, or hippocampal GABAergic axon terminals are examples for release-inhibiting 5-HT heteroreceptors; 5-HT3 receptors on hippocampal GABAergic or 5-HT4 receptors on hippocampal cholinergic axon terminals are examples for release-facilitating 5-HT heteroreceptors. GABA released from GABAergic interneurons upon activation of facilitatory 5-HT receptors, e.g., 5-HT2A or 5-HT3 receptors, mediates inhibition of the release of other neurotransmitters such as prefrontal neocortical dopamine or neocortical acetylcholine release, respectively. Conversely, attenuated GABA release in response to activation of inhibitory 5-HT heteroreceptors, e.g., 5-HT1A or 5-HT1B receptors on GABAergic interneurons is involved in paradoxical facilitation of hippocampal acetylcholine and striatal dopamine release, respectively. Such 5-HT heteroreceptors are considered potential targets for appropriate 5-HT receptor ligands which, by enhancing the release of a relevant neurotransmitter, can compensate for its hypothesized deficiency in distinct brain areas. Examples for such deficiencies are the impaired release of hippocampal or neocortical acetylcholine, striatal dopamine, and hippocampal or neocortical noradrenaline in disorders such as Alzheimer's disease, Parkinson's disease, and major depression, respectively.

Address correspondence to: Dr. Klaus B. Fink, Department of Pharmacology, Bonn University Clinic, Reuterstr. 2b, 53113 Bonn, Germany. E-mail: finkk{at}uni-bonn.de




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