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5-HT1B autoreceptor regulation of serotonin transporter activity in synaptosomes

Authors

  • Catherine E. Hagan,

    Corresponding author
    1. Department of Comparative Medicine and Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington 98195
    • Department of Comparative Medicine and Graduate Program in Molecular and Cellular Biology, University of Washington, Box 357190, Seattle, WA 98195, USA
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  • Ross A. Mcdevitt,

    1. Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195
    2. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98104
    Current affiliation:
    1. Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD
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  • Yusha Liu,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98104
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  • Amy R. Furay,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98104
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  • John F. Neumaier

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98104
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Abstract

Serotonin-1B (5-HT1B) autoreceptors are located in serotonin (5-HT) terminals, along with serotonin transporters (SERT), and play a critical role in autoregulation of serotonergic neurotransmission and are implicated in disorders of serotonergic function, particularly emotional regulation. SERT modulates serotonergic neurotransmission by high-affinity reuptake of 5-HT. Alterations in SERT activity are associated with increased risk for depression and anxiety. Several neurotransmitter receptors are known to regulate SERT Km and Vmax, and previous work suggests that 5-HT1B autoreceptors may regulate 5-HT reuptake, in addition to modulating 5-HT release and synthesis. We used rotating disk electrode voltammetry to investigate 5-HT1B autoreceptor regulation of SERT-mediated 5-HT uptake into synaptosomes. The selective 5-HT1B antagonist SB224289 decreased SERT activity in synaptosomes prepared from wild-type but not 5-HT1B knockout mice, whereas SERT uptake was enhanced after pretreatment with the selective 5-HT1B agonist CP94253. Furthermore, SERT activity varies as a function of 5-HT1B receptor expression—specifically, genetic deletion of 5-HT1B decreased SERT function, while viral-mediated overexpression of 5-HT1B autoreceptors in rat raphe neurons increased SERT activity in rat hippocampal synaptosomes. Considered collectively, these results provide evidence that 5-HT1B autoreceptors regulate SERT activity. Because SERT clearance rate varies as a function of 5-HT1B autoreceptor expression levels and is modulated by both activation and inhibition of 5-HT1B autoreceptors, this dynamic interaction may be an important mechanism of serotonin autoregulation with therapeutic implications. Synapse, 2012. © 2012 Wiley Periodicals, Inc.

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