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Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study

Molecular Psychiatry volume 17, pages 1254–1260 (2012)Cite this article

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Abstract

Serotonin (5-HT) neurotransmission is implicated in cognitive and emotional processes and a number of neuropsychiatric disorders. The use of positron emission tomography (PET) to measure ligand displacement has allowed estimation of endogenous dopamine release in the human brain; however, applying this methodology to assess central 5-HT release has proved more challenging. The aim of this study was to assess the sensitivity of a highly selective 5-HT1A partial agonist radioligand [11C]CUMI-101 to changes in endogenous 5-HT levels induced by an intravenous challenge with the selective 5-HT re-uptake inhibitor (SSRI), citalopram, in healthy human participants. We studied 15 healthy participants who underwent PET scanning in conjunction with [11C]CUMI-101 after receiving an intravenous infusion of citalopram 10 mg or placebo in a double-blind, crossover, randomized design. Regional estimates of binding potential (BPND) were obtained by calculating total volumes of distribution (VT) for presynaptic dorsal raphe nucleus (DRN) and postsynaptic cortical regions. Relative to placebo, citalopram infusion significantly increased [11C]CUMI-101 BPND at postsynaptic 5-HT1A receptors in several cortical regions, but there was no change in binding at 5-HT1A autoreceptors in the DRN. Across the postsynaptic brain regions, citalopram treatment induced a mean 7% in [11C]CUMI-101 BPND (placebo 1.3 (0.2); citalopram 1.4 (0.2); paired t-test P=0.003). The observed increase in postsynaptic [11C]CUMI-101 availability identified following acute citalopram administration could be attributable to a decrease in endogenous 5-HT availability in cortical terminal regions, consistent with preclinical animal studies, in which acute administration of SSRIs decreases DRN cell firing through activation of 5-HT1A autoreceptors to reduce 5-HT levels in postsynaptic regions. We conclude that [11C]CUMI-101 may be sensitive to changes in endogenous 5-HT release in humans.

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Acknowledgements

This study was funded by the Medical Research Council, UK. We thank the staff at Hammersmith Imanet (Andrew Blyth, Hope McDevitt, Andreanna Williams, Safiye Osman and Noora Ali) for the technical expertise they provided.

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Authors and Affiliations

  1. Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK

    S Selvaraj, E Mouchlianitis & O Howes

  2. Department of Psychosis Studies, Institute of Psychiatry, Hammersmith Hospital, King's College London, London, UK

    S Selvaraj, P McGuire & O Howes

  3. Department of Medicine, Imperial College London, London, UK

    F Turkheimer & L Rosso

  4. Institute of Cognitive Neuroscience, University College London, London, UK

    P Faulkner & J P Roiser

  5. Department of Psychiatry, University of Oxford, Oxford, UK

    P J Cowen

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Correspondence to S Selvaraj.

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Sudhakar Selvaraj, Federico Turkheimer, Lula Rosso, Elias Mouchlianitis, Paul Faulkner, Jonathan Roiser, Philip McGuire and Oliver Howes report no competing interests. Philip Cowen has been a member of advisory boards of Eli Lilly, Servier and Lundbeck and has been a paid lecturer for Eli Lilly, Servier, Lundbeck and GlaxoSmithKline.

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Selvaraj, S., Turkheimer, F., Rosso, L. et al. Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study. Mol Psychiatry 17, 1254–1260 (2012). https://doi.org/10.1038/mp.2012.78

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