Abstract
Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) − 1. ∆BPNDfrontal = 1 − (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson’s disease is enabled.
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References
Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab. 2000;20:423–51.
Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab. 2010;30:1682–706.
Hirani E, Sharp T, Sprakes M, Grasby P, Hume S. Fenfluramine evokes 5-HT2A receptor-mediated responses but does not displace [11C]MDL 100907: small animal PET and gene expression studies. Synapse. 2003;50:251–60.
Staley JK, Van Dyck CH, Tan PZ, Al Tikriti M, Ramsby Q, Klump H, et al. Comparison of [18F]altanserin and [18F]deuteroaltanserin for PET imaging of serotonin2A receptors in baboon brain: pharmacological studies. Nucl Med Biol. 2001;28:271–9.
Matusch A, Hurlemann R, Rota Kops E, Winz OH, Elmenhorst D, Herzog H, et al. Acute S-ketamine application does not alter cerebral [18F]altanserin binding: a pilot PET study in humans. J Neural Transm (Vienna). 2007;114:1433–42.
Meyer JH, Cho R, Kennedy S, Kapur S. The effects of single dose nefazodone and paroxetine upon 5-HT2A binding potential in humans using [18F]-setoperone PET. Psychopharmacology. 1999;144:279–81.
Pinborg LH, Adams KH, Yndgaard S, Hasselbalch SG, Holm S, Kristiansen H, et al. [18F]altanserin binding to human 5HT2A receptors is unaltered after citalopram and pindolol challenge. J Cereb Blood Flow Metab. 2004;24:1037–45.
Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM. 5-HT radioligands for human brain imaging with PET and SPECT. Med Res Rev. 2013;33:54–111.
Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, et al. Application of cross-species PET imaging to assess neurotransmitter release in brain. Psychopharmacology. 2015;232:4129–57.
Larisch R, Klimke A, Hamacher K, Henning U, Estalji S, Hohlfeld T, et al. Influence of synaptic serotonin level on [18F]altanserin binding to 5HT2 receptors in man. Behav Brain Res. 2003;139:21–9.
Quednow BB, Treyer V, Hasler F, Dorig N, Wyss MT, Burger C, et al. Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [18F]altanserin positron emission tomography. Neuroimage. 2012;59:3922–32.
Sibon I, Benkelfat C, Gravel P, Aznavour N, Costes N, Mzengeza S, et al. Decreased [18F]MPPF binding potential in the dorsal raphe nucleus after a single oral dose of fluoxetine: a positron-emission tomography study in healthy volunteers. Biol Psychiatry. 2008;63:1135–40.
Selvaraj S, Turkheimer F, Rosso L, Faulkner P, Mouchlianitis E, Roiser JP, et al. Measuring endogenous changes in serotonergic neurotransmission in humans: a [11C]CUMI-101 PET challenge study. Mol Psychiatry. 2012;17:1254–60.
Nord M, Finnema SJ, Halldin C, Farde L. Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. Int J Neuropsychopharmacol. 2013;16:1577–86.
Tyacke RJ, Nutt DJ. Optimising PET approaches to measuring 5-HT release in human brain. Synapse. 2015;69:505–11.
Jorgensen LM, Weikop P, Villadsen J, Visnapuu T, Ettrup A, Hansen HD, et al. Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain. J Cereb Blood Flow Metab. 2016;37:425–34.
Yang KC, Stepanov V, Martinsson S, Ettrup A, Takano A, Knudsen GM, et al. Fenfluramine reduces [11C]Cimbi-36 binding to the 5-HT2A receptor in the nonhuman primate brain. Int J Neuropsychopharmacol. 2017;20:683–91.
da Cunha-Bang S, Ettrup A, Mc Mahon B, Skibsted AP, Schain M, Lehel S, et al. Measuring endogenous changes in serotonergic neurotransmission with [(11)C]Cimbi-36 positron emission tomography in humans. Transl Psychiatry. 2019;9:134.
Heal DJ, Cheetham SC, Prow MR, Martin KF, Buckett WR. A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents. Br J Pharm. 1998;125:301–8.
Kuczenski R, Segal DS, Cho AK, Melega W. Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci. 1995;15:1308–17.
Ridler K, Plisson C, Rabiner EA, Gunn RN, Easwaramoorthy B, Abi-Dargham A, et al. Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis. Synapse. 2011;65:1119–27.
Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, et al. Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats. Br J Pharm. 2011;164:1949–58.
Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, et al. Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr. 1998;178:440–66.
Ettrup A, Hansen M, Santini MA, Paine J, Gillings N, Palner M, et al. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers. Eur J Nucl Med Mol Imaging. 2011;38:681–93.
Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, Jenkinson M, et al. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage. 2011;54:264–77.
Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, et al. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. J Cereb Blood Flow Metab. 2014;34:1188–96.
Ichise M, Toyama H, Innis RB, Carson RE. Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab. 2002;22:1271–81.
Beliveau V, Ganz M, Feng L, Ozenne B, Hojgaard L, Fisher PM, et al. A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci. 2017;37:120–8.
Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, et al. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36: test-retest reproducibility and head-to-head comparison with the antagonist [18F]altanserin. Neuroimage. 2016;130:167–74.
Colasanti A, Searle GE, Long CJ, Hill SP, Reiley RR, Quelch D, et al. Endogenous opioid release in the human brain reward system induced by acute amphetamine administration. Biol Psychiatry. 2012;72:371–7.
Mick I, Myers J, Stokes PR, Erritzoe D, Colasanti A, Bowden-Jones H, et al. Amphetamine induced endogenous opioid release in the human brain detected with [11C]carfentanil PET: replication in an independent cohort. Int J Neuropsychopharmacol. 2014;17:2069–74.
Narendran R, Mason NS, Paris J, Himes ML, Douaihy AB, Frankle WG. Decreased prefrontal cortical dopamine transmission in alcoholism. Am J Psychiatry. 2014;171:881–8.
Shotbolt P, Tziortzi AC, Searle GE, Colasanti A, van der Aart J, Abanades S, et al. Within-subject comparison of [11C]-(+)-PHNO and [11C]raclopride sensitivity to acute amphetamine challenge in healthy humans. J Cereb Blood Flow Metab. 2012;32:127–36.
Erritzoe D, Talbot P, Frankle WG, Abi-Dargham A. Positron emission tomography and single photon emission CT molecular imaging in schizophrenia. Neuroimaging Clin N Am. 2003;13:817–32.
Martinez D, Narendran R. Imaging neurotransmitter release by drugs of abuse. Curr Top. Behav Neurosci. 2010;3:219–45.
Yang KC, Takano A, Halldin C, Farde L, Finnema SJ. Serotonin concentration enhancers at clinically relevant doses reduce [11C]AZ10419369 binding to the 5-HT1B receptors in the nonhuman primate brain. Transl Psychiatry. 2018;8:132.
Baumann MH, Wang X, Rothman RB. 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacol (Berl). 2007;189:407–24.
Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337:581–8.
Elmenhorst D, Kroll T, Matusch A, Bauer A. Sleep deprivation increases cerebral serotonin 2A receptor binding in humans. Sleep. 2012;35:1615–23.
Derry C, Benjamin C, Bladin P, le Bars D, Tochon-Danguy H, Berkovic SF. et al. Increased serotonin receptor availability in human sleep: evidence from an [18F]MPPF PET study in narcolepsy. Neuroimage. 2006;30:341–8.
Abi-Dargham A, Kegeles LS, Martinez D, Innis RB, Laruelle M. Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naive healthy volunteers: results from a large cohort. Eur Neuropsychopharmacol. 2003;13:459–68.
Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab. 2003;23:285–300.
Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, et al. Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry. 2001;49:81–96.
Le Merrer J, Becker JA, Befort K, Kieffer BL. Reward processing by the opioid system in the brain. Physiol Rev. 2009;89:1379–412.
Schultz W. Dopamine reward prediction error coding. Dialogues Clin Neurosci. 2016;18:23–32.
Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–8.
Hervas I, Artigas F. Effect of fluoxetine on extracellular 5-hydroxytryptamine in rat brain. Role of 5-HT autoreceptors. Eur J Pharm. 1998;358:9–18.
Romero L, Bel N, Artigas F, de Montigny C, Blier P. Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain. Neuropsychopharmacology. 1996;15:349–60.
Ettrup A, McMahon B, Skibsted A, da Cunha-Bang S, Lehel S, Dyssegaard A, et al. Serotonin 2A receptor agonist binding with [11C]Cimbi-36 in the human brain is unaltered by citalopram/pindolol and acute tryptophan depletion, in 29th ECNP Congress 2016: Vienna. S307-8; 2016.
Acknowledgements
We would like to thank all the volunteers for their participation as well as the invaluable contributions of the Imanova/Invicro clinical staff for their excellent technical support. EAR wishes to acknowledge the support and funding by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.
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Erritzoe, D., Ashok, A.H., Searle, G.E. et al. Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge. Neuropsychopharmacol. 45, 804–810 (2020). https://doi.org/10.1038/s41386-019-0567-5
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DOI: https://doi.org/10.1038/s41386-019-0567-5
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