Abstract
Serotonin 1A (5-HT1A) receptors mediate serotonin trophic role in brain neurogenesis. Gray matter volume (GMV) loss and 5-HT1A receptor binding alterations have been identified in major depressive disorder (MDD). Here we investigated the relationship between 5-HT1A receptor binding and GMV in 40 healthy controls (HCs) and, for the first time, 47 antidepressant-free MDD patients using Voxel-Based Morphometry and [11C]WAY100635 Positron Emission Tomography. Values of GMV and 5-HT1A binding (expressed as BPF, one of the types of binding potentials that refer to displaceable or specific binding that can be quantified in vivo with PET) were obtained in 13 regions of interest, including raphe, and at the voxel level. We used regression analysis within each group to predict GMV from BPF, while covarying for age, sex, total gray matter volume and medication status. In the HCs group, we found overall a positive correlation between terminal field 5-HT1A receptor binding and GMV, which reached statistical significance in regions such as hippocampus, insula, orbital prefrontal cortex, and parietal lobe. We observed a trend towards inverse correlation between raphe 5-HT1A autoreceptor binding and anterior cingulate GMV in both groups, and a statistically significant positive correlation between raphe 5-HT1A binding and temporal GMV in MDD. Analysis of covariance at the voxel-level revealed a trend towards interaction between diagnosis and raphe 5-HT1A binding in predicting GMV in cerebellum and supramarginal gyrus (higher correlation in HCs compared with MDD). Our results replicated previous findings in the normative brain, but did not extend them to the brain in MDD, and indicated a trend towards dissociation between MDD and HCs in the relationship of raphe 5-HT1A binding with postsynaptic GMV. These results suggest that 5-HT1A receptors contribute to altered neuroplasticity in MDD, possibly via effects predating depression onset.
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References
Akimova E, Lanzenberger R, Kasper S (2009) The serotonin-1A receptor in anxiety disorders. Biol Psychiatry 66:627–635. https://doi.org/10.1016/j.biopsych.2009.03.012
Ashburner J (2007) A fast diffeomorphic image registration algorithm. NeuroImage. 38:95–113 https://doi.org/10.1016/j.neuroimage.2007.07.007
Azmitia EC (2001) Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis. Brain Res Bull 56:413–424
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571
Benninghoff J et al (2010) Serotonin depletion hampers survival and proliferation in neurospheres derived from adult neural stem cells. Neuropsychopharmacol 35:893–903. https://doi.org/10.1038/npp.2009.181
Borroto-Escuela DO et al (2015a) Evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system biochem. Biophys Res Commun 456:489–493. https://doi.org/10.1016/j.bbrc.2014.11.112
Borroto-Escuela DO et al (2015b) Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity depression. Biochem Biophys Res Commun 463:180–186. https://doi.org/10.1016/j.bbrc.2015.04.133
Borroto-Escuela DO, Tarakanov AO, Fuxe K (2016) FGFR1-5-HT1A heteroreceptor complexes: implications for understanding and treating major. Depression Trends Neurosci 39:5–15. https://doi.org/10.1016/j.tins.2015.11.003
Braestrup C, Squires RF (1978) Pharmacological characterization of benzodiazepine receptors in the brain European. J Pharmacol 48:263–270
Casanova R et al (2007) Biological parametric mapping: a statistical toolbox for multimodality brain. Image Anal Neuroimage 34:137–143. https://doi.org/10.1016/j.neuroimage.2006.09.011
Citri A, Malenka RC (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacol 33:18–41. https://doi.org/10.1038/sj.npp.1301559
Dannlowski U et al (2014) Serotonin transporter gene methylation is associated with hippocampal gray matter volume. Hum Brain Mapp 35:5356–5367. https://doi.org/10.1002/hbm.22555
Daubert EA, Condron BG (2010) Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci 33:424–434. https://doi.org/10.1016/j.tins.2010.05.005
Dayer A (2014) Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders. Dialog Clin Neurosci 16:29–41
DeLorenzo CKA, Mikhno A, Gray N, Zanderigo F, Mann JJ, Parsey RV (2009) A new method for assessing PET-MRI coregistration. In: Medical Imaging 2009: Image Processing; 2009, Lake Buena Vista. SPIE, FL
Depping MS, Wolf ND, Vasic N, Sambataro F, Thomann PA, Christian Wolf R (2015) Specificity of abnormal brain volume in major depressive disorder: a comparison with borderline personality disorder. J Affective Disorders 174:650–657. https://doi.org/10.1016/j.jad.2014.11.059
Dompert WU, Glaser T, Traber J (1985) 3H-TVX Q 7821: identification of 5-HT1 binding sites as target for a novel putative anxiolytic Naunyn-Schmiedeberg’s. Arch Pharmacol 328:467–470
Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A (2004) Neuroplasticity: changes in grey matter induced. by training. Nature 427:311–312. https://doi.org/10.1038/427311a
Drevets WC et al (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46:1375–1387
Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nuclear Med Biol 34:865–877. https://doi.org/10.1016/j.nucmedbio.2007.06.008
Duvernoy H (1991) The human brain: surface, three-dimensional sectional anatomy and MRI. New York
First MSR, Gibbon M, Williams J (1995) Structured clinical interview for DSM-IV axis I disorders (SCID-I/P, Version 2.0). Biometrics Research Dept., New York State Psychiatric Institute, New York
First MB, Spitzer RL, Gibbon M, Williams JB (2012) Structured clinical interview for DSM-IV® Axis I disorders (SCID-I), clinician version,. American Psychiatric Pub.
Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4:1002–1012. https://doi.org/10.1038/nrn1256
Geuze E, Vermetten E, Bremner JD (2005) MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed. Mol Psychiatry 10:147–159. https://doi.org/10.1038/sj.mp.4001580
Goodkind M et al (2015) Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry 72:305–315. https://doi.org/10.1001/jamapsychiatry.2014.2206
Gunn RN, Gunn SR, Turkheimer FE, Aston JA, Cunningham VJ (2002) Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J Cereb Blood Flow Metabol 22:1425–1439. https://doi.org/10.1097/00004647-200212000-00003
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hirvonen J et al (2008) Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int J Neuropsychopharmacol 11:465–476
Hsiung SC, Adlersberg M, Arango V, Mann JJ, Tamir H, Liu KP (2003) Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J Neurochem 87:182–194
Innis RB et al (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539. https://doi.org/10.1038/sj.jcbfm.9600493
Jasinska AJ, Lowry CA, Burmeister M (2012a) Corrigendum: serotonin transporter gene, stress, and raphe-raphe interactions: a molecular mechanism of depression. Trends Neurosci 35:454–455
Jasinska AJ, Lowry CA, Burmeister M (2012b) Serotonin transporter gene, stress and raphe-raphe interactions: a molecular mechanism of depression. Trends Neurosci 35:395–402. https://doi.org/10.1016/j.tins.2012.01.001
Kanai R, Rees G (2011) The structural basis of inter-individual differences in human behaviour and cognition. Nat Rev Neurosci 12:231–242. https://doi.org/10.1038/nrn3000
Kraus C et al (2012) Serotonin-1A receptor binding is positively associated with gray matter volume—a multimodal neuroimaging study combining PET and structural. MRI NeuroImage 63:1091–1098. https://doi.org/10.1016/j.neuroimage.2012.07.035
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19:1233–1239
Malykhin NV, Coupland NJ (2015) Hippocampal neuroplasticity in major. depressive disorder. Neuroscience 309:200–213. https://doi.org/10.1016/j.neuroscience.2015.04.047
Matheson GJ et al (2015) Diurnal and seasonal variation of the brain serotonin system in healthy male subjects. NeuroImage. 112:225–231 https://doi.org/10.1016/j.neuroimage.2015.03.007
Maya Vetencourt JF et al (2008) The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science (New York, NY) 320:385–388. https://doi.org/10.1126/science.1150516
Meltzer CC et al (2004) Serotonin 1A receptor binding and treatment response in late—life depression. Neuropsychopharmacology 29:2258–2265
Milak MS et al (2010) In vivo quantification of human serotonin 1A receptor using 11C-CUMI-101, an agonist PET radiotracer. J Nuclear Med 51:1892–1900. https://doi.org/10.2967/jnumed.110.076257
Miller JM, Brennan KG, Ogden TR, Oquendo MA, Sullivan GM, Mann JJ, Parsey RV (2009) Elevated serotonin 1A binding in remitted major depressive disorder: evidence for a trait biological abnormality. Neuropsychopharmacology 34:2275–2284. https://doi.org/10.1038/npp.2009.54
Miller JM, Hesselgrave N, Ogden RT, Zanderigo F, Oquendo MA, Mann JJ, Parsey RV (2013) Brain serotonin 1A receptor binding as a predictor of treatment outcome in major depressive disorder. Biological psychiatry 74:760–767. https://doi.org/10.1016/j.biopsych.2013.03.021
Nautiyal KM, Hen R (2017) Serotonin receptors in depression: from A to B F1000Res 6:123 https://doi.org/10.12688/f1000research.9736.1
Ogren SO et al (2008) The role of 5-HT(1A) receptors in learning and memory. Behav Brain Res 195:54–77. https://doi.org/10.1016/j.bbr.2008.02.023
Parsey RV et al (2000) Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions. J Cereb Blood Flow Metab 20:1111–1133. https://doi.org/10.1097/00004647-200007000-00011
Parsey RV, Arango V, Olvet DM, Oquendo MA, Van Heertum RL, John Mann J (2005) Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography. J Cereb Blood Flow Metab 25:785–793. https://doi.org/10.1038/sj.jcbfm.9600072
Parsey RV, Olvet DM, Oquendo MA, Huang YY, Ogden RT, Mann JJ (2006a) Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacol 31:1745–1749. https://doi.org/10.1038/sj.npp.1300992
Parsey RV et al (2006b) Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 59:106–113. https://doi.org/10.1016/j.biopsych.2005.06.016
Parsey RV et al (2010) Higher serotonin 1A binding in a second major depression cohort: modeling and reference region considerations. Biol Psychiatry 68:170–178. https://doi.org/10.1016/j.biopsych.2010.03.023
Persico AM, Di Pino G, Levitt P (2006) Multiple receptors mediate the trophic effects of serotonin on ventroposterior thalamic neurons in vitro. Brain Res 1095:17–25. https://doi.org/10.1016/j.brainres.2006.04.006
Pike VW et al (1996) Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635. Eur J Pharmacol 301:R5-7
Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacol 33:88–109. https://doi.org/10.1038/sj.npp.1301574
Rabiner EA, Wilkins MR, Turkheimer F, Gunn RN, Udo de Haes J, de Vries M, Grasby PM (2002) 5-Hydroxytryptamine1A receptor occupancy by novel full antagonist 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzi sothiazol-3-(2H)-one-1,1-dioxide: a[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) positron emission tomography study in humans. J Pharmacol Exp Ther 301:1144–1150
Salvadore G et al (2011) Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder. NeuroImage 54:2643–2651 https://doi.org/10.1016/j.neuroimage.2010.11.011
Sargent PA et al (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180
Savitz JB, Drevets WC (2009) Imaging phenotypes of major depressive disorder:. genetic correlates. Neuroscience 164:300–330. https://doi.org/10.1016/j.neuroscience.2009.03.082
Savitz J, Lucki I, Drevets WC (2009) 5-HT(1A) receptor function in major depressive. disorder. Prog Neurobiol 88:17–31. https://doi.org/10.1016/j.pneurobio.2009.01.009
Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18:391–418. https://doi.org/10.1097/FBP.0b013e3282ee2aa8
Smith R, Chen K, Baxter L, Fort C, Lane RD (2013) Antidepressant effects of sertraline associated with volume increases in dorsolateral prefrontal cortex. J Affective Disord 146:414–419. https://doi.org/10.1016/j.jad.2012.07.029
Sullivan GM et al (2015) Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. JAMA Psychiatry 72:169–178. https://doi.org/10.1001/jamapsychiatry.2014.2406
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain: three-dimensional proportional system. Thieme Medical, New York
Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M (2006) Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacological reviews 58:115–134. https://doi.org/10.1124/pr.58.1.7
Tost H, Braus DF, Hakimi S, Ruf M, Vollmert C, Hohn F, Meyer-Lindenberg A (2010) Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci 13:920–922. https://doi.org/10.1038/nn.2572
van Spronsen M, Hoogenraad CC (2010) Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep 10:207–214. https://doi.org/10.1007/s11910-010-0104-8
van Tol MJ et al (2010) Regional brain volume in depression and anxiety disorders. Arch Gen Psychiatry 67:1002–1011. https://doi.org/10.1001/archgenpsychiatry.2010.121
Woodward ND et al (2009) Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study. NeuroImage. 46:31–38 https://doi.org/10.1016/j.neuroimage.2009.01.049
Wright IC et al (1995) A voxel-based method for the statistical analysis of gray and white matter density applied to schizophrenia. NeuroImage. 2:244–252 https://doi.org/10.1006/nimg.1995.1032
Yan W, Wilson CC, Haring JH (1997) 5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells. Brain Res Dev Brain Res 98:185–190
Zatorre RJ, Fields RD, Johansen-Berg H (2012) Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nat Neurosci 15:528–536. https://doi.org/10.1038/nn.3045
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Drs. Zanderigo and Ogden, Mr. Rubin-Falcone and Mr. Binod Thapa Chhetry have no conflicts of interest to declare. Dr. Pantazatos’s contribution to this work was supported by NIMH K01MH108721. Drs. Mann and Oquendo receive royalties for commercial use of the Columbia-Suicide Severity Rating Scales from the Research Foundation for Mental Hygeine and Dr. Oquendo receives an honorarium as President of the American Psychiatric Association. Her family owns stock in Bristol Myers Squibb. Dr. Miller’s family previously owned stock in Johnson & Johnson, unrelated to the current manuscript. Dr. Sullivan is currently employed by Tonix Pharmaceuticals, Inc. and holds stock in the same, unrelated to the current manuscript.
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Zanderigo, F., Pantazatos, S., Rubin-Falcone, H. et al. In vivo relationship between serotonin 1A receptor binding and gray matter volume in the healthy brain and in major depressive disorder. Brain Struct Funct 223, 2609–2625 (2018). https://doi.org/10.1007/s00429-018-1649-6
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DOI: https://doi.org/10.1007/s00429-018-1649-6