Original article
Serotonin type-1A receptor imaging in depression

https://doi.org/10.1016/S0969-8051(00)00119-0Get rights and content

Abstract

Regional 5-hydroxytryptamine1A (5-HT1A) receptor binding potential (BP) of depressed subjects with primary, recurrent, familial mood disorders was compared to that of healthy controls by using positron emission tomography and [carbonyl-11C]WAY-100635 {[11C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide}. The mean 5-HT1A receptor BP was reduced 42% in the midbrain raphe and 25–33% in limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. The magnitude of these abnormalities was most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. These abnormal reductions in 5-HT1A receptor BP are consistent with in vivo evidence that 5-HT1A receptor sensitivity is reduced in major depressive disorder and postmortem data showing a widespread deficit of 5-HT1A receptor expression in primary mood disorders.

Section snippets

Background

The serotonin type-1A receptor (5-HT1A receptor) has been implicated in mood disorders by evidence that major depressives have blunted physiological responses to 5-hydroxytryptamine1A (5-HT1A) receptor agonists in vivo and abnormal 5-HT1A receptor binding postmortem 11, 37, 40, 45, 71. During 5-HT1A receptor agonist challenge, the physiological elevations of plasma concentrations of adrenocorticotrophic hormone (ACTH) and cortisol and decrement of body temperature are attenuated in unmedicated

Methods

Depressed subjects (N = 12) met DSM-IV criteria (1) for primary, recurrent MDD and had at least one first-degree relative with primary MDD or BD. Four had BD, most recent episode depressed (BD-D), and eight had recurrent MDD (1). Of the MDD subjects, four had both BD and MDD relatives (MDD/bdr) and four had only MDD relatives (MDD/mdr). Exclusion criteria included medical or neurological illnesses, magnetic resonance image (MRI) evidence of neuromorphological abnormalities, suicidal intent,

Results

Demographic, clinical, and laboratory data for the subjects appear in Table 1. The groups significantly differed for HRSD scores and “stressed” plasma cortisol concentrations. The mean volumes of the MTC ROI were 9.73 ± 1.22 mL and 9.01 ± 0.785 mL for the depressives and controls, respectively (NS). The total raphe ROI volume for all subjects was 0.594 mL.

Although not used in the kinetic analysis, arterial blood was sampled in all of the controls and eight of the depressives. [11C]WAY-100635

Discussion

In summary, the mean 5-HT1A receptor BP was decreased 42% in the midbrain raphe and 25–33% in limbic and neocortical areas in depressives relative to controls. These differences were most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. The reduction in 5-HT1A receptor BP in the MTC was consistent with postmortem data showing 31–49% reductions in 5-HT1A receptor mRNA concentrations across hippocampal subfields in MDD (45). The reduction in 5-HT1A receptor BP

Summary

By using PET with [11C]WAY-100635, we demonstrated abnormal 5-HT1A receptor binding in the midbrain raphe and MTC in unmedicated, major depressives that was most prominent in cases with bipolar spectrum disorders. The reduction in 5-HT1A receptor BP in the MTC was similar in magnitude to concomitant reductions in the neocortex. Taken together with the results of postmortem studies, these findings suggest a widespread alteration of 5-HT1A receptor expression in major depression.

Acknowledgements

Supported by NIH grants MH59769, MH30915, MH51137, MH54715, and MH52247. The authors thank Dr. Bruce McEwen for discussions related to the design and interpretation of the image data and Dr. Roger Gunn for providing software for implementing the reference tissue model.

References (80)

  • J.F López et al.

    Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampusImplications for the neurobiology of depression

    Biol. Psychiatry

    (1998)
  • S Lowther et al.

    5-HT1A Receptor binding sites in post mortem brain samples from depressed suicides and controls

    J. Affective Disorders

    (1997)
  • O.C Meijer et al.

    Corticosterone suppresses the expression of 5-HT1A receptor mRNA in rat dentate gyrus

    Eur. J. Pharmacol. (Mol. Pharmacol.)

    (1994)
  • O.C Meijer et al.

    Elevated basal trough levels of corticosterone suppress hippocampal 5-HT1A receptor expression in adrenally intact ratsImplication for the pathogenesis of depression

    Neurosci

    (1997)
  • S Osman et al.

    Characterization of the appearance of radioactive metabolites in monkey and human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635—Explanation of high signal contrast in PET and an aid to biomathematical modelling

    Nucl. Med. Biol.

    (1998)
  • V.W Pike et al.

    Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11C]WAY-100635

    Eur. J. Pharmacol.

    (1996)
  • G Rajkowska et al.

    Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

    Biol. Psychiatry

    (1999)
  • G Spurlock et al.

    Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors, synthetic enzymes and 5-HT transporter

    Neuropharmacology

    (1994)
  • C.A Stockmeier et al.

    Serotonin receptors in suicide victims with major depression

    Neuropsychopharmacology

    (1997)
  • American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American...
  • G.W Arana et al.

    The dexamethasone suppression test for diagnosis and prognosis in psychiatry

    Arch. Gen. Psychiatry

    (1985)
  • V Arango et al.

    Reduction in serotonin transporter sites in PFC is localized in suicide and widespread in major depression

    Soc. Neurosci. Abstr.

    (1999)
  • E.C Azmitia et al.

    Awakening the sleeping giantAnatomy and plasticity of the brain serotonergic system

    J. Clin. Psychiatry

    (1991)
  • G Bagdv et al.

    Long-term cortisol treatment impairs behavioral and neuroendocrine responses to 5-HT1 agonists in the rat

    Neuroendocrinology

    (1989)
  • Baumann B. G. and Bogerts B. (1998) Post mortem studies of bipolar disorder. Presented at the Stanley Foundation...
  • D.M Bowen et al.

    Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life

    Proc. Natl. Acad. Sci.

    (1989)
  • M Carli et al.

    [3H]8-OH-DPAT binding and serotonin content in rat cerebral cortex after acute fluoxetine, desipramine, or pargyline

    J. Psychiatry Neurosci.

    (1996)
  • D.T Chalmers et al.

    Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression

    J. Neurosci.

    (1993)
  • Chaput Y., de Montigny C. and Blier P. (1991) Presynaptic and postsynaptic modifications of the serotonin system by...
  • S Cheetham et al.

    Brain 5-HT1 binding sites in depressed suicides

    Psychopharmacology

    (1990)
  • P.J Cowan

    Psychopharmacology of 5-HT1A receptors

    Nucl. Med. Biol.

    (2000)
  • M Detke et al.

    Blockade of the antidepressant-like effects of 8-OH-DPAT, buspirone and desipramine in the rat forced swim test by 5-HT1A receptor antagonists

    Psychopharmacology

    (1995)
  • W Drevets et al.

    Functional anatomical differences between major depressive subtypes

    J. Cereb. Blood Flow Metab.

    (1995)
  • W.C Drevets et al.

    Subgenual prefrontal cortex abnormalities in mood disorders

    Nature

    (1997)
  • W.C Drevets et al.

    Amygdala hypermetabolism in unipolar and bipolar depression correlation with plasma cortisol

    Soc. Neurosci. Abstr.

    (1997)
  • Drevets W. C., Gadde K. M. and Krishnan K. R. R. (1999) Neuroimaging studies of mood disorders. In: The Neurobiological...
  • Drevets W. C. and Todd R. D. (1997). Depression, mania and related disorders. In: Adult Psychiatry (Edited by Guze S....
  • W.C Drevets et al.

    A functional anatomical study of unipolar depression

    J. Neurosci.

    (1992)
  • A Fletcher et al.

    A pharmacological profile of WAY-100635, a potent and highly effective 5-HT1A receptor antagonist

    Br. J. Pharmacol.

    (1993)
  • Forster E. A., Cliffe I. A., Bill D. J., Dover G. M., Jones D., Reilly Y. and Fletcher A. A. (1995) Pharmacological...

    • Cited by (0)

    View full text
    Copyright © 2000 Elsevier Science Inc. All rights reserved.