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Published Online: 1 August 2012

Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder

Aybala Saricicek, M.D., Irina Esterlis, Ph.D., Kathleen H. Maloney, B.A., Yann S. Mineur, Ph.D., Barbara M. Ruf, B.A., Anjana Muralidharan, B.A., Jason I. Chen, B.A., … Show All … , Kelly P. Cosgrove, Ph.D., Rebecca Kerestes, Ph.D., Subroto Ghose, M.D., Ph.D., Carol A. Tamminga, M.D., Brian Pittman, M.S., Frederic Bois, Ph.D., Gilles Tamagnan, Ph.D., John Seibyl, M.D., Marina R. Picciotto, Ph.D., Julie K. Staley, Ph.D., and Zubin Bhagwagar, M.D., Ph.D., M.R.C.Psych.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 169, Number 8
https://doi.org/10.1176/appi.ajp.2012.11101546
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Abstract

Background:

Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subjects.

Method:

The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of β2*-nAChRs was quantified as VT/fP. Postmortem analysis of β2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects.

Results:

The β2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, β2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in β2*-nAChR number between groups in the postmortem study.

Conclusions:

Depressed patients have lower β2*-nAChR availability than do healthy subjects. The difference between β2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 169 • Number 8 • August 2012
Pages: 851 - 859
PubMed: 22772158

History

Received: 20 October 2011
Revision received: 7 January 2012
Revision received: 3 April 2012
Accepted: 9 April 2012
Published online: 1 August 2012
Published in print: August 2012

Authors

Details

Aybala Saricicek, M.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Irina Esterlis, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Kathleen H. Maloney, B.A.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Yann S. Mineur, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Barbara M. Ruf, B.A.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Anjana Muralidharan, B.A.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Jason I. Chen, B.A.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Kelly P. Cosgrove, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Rebecca Kerestes, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Subroto Ghose, M.D., Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Carol A. Tamminga, M.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Brian Pittman, M.S.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Frederic Bois, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Gilles Tamagnan, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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John Seibyl, M.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Marina R. Picciotto, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Julie K. Staley, Ph.D.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Zubin Bhagwagar, M.D., Ph.D., M.R.C.Psych.
From the Department of Psychiatry, Yale University, New Haven, Conn.; the Neuroscience Group, Bristol-Myers Squibb, Wallingford, Conn.; the Institute for Neurodegenerative Disorders, New Haven, Conn.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
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Notes

Address correspondence to Dr. Saricicek ([email protected]) or Dr. Bhagwagar ([email protected]).

Funding Information

Dr. Seibyl reports being a consultant for Bayer Healthcare and GE Healthcare and holding equity in Molecular Neuroimaging. Dr. Bhagwagar is a full-time employee of Bristol-Myers Squibb while retaining a faculty position at Yale University. Disclosures for Dr. Tamminga, as a Deputy Editor of the American Journal of Psychiatry, were published in the January issue. The other authors report no financial relationships with commercial interests.Supported by the Clinical Neuroscience Research Unit at the Connecticut Mental Health Center and the Connecticut Department of Mental Health and Addictions Services, by NIMH research grants MH-077681 (Dr. Picciotto) and MH-077914 (Dr. Bhagwagar), by the Brain & Behavior Research Foundation (Dr. Bhagwagar), by the Freedman Fellowship (Dr. Saricicek), and by Clinical and Translational Science Award grant UL1 RR-024139 from the NIH National Center for Research Resources to Yale University (Dr. Bhagwagar).

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