CYP2D6 in the brain: genotype effects on resting brain perfusion

Original Article - Click here for the paper.

J Kirchheiner¹, A Seeringer¹, A L Godoy^1,5, B Ohmle¹, C Maier², P Beschoner^3,4, E-J Sim³ and R Viviani³

1. ¹Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
2. ²Institute of Human Genetics, University of Ulm, Ulm, Germany
3. ³Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany
4. ⁴Department of Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
5. ⁵Faculty of Pharmaceutical Sciences de Ribeirão Preto, University Ribeirão Preto, Brazil

Correspondence: Dr J Kirchheiner, University of Ulm, Institute of Pharmacology of Natural Products and Clinical Pharmacology, Helmholtzstr 20, Ulm D-89081, Germany. E-mail: julia.kirchheiner@uni-ulm.de

Received 29 July 2009; Revised 31 January 2010; Accepted 8 February 2010; Published online 6 April 2010.

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Abstract

The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain, such as the hippocampus, thalamus, hypothalamus and the cortex, but its function in the brain is not well understood. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N=188 healthy individuals and compared with brain perfusion levels at rest, which may reflect an ongoing biological process regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. Relative to N=42 matched extensive metabolizers,N=14 poor metabolizers were associated with 15% higher perfusion levels in the thalamus (P=0.03 and 0.003). Effects were also present in the whole (N=188) sample divided into metabolizer groups, or finely graded into seven CYP2D6 activity levels. A weaker effect was observed in the right hippocampus (P=0.05). An exploratory analysis, extended to the whole brain, suggested the involvement of CYP2D6 in regions associated with alertness or serotonergic function. These findings support the hypothesis of a functional role of CYP2D6 in the brain.

Keywords:

CYP2D6; resting brain perfusion; arterial spin labeling

Original Article

Molecular Psychiatry advance online publication 13 April 2010; doi: 10.1038/mp.2010.44

For the article, click here.

Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression

R Bernard^1,2,*, I A Kerman^1,*, R C Thompson³, E G Jones⁴, W E Bunney⁵, J D Barchas⁶, A F Schatzberg⁷, R M Myers⁸, H Akil¹ and S J Watson¹

1. ¹Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
2. ²Institute for Integrative Neuroanatomy, Charité University Medicine, Berlin, Germany
3. ³Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
4. ⁴Center for Neuroscience, University of California, Davis, CA, USA
5. ⁵Department of Psychiatry, University of California, Irvine, CA, USA
6. ⁶Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY, USA
7. ⁷Department of Psychiatry, Stanford University, Stanford, CA, USA
8. ⁸HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

Correspondence: Dr R Bernard, Department of Psychiatry, Charite University Medicine, Institute for Integrative Neuroanatomy, Philippstrasse 12, Berlin 10115, Germany. E-mail: rbbernard@gmail.com

^*These two authors contributed equally to this work.

Received 21 September 2009; Revised 25 February 2010; Accepted 8 March 2010; Published online 13 April 2010.

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Abstract

Several studies have proposed that brain glutamate signaling abnormalities and glial pathology have a role in the etiology of major depressive disorder (MDD). These conclusions were primarily drawn from post-mortem studies in which forebrain brain regions were examined. The locus coeruleus (LC) is the primary source of extensive noradrenergic innervation of the forebrain and as such exerts a powerful regulatory role over cognitive and affective functions, which are dysregulated in MDD. Furthermore, altered noradrenergic neurotransmission is associated with depressive symptoms and is thought to have a role in the pathophysiology of MDD. In the present study we used laser-capture microdissection (LCM) to selectively harvest LC tissue from post-mortem brains of MDD patients, patients with bipolar disorder (BPD) and from psychiatrically normal subjects. Using microarray technology we examined global patterns of gene expression. Differential mRNA expression of select candidate genes was then interrogated using quantitative real-time PCR (qPCR) and in situ hybridization (ISH). Our findings reveal multiple signaling pathway alterations in the LC of MDD but not BPD subjects. These include glutamate signaling genes, SLC1A2, SLC1A3 and GLUL, growth factor genes FGFR3 and TrkB, and several genes exclusively expressed in astroglia. Our data extend previous findings of altered glutamate, astroglial and growth factor functions in MDD for the first time to the brainstem. These findings indicate that such alterations: (1) are unique to MDD and distinguishable from BPD, and (2) affect multiple brain regions, suggesting a whole-brain dysregulation of such functions.

Keywords:

laser-capture microdissection; human; monoamine; norepinephrine; post mortem; microarray