Role of genetic polymorphisms in drug metabolizing cytochrome P450 enzymes expressed in the brain for affective disorders
The effects of genetic variation on cytochrome P450 (CYP)-mediated drug metabolism have been known for a long time [1-2]. However, some key recent findings provide strong evidence for a role CYP in brain function  and for an association of CYP polymorphisms and affective disorders [4-5]. Furthermore, neuroimaging investigations have demonstrated differences in brain activity in man associated with CYP2D6 genotype [6-7]. The aim of the present research project is to investigate the role of CYPs in the vulnerability to mental disorders through their action on endogenous substrates in the brain and their resulting effects on brain morphology and function. Based on specific preliminary findings [3-5], our research will focus on the hypothesis that genetic polymorphisms leading to overexpression of CYP2C19 and CYP2D6 in the brain will be associated with an anxious-depressive phenotype, thus contributing to clarifying the aetiology of related affective disorders. Cooperating partners Partner 3 (Karolinska) and Partner 4 (Toronto) will investigate the effects of CYP2C19 and CYP2D6 overexpression in transgenic mouse models. Rescue of the overexpressed phenotype with a CNS-selective pharmacological probe and neurotransmitter assays of brain tissue will demonstrate the central nature of the genetic effect and clarify its downstream effects in the involved pathways. Relevance to affective function will be tested with behavioural models of depression in the mouse. These data will be made available to cooperating partners Partner 1 and Partner 2 (Bonn and Ulm), which will assay the effect of the same polymorphisms on a DNA+neuroimaging database providing information on brain structure (for morphological effects) and function (through functional imaging probes specific for anxiety-depressive intermediate phenotypes). Cooperating partners Partner 1 and Partner 2 will in turn make available data from a separate cohort of DNA+neuroimaging data acquired in depressives in the initial phases of SSRI treatment for translational application of the insight gained in the preceding phases; this will mirrored by SSRI treatment in the transgenic animal model. Knowledge acquired here may in the future complement implications of DNA genotyping extending their significance from individual effects in drug metabolism to vulnerability to mental disorders.
Imaging techniques, affective disorders, Pharmacology, Behavioural methodologies, aetiology, drug metabolizing enzymes, pharmacogenetics
2014 - 2018
Julia Stingl (Coordinator)