Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
06 10 2020
06 10 2020
Historique:
received:
22
05
2020
accepted:
05
08
2020
revised:
01
08
2020
entrez:
7
10
2020
pubmed:
8
10
2020
medline:
22
6
2021
Statut:
epublish
Résumé
The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.
Identifiants
pubmed: 33024081
doi: 10.1038/s41398-020-01020-z
pii: 10.1038/s41398-020-01020-z
pmc: PMC7539151
doi:
Substances chimiques
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
338Références
Kirchheiner, J. et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol. Psychiatry 9, 442–473 (2004).
pubmed: 15037866
doi: 10.1038/sj.mp.4001494
pmcid: 15037866
Stingl, J. & Viviani, R. Polymorphism in CYP2D6 and CYP2C19, members of the cytochrome P450 mixed-function oxidase system, in the metabolism of psychotropic drugs. J. Intern. Med. 277, 167–177 (2015).
pubmed: 25297512
doi: 10.1111/joim.12317
pmcid: 25297512
Miksys, S., Rao, Y., Hoffmann, E., Mash, D. C. & Tyndale, R. F. Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics. J. Neurochem. 82, 1376–1378 (2002).
pubmed: 12354285
doi: 10.1046/j.1471-4159.2002.01069.x
pmcid: 12354285
Dutheil, F., Beaune, P. & Loriot, M. A. Xenobiotic metabolizing enzymes in the central nervous system: contribution of cytochromic P450 enzymes in normal and pathological human brain. Biochimie 90, 426–436 (2008).
pubmed: 17997991
doi: 10.1016/j.biochi.2007.10.007
pmcid: 17997991
Ferguson, C. S. & Tyndale, R. F. Cytochrome P450 enzymes in the brain: emerging evidence for biological significance. Trends Pharmacol. Sci. 32, 798–714 (2011).
doi: 10.1016/j.tips.2011.08.005
Stingl, J. C., Brockmöller, J. & Viviani, R. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol. Psychiatry 18, 273–287 (2013).
pubmed: 22565785
doi: 10.1038/mp.2012.42
pmcid: 22565785
Ingelman-Sundberg, M. Genetic polymorphism of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogen. J. 5, 6–13 (2005).
doi: 10.1038/sj.tpj.6500285
LLerena, A. et al. Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin. Drug Metab. Toxicol. 10, 1569–1583 (2014).
pubmed: 25316321
doi: 10.1517/17425255.2014.964204
pmcid: 25316321
Ingelman-Sundberg, M., Persson, A. & Jukic, M. M. Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates. Pharmacogenomics 15, 1841–1844 (2014).
pubmed: 25495406
doi: 10.2217/pgs.14.151
pmcid: 25495406
Steffens, M., Hübner, T., Scholl, C., Viviani, R. & Stingl, J. C. Was the Neanderthal a poor metabolizer of CYP2D6. In EMBO-EMBL Symposium: Reconstructing the Human Past Using Ancient and Modern Genomics, Heidelberg, March 31 to 3 April 2019 (2019).
Bertilsson, L. et al. Debrisoquine hydroxylation polymorphism and personality. Lancet 333, 555 (1989).
doi: 10.1016/S0140-6736(89)90094-9
Kirchheiner, J. et al. CYP2D6 in the brain: genotype effects on resting brain perfusion. Mol. Psychiatry 16, 333–341 (2011).
doi: 10.1038/mp.2010.42
Stingl, J. C. et al. Genetic variation in CYP2D6 impacts neural activation during cognitive tasks in humans. NeuroImage 59, 2818–2823 (2012).
pubmed: 21835244
doi: 10.1016/j.neuroimage.2011.07.052
pmcid: 21835244
Peñas-LLedó, E. M., Dorado, P., Pacheco, R., González, I. & LLerena, A. Relation between CYP2D6 genotype, personality, neurocognition and overall psychopathology in healthy volunteers. Pharmacogenomics 10, 1111–1120 (2009).
pubmed: 19604084
doi: 10.2217/pgs.09.75
pmcid: 19604084
Parasumaran, R. & Davies, D. R., Varieties of Attention (Academic Press, Orlando, 1984).
Parasumaran, R. Consistency of individual differences in human vigilance performance: an abilities classificaton analysis. J. Appl. Psychol. 61, 486–492 (1976).
doi: 10.1037/0021-9010.61.4.486
Polderman, T. J. C. et al. Genetic analyses of the stability of executive functioning during childhood. Biol. Psychol. 76, 11–20 (2007).
pubmed: 17597285
doi: 10.1016/j.biopsycho.2007.05.002
pmcid: 17597285
Bromek, E., Haduch, A. & Daniel, W. A. The ability of cytochrome P450 2D isoforms to synthesize dopamine in the brain: an in vitro study. Eur. J. Pharmacol. 626, 171–178 (2010).
pubmed: 19818757
doi: 10.1016/j.ejphar.2009.09.062
Ozdemir, V. et al. Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness? Pharmacogenomics 8, 1199–1210 (2006).
doi: 10.2217/14622416.7.8.1199
Della Libera, C. & Chelazzi, L. Visual selective attention and the effects of monetary rewards. Psychol. Sci. 17, 222–227 (2006).
pubmed: 16507062
doi: 10.1111/j.1467-9280.2006.01689.x
pmcid: 16507062
Della Libera, C., Perlato, A. & Chelazzi, L. Dissociable effects of reward on attentional learning: From passive associations to active monitoring. PLoS ONE 6, e19460 (2011).
pubmed: 21559388
pmcid: 3084870
doi: 10.1371/journal.pone.0019460
Serences, J. T. Value-based modulations in human visual cortex. Neuron 60, 1169–1181 (2008).
pubmed: 19109919
pmcid: 3384552
doi: 10.1016/j.neuron.2008.10.051
Anderson, B. A., Laurent, P. A. & Yantis, S. Reward predictions bias attentional selection. Front. Hum. Neurosci. https://doi.org/10.3389/fnhum.2013.00262 (2013).
Schultz, W. Neuronal reward and decision signals: from theories to data. Physiol. Rev. 95, 853–951 (2015).
pubmed: 26109341
pmcid: 4491543
doi: 10.1152/physrev.00023.2014
Nicola, S. M. The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behaviour. J. Neurosci. 30, 16585–16600 (2010).
pubmed: 21147998
pmcid: 3030450
doi: 10.1523/JNEUROSCI.3958-10.2010
Schultz, W. Dopamine reward prediction-error signalling: a two-component response. Nat. Rev. Neurosci. 17, 183–195 (2016).
pubmed: 26865020
pmcid: 5549862
doi: 10.1038/nrn.2015.26
Maunsell, J. H. R. Neuronal representations of cognitive state: reward or attention? Trends Cogn. Sci. 8, 261–265 (2004).
pubmed: 15165551
doi: 10.1016/j.tics.2004.04.003
pmcid: 15165551
Viviani, R. et al. Signal of anticipation of reward and of mean reward rates in the human brain. Sci. Rep. 10, 4287 (2020).
pubmed: 32152378
pmcid: 7062891
doi: 10.1038/s41598-020-61257-y
Knutson, B., Westdorp, A., Kaiser, E. & Hommer, D. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J. Neurosci. 21, RC159 (2001).
pubmed: 11459880
pmcid: 6763187
doi: 10.1523/JNEUROSCI.21-16-j0002.2001
Berns, G. S., McClure, S. M., Pagnoni, G. & Montague, P. R. Predictability modulates human brain response to reward. J. Neurosci. 21, 2793–2795 (2001).
pubmed: 11306631
pmcid: 6762527
doi: 10.1523/JNEUROSCI.21-08-02793.2001
Paus, T. et al. Time-related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task. J. Cogn. Neurosci. 9, 392–408 (1997).
pubmed: 23965014
doi: 10.1162/jocn.1997.9.3.392
pmcid: 23965014
Paus, T. Functional anatomy of arousal and attention systems in the human brain. Prog. Brain Res. 126, 65–77 (2000).
pubmed: 11105640
doi: 10.1016/S0079-6123(00)26007-X
pmcid: 11105640
Corbetta, M. & Shulman, G. L. Control of goal-directed and stimulus-driven attention in the brain. Nat. Rev. Neurosci. 3, 201–215 (2002).
pubmed: 11994752
pmcid: 11994752
doi: 10.1038/nrn755
Haber, S. N. & Knutson, B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 4–26 (2010).
pubmed: 19812543
doi: 10.1038/npp.2009.129
pmcid: 19812543
Sheehan, D. V. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.) The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59(Suppl. 20), 22–33 (1998).
pubmed: 9881538
pmcid: 9881538
Sistonen, J., Fuselli, S., Levo, A. & Sajantila, A. CYP2D6 genotyping by a multiplex primer extension reaction. Clin. Chem. 51, 1291–1295 (2005).
pubmed: 15905314
doi: 10.1373/clinchem.2004.046466
pmcid: 15905314
Gaedick, A., Sangkuhl, K., Whirl-Carrillo, M., Klein, T. & Leeder, J. S. Prediction of CYP2D6 phenotype from genotype across world populations. Gen. Med. 19, 69–76 (2017).
Stöcker, T. et al. Dependence of amygdala activation on echo time: results from olfactory fMRI experiments. NeuroImage 30, 151–159 (2006).
pubmed: 16305825
doi: 10.1016/j.neuroimage.2005.09.050
pmcid: 16305825
Bates, D., Mächler, M., Bolker, B. M. & Walker, S. C. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1 (2015).
doi: 10.18637/jss.v067.i01
Friston, K. J. et al. Statistical parametric maps in functional imaging: a general linear approach. Hum. Brain Mapp. 2, 189–210 (1995).
doi: 10.1002/hbm.460020402
Holmes, A. P., Blair, R. C., Watson, J. D. G. & Ford, I. Nonparametric analysis of statistic images from functional mapping experiments. J. Cereb. Blood Flow Metab. 16, 7–22 (1996).
pubmed: 8530558
doi: 10.1097/00004647-199601000-00002
pmcid: 8530558
Smith, S. M. & Nichols, T. E. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage 44, 83–98 (2009).
pubmed: 18501637
doi: 10.1016/j.neuroimage.2008.03.061
pmcid: 18501637
Buxton, R. B. Introduction to Functional Magnetic Resonance Imaging. Principles and Techniques (Cambridge University Press, Cambridge, 2002).
Honey, G. D., Bullmore, E. T. & Sharma, T. Prolonged reaction time to a verbal working memory task predicts increased power of posterior parietal cortical activation. NeuroImage 12, 495–503 (2000).
pubmed: 11034857
doi: 10.1006/nimg.2000.0624
pmcid: 11034857
Binder, J. R., Liebenthal, E., Possing, E. T., Medler, D. A. & Ward, B. D. Neural correlates of sensory and decision processes in auditory object identification. Nat. Neurosci. 7, 295–301 (2004).
pubmed: 14966525
doi: 10.1038/nn1198
pmcid: 14966525
Roberts, R. L., Luty, S. E., Mulder, R. T., Joyce, P. R. & Kennedy, M. A. Association between cytochrome P450 2D6 genotype and harm avoidance. Am. J. Med. Genet. 127B, 90–93 (2004).
pubmed: 15108188
doi: 10.1002/ajmg.b.20163
pmcid: 15108188
Corbetta, M., Miezin, F. M., Dobneyer, S., Shulman, G. L. & Petersen, S. E. Attentional modulation of neural processing of shape, color and velocity in humans. Science 248, 1556–1559 (1990).
pubmed: 2360050
doi: 10.1126/science.2360050
pmcid: 2360050
Gandhi, S. P., Heeger, D. J. & Boynton, G. M. Spatial attention affects brain activity in human primary visual cortex. Proc. Natl Acad. Sci. USA 96, 3314–3319 (1999).
pubmed: 10077681
doi: 10.1073/pnas.96.6.3314
pmcid: 10077681
Najdenovska, E. et al. In-vivo probabilistic atlas of human thalamic nuclei based on diffusion-weighted magnetic resonance imaging. Sci. Data 5, 180270 (2018).
pubmed: 30480664
pmcid: 6257045
doi: 10.1038/sdata.2018.270
Behrens, T. E. J. et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat. Neurosci. 6, 750–757 (2003).
pubmed: 12808459
doi: 10.1038/nn1075
pmcid: 12808459
Schmahmann, J. D. Vascular syndromes of the thalamus. Stroke 34, 2264–2278 (2003).
pubmed: 12933968
doi: 10.1161/01.STR.0000087786.38997.9E
pmcid: 12933968
Kurzban, R., Duckworth, A., Kable, J. W. & Myers, J. An opportunity cost model of subjective effort and task performance. Behav. Brain Sci. 36, 881–726 (2013).