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Mol Psychiatry. 2019 Dec 10. doi: 10.1038/s41380-019-0617-8. [Epub ahead of print]

Chronic methamphetamine interacts with BDNF Val66Met to remodel psychosis pathways in the mesocorticolimbic proteome.

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Baker Heart and Diabetes Institute, Molecular Proteomics, Melbourne, VIC, Australia.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
Weill Cornell Medical College, Cornell University, New York, NY, USA.
Australian Centre for Blood Diseases (ACBD), Central Clinical School, Monash University, Melbourne, VIC, Australia.
Biological Research Unit, Racing Analytical Services Ltd, Flemington, VIC, Australia.
School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia.
Department of Pharmacology, University of Melbourne, Melbourne, VIC, Australia.
College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia.


Methamphetamine (Meth) abuse has reached epidemic proportions in many countries and can induce psychotic episodes mimicking the clinical profile of schizophrenia. Brain-derived neurotrophic factor (BDNF) is implicated in both Meth effects and schizophrenia. We therefore studied the long-term effects of chronic Meth exposure in transgenic mice engineered to harbor the human BDNFVal66Met polymorphism expressed via endogenous mouse promoters. These mice were chronically treated with an escalating Meth regime during late adolescence. At least 4 weeks later, all hBDNFVal66Met Meth-treated mice exhibited sensitization confirming persistent behavioral effects of Meth. We used high-resolution quantitative mass spectrometry-based proteomics to biochemically map the long-term effects of Meth within the brain, resulting in the unbiased detection of 4808 proteins across the mesocorticolimbic circuitry. Meth differentially altered dopamine signaling markers (e.g., Dat, Comt, and Th) between hBDNFVal/Val and hBDNFMet/Met mice, implicating involvement of BDNF in Meth-induced reprogramming of the mesolimbic proteome. Targeted analysis of 336 schizophrenia-risk genes, as well as 82 growth factor cascade markers, similarly revealed that hBDNFVal66Met genotype gated the recruitment of these factors by Meth in a region-specific manner. Cumulatively, these data represent the first comprehensive analysis of the long-term effects of chronic Meth exposure within the mesocorticolimbic circuitry. In addition, these data reveal that long-term Meth-induced brain changes are strongly dependent upon BDNF genetic variation, illustrating how drug-induced psychosis may be modulated at the molecular level by a single genetic locus.


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