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

Abstract

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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Fig. 1: Chronic Meth treatment induces long-term behavioral hypersensitivity to an acute Meth challenge in hBDNFVal66Met mice.
Fig. 2: Quantitative proteomic profiling reveals that methamphetamine remodels the mesocorticolimbic proteome.
Fig. 3: Mesocorticolimbic proteome in response to methamphetamine reflects alteration in neurotrophin signaling and schizophrenia.
Fig. 4: Functional enrichment analysis shows recruitment of schizophrenia-risk factors by Meth in a region-specific manner for each genotype.

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Acknowledgements

This work was funded, in part, by project grants from the NHMRC of Australia to DG and an NHMRC Senior Research Fellowship to MvdB. These studies were furthermore supported by a Research Focus Area—Understanding Disease grant from La Trobe University. The authors acknowledge the La Trobe Comprehensive Proteomics Platform for access to equipment and expertise employed in this study. We also acknowledge the expert contributions of Dr Rohan Steel of the Biological Research Unit, Racing Analytical Services Ltd, Flemington, Australia, and of Dr Emily Jaehne, Mr Matt Maher and Ms Michelle Corrone of the School of Psychology and Public Health, La Trobe University, Melbourne, Australia.

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Greening, D.W., Notaras, M., Chen, M. et al. Chronic methamphetamine interacts with BDNF Val66Met to remodel psychosis pathways in the mesocorticolimbic proteome. Mol Psychiatry 26, 4431–4447 (2021). https://doi.org/10.1038/s41380-019-0617-8

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