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J Neurosci. 2019 Nov 8. pii: 1808-19. doi: 10.1523/JNEUROSCI.1808-19.2019. [Epub ahead of print]

A mutation in Hnrnph1 that decreases methamphetamine-induced reinforcement, reward, and dopamine release and increases synaptosomal hnRNP H and mitochondrial proteins.

Author information

1
Biomolecular Pharmacology Training Program, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118.
2
Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118.
3
Transformative Training Program in Addiction Science, Boston University, 02118.
4
Center for Network Systems Biology, Boston University School of Medicine, 02118.
5
Department of Psychological and Brain Sciences, University of California, Santa Barbara, 93106.
6
Department of Anatomy and Neurobiology, Boston University School of Medicine, 02118.
7
Laboratory of Neurodegeneration, Department of Pharmacology and Experimental Therapeutics and Neurology, Boston University School of Medicine, 02118.
8
Department of Pharmacology & Toxicology, Virginia Commonwealth University, 23284.
9
Biomolecular Pharmacology Training Program, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118 camron@bu.edu.
10
Department of Psychiatry, Boston University School of Medicine, 02118.

Abstract

Individual variation in the addiction liability of amphetamines has a heritable genetic component. We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying decreased methamphetamine-induced locomotor activity in mice. Here, we showed that mice (both females and males) with a heterozygous mutation in the first coding exon of Hnrnph1 (H1+/-) showed reduced methamphetamine reinforcement and intake and dose-dependent changes in methamphetamine reward as measured via conditioned place preference. Furthermore, H1+/- mice showed a robust decrease in methamphetamine-induced dopamine release in the nucleus accumbens with no change in baseline extracellular dopamine, striatal whole tissue dopamine, dopamine transporter protein, dopamine uptake, or striatal methamphetamine and amphetamine metabolite levels. Immunohistochemical and immunoblot staining of midbrain dopaminergic neurons and their forebrain projections for tyrosine hydroxylase did not reveal any major changes in staining intensity, cell number, or forebrain puncta counts. Surprisingly, there was a two-fold increase in hnRNP H protein in the striatal synaptosome of H1+/- mice with no change in whole tissue levels. To gain insight into the mechanisms linking increased synaptic hnRNP H with decreased methamphetamine-induced dopamine release and behaviors, synaptosomal proteomic analysis identified an increased baseline abundance of several mitochondrial complex I and V proteins that rapidly decreased at 30 min post-methamphetamine administration in H1+/- mice. In contrast, the much lower level of basal synaptosomal mitochondrial proteins in wild-type mice showed a rapid increase. We conclude that H1+/- decreases methamphetamine--induced dopamine release, reward, and reinforcement and induces dynamic changes in basal and methamphetamine-induced synaptic mitochondrial function.SIGNIFICANCE STATEMENTMethamphetamine dependence is a significant public health concern with no FDA-approved treatment. We discovered a role for the RNA binding protein hnRNP H in methamphetamine reward and reinforcement. Hnrnph1 mutation also blunted methamphetamine-induced dopamine release in the nucleus accumbens -- a key neurochemical event contributing to methamphetamine addiction liability. Finally, Hnrnph1 mutants showed a marked increase in basal level of synaptosomal hnRNP H and mitochondrial proteins that decreased in response to methamphetamine whereas wild-type mice showed a methamphetamine-induced increase in synaptosomal mitochondrial proteins. Thus, we identified a potential role for hnRNP H in basal and dynamic mitochondrial function that informs methamphetamine-induced cellular adaptations associated with reduced addiction liability.

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