A Mutation in Hnrnph1 That Decreases Methamphetamine-Induced Reinforcement, Reward, and Dopamine Release and Increases Synaptosomal hnRNP H and Mitochondrial Proteins

• Published in: The Journal of neuroscience Vol. 40; no. 1; pp. 107 - 130
• Main Authors: Ruan, Qiu T, Yazdani, Neema, Blum, Benjamin C, Beierle, Jacob A, Lin, Weiwei, Coelho, Michal A, Fultz, Elissa K, Healy, Aidan F, Shahin, John R, Kandola, Amarpreet K, Luttik, Kimberly P, Zheng, Karen, Smith, Nathaniel J, Cheung, Justin, Mortazavi, Farzad, Apicco, Daniel J, Ragu Varman, Durairaj, Ramamoorthy, Sammanda, Ash, Peter E A, Rosene, Douglas L, Emili, Andrew, Wolozin, Benjamin, Szumlinski, Karen K, Bryant, Camron D
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 02-01-2020
• Subjects: Addictions; Amphetamines; Cell number; Coding; Dopamine; Dopamine receptors; Dopamine transporter; Drug abuse; Electron transport chain; Females; Forebrain; H protein; Levels; Liability; Locomotor activity; Males; Mesencephalon; Metabolites; Methamphetamine; Mitochondria; Mutation; NADH-ubiquinone oxidoreductase; Neostriatum; Place preference conditioning; Protein transport; Proteins; Reinforcement; Rodents; Staining; Hnrnph1; psychostimulants; methamphetamine; mitochondria; RNA binding protein; addiction
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1808-19.2019

Individual variation in the addiction liability of amphetamines has a heritable genetic component. We previously identified
(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
(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 NAc 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 TH did not reveal any major changes in staining intensity, cell number, or forebrain puncta counts. Surprisingly, there was a twofold 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 after methamphetamine administration in H1
mice. In contrast, the much lower level of basal synaptosomal mitochondrial proteins in WT 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.
Methamphetamine 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.
mutation also blunted methamphetamine-induced dopamine release in the NAc, a key neurochemical event contributing to methamphetamine addiction liability. Finally,
mutants showed a marked increase in basal level of synaptosomal hnRNP H and mitochondrial proteins that decreased in response to methamphetamine, whereas WT 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.