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

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, mice (both male and female) 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, or dopamine uptake. 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 in the number of forebrain puncta. 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 molecular 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 in response to methamphetamine. 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.

Zhx2 is a candidate gene underlying oxymorphone metabolite brain concentration associated with state-dependent oxycodone reward

“…We did not identify any genome-wide significant QTLs underlying BALB/c substrain differences in state-dependent OXY-CPP when considering treatment as an interactive covariate and sex as an additive covariate ( Supplementary Figure 3A,B ). This null result supports previous observations from our group and others that CPP is not a highly heritable trait (Bryant et al, 2014; Cunningham et al, 1991; Gonzales et al, 2018; Kirkpatrick et al, 2017; Philip et al, 2010; Ruan et al, 2020). Nevertheless, CPP is clearly a useful phenotype as it led us to measure a more heritable trait - brain concentration of OXY and its metabolites and to ultimately identify a plausible candidate gene that could influence both traits.…”

P38α‐MAPK phosphorylates Snapin and reduces Snapin‐mediated BACE1 transportation in APP‐transgenic mice

“…Synaptosomes were isolated from right hemispheres of APP tg p38 fl/fl Nex cre/wt and APP tg p38 fl/fl Nex wt/wt littermate mice according to published methods 19,20 with minor modifications. Briefly, brain tissues were homogenized in 10× volumes of sucrose buffer (2 mM HEPES, pH 7.4, 320 mM sucrose, 50 mM EDTA, 20 mM DTT) supplemented with protease inhibitor cocktail (Merck KGaA) and phosphatase inhibitors, and then centrifuged at 3000 g for 2 minutes.…”

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

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