Abstract
Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512–50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)—a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes—heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J < C57BL/6J; p 4.2 x 10−15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders.
Highlights
Substance use disorders (SUDs) involving psychostimulants such as cocaine and methamphetamine (MA) are heritable; their major genetic determinants remain poorly defined [1,2,3,4]
Quantitative trait locus (QTL) mapping is an unbiased discoverybased approach that is used to identify novel genetic factors and provide new mechanistic insight into phenotypic variation associated with disease
We focused on the genetic basis of variation in sensitivity to the acute locomotor stimulant response to methamphetamine which is a behavioral phenotype in rodents that is associated with stimulated dopamine release and activation of the brain reward circuitry involved in addiction
Summary
Substance use disorders (SUDs) involving psychostimulants such as cocaine and methamphetamine (MA) are heritable; their major genetic determinants remain poorly defined [1,2,3,4]. Sensitivity to the locomotor stimulant response to MA is heritable and may share a genetic basis with the addictive, neurotoxic, and therapeutic properties of amphetamines [8, 12,13,14,15]. Determining the genetic basis of sensitivity to amphetamines may provide insight into the neurobiology of other conditions involving perturbations in dopaminergic signaling, including attention deficit hyperactive disorder (ADHD), schizophrenia, and Parkinson’s disease [16]. This hypothesis is supported by our recent identification of a genetic correlation between alleles that increased amphetamine-induced euphoria and alleles that decreased risk of schizophrenia and ADHD [17]
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