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bioRxiv · 10.1101/2020.06.05.137190

Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice

Borrelli, K. N.·Dubinsky, K. R.·Szumlinski, K. K.·Carlezon, W. A.·Chartoff, E. H.·Bryant, C. D.
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Abstract

RationaleAddiction to methamphetamine (MA) is a major public health issue in the United States. While psychostimulant use disorders are heritable, their genetic basis remains poorly understood. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced locomotor activity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/-) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/- on innate and MA-modulated reward sensitivity are not known. ObjectivesWe examined innate reward sensitivity and modulation by MA in H1+/- mice via intracranial self-stimulation (ICSS). MethodsWe used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5-4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. ResultsH1+/- mice displayed reduced normalized maximum response rates, H1+/- females showed lower normalized M50 values compared to wild-type females following MA, and H1+/- influenced ICSS responding relative to maximum baseline rates. There was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of reward-related behavior. ConclusionsH1+/- mice displayed reduced reward facilitation following MA in a sex- and dose-dependent manner. This result expands upon the set of MA-induced phenotypes observed in H1+/- mice.

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Borrelli, K. N., Dubinsky, K. R., Szumlinski, K. K., Carlezon, W. A., Chartoff, E. H., Bryant, C. D.. 2020-06-07. Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice. https://doi.org/10.1101/2020.06.05.137190

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