Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.137190v1?rss=1 Authors: Borrelli, K. N., Dubinsky, K. R., Szumlinski, K. K., Carlezon, W. A., Chartoff, E. H., Bryant, C. D. Abstract: Rationale: Addiction to methamphetamine (MA) is a 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-induced 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. Objectives: We examined innate reward sensitivity and modulation by MA in H1+/- mice via intracranial self-stimulation (ICSS). Methods: We 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.) at 10 min or 2 h post-MA. We also assessed video-recorded behaviors during ICSS testing sessions. Results: Ten min post-MA, H1+/- mice displayed reduced maximum response rates, H1+/- females had lower M50 values than wild-type females, and H1+/- influenced ICSS responding relative to maximum control rates (MCR). Two h post-MA, higher response rates were observed in females, irrespective of genotype. There was a dose-dependent reduction in distance to the response wheel 10 min post-MA and reduced immobility time in the perimeter corners both 10 min and 2 h post-MA. Conclusions: H1+/- mice displayed altered MA-induced reward modulation in a time-, sex-, and dose-dependent manner. This expands the set of MA-induced phenotypes observed in H1+/- mice. Keywords: Intracranial Self-Stimulation (ICSS), methamphetamine, genetics, addiction, behavioral genetics, psychostimulants, mouse, forward genetics, QTL, sensitization Copy rights belong to original authors. Visit the link for more info