Kristyn N Borrelli1,2,3,4, Carly R Langan1, Kyra R Dubinsky1, Karen K Szumlinski5, William A Carlezon6, Elena H Chartoff6, Camron D Bryant7. 1. Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, 72 E. Concord St, L-606C, Boston, MA, 02118, USA. 2. Ph.D. Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA. 3. Graduate Program for Neuroscience, Boston University, Boston, MA, USA. 4. Transformative Training Program in Addiction Science, Boston University, Boston, MA, USA. 5. Department of Psychological and Brain Sciences; Department of Molecular, Cellular and Developmental Biology; and the Neuroscience Research Institute, University of California, Santa Barbara, CA, USA. 6. Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA. 7. Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, 72 E. Concord St, L-606C, Boston, MA, 02118, USA. camron@bu.edu.
Abstract
RATIONALE: Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. 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. OBJECTIVES: We examined innate reward sensitivity and facilitation 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.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. RESULTS: H1+/- mice displayed reduced normalized maximum response rates in response to MA. H1+/- females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. CONCLUSIONS: H1+/- mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/- females (lower normalized M50 values).
RATIONALE: Methamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. 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. OBJECTIVES: We examined innate reward sensitivity and facilitation 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.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions. RESULTS: H1+/- mice displayed reduced normalized maximum response rates in response to MA. H1+/- females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior. CONCLUSIONS: H1+/- mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/- females (lower normalized M50 values).
Authors: Qiu T Ruan; Neema Yazdani; Eric R Reed; Jacob A Beierle; Lucy P Peterson; Kimberly P Luttik; Karen K Szumlinski; William E Johnson; Peter E A Ash; Benjamin Wolozin; Camron D Bryant Journal: FASEB J Date: 2020-05-13 Impact factor: 5.191
Authors: Kevin D Lominac; Courtney L McKenna; Lisa M Schwartz; Paige N Ruiz; Melissa G Wroten; Bailey W Miller; John J Holloway; Katherine O Travis; Ganesh Rajasekar; Dan Maliniak; Andrew B Thompson; Lawrence E Urman; Tamara J Phillips; Karen K Szumlinski Journal: Front Syst Neurosci Date: 2014-05-07
Authors: Neema Yazdani; Clarissa C Parker; Ying Shen; Eric R Reed; Michael A Guido; Loren A Kole; Stacey L Kirkpatrick; Jackie E Lim; Greta Sokoloff; Riyan Cheng; W Evan Johnson; Abraham A Palmer; Camron D Bryant Journal: PLoS Genet Date: 2015-12-10 Impact factor: 5.917