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

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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).

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References

  • Albers DS, Sonsalla PK (1995) Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents. J Pharmacol Exp Ther 275(3):1104–1114

    CAS  PubMed  Google Scholar 

  • Bauer CT, Banks ML, Blough BE, Negus SS (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168(4):850–862. https://doi.org/10.1111/j.1476-5381.2012.02214.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bauer CT, Banks ML, Negus SS (2014) The effect of chronic amphetamine treatment on cocaine-induced facilitation of intracranial self-stimulation in rats. Psychopharmacology 231(12):2461–2470. https://doi.org/10.1007/s00213-013-3405-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bielajew C, Shizgal P (1986) Evidence implicating descending fibers in self-stimulation of the medial forebrain bundle. J Neurosci 6(4):919–929

    Article  CAS  Google Scholar 

  • Bousman CA, Glatt SJ, Everall IP, Tsuang MT (2009a) Genetic association studies of methamphetamine use disorders: a systematic review and synthesis. Am J Med Genet 150B(8):1025–1049. https://doi.org/10.1002/ajmg.b.30936

    Article  CAS  PubMed  Google Scholar 

  • Bousman CA, Glatt SJ, Everall IP, Tsuang MT (2009b) Genetic association studies of methamphetamine use disorders: a systematic review and synthesis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 150B(8):1025–1049. https://doi.org/10.1002/ajmg.b.30936

    Article  CAS  Google Scholar 

  • Bryant CD, Yazdani N (2016) RNA binding proteins, neural development and the addictions. Genes, Brain and Behavior 15:169–186

    Article  CAS  Google Scholar 

  • Carlezon WA, Chartoff EH (2007) Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2:2987–2995

    Article  CAS  Google Scholar 

  • Chan P, Di Monte DA, Luo J et al (1994) Rapid ATP loss caused by methamphetamine in the mouse striatum: relationship between energy impairment and dopaminergic neurotoxicity. J Neurochem 62(6):2484–2487. https://doi.org/10.1046/j.1471-4159.1994.62062484.x

    Article  CAS  PubMed  Google Scholar 

  • Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104(7):1085–1099. https://doi.org/10.1111/j.1360-0443.2009.02564.x

    Article  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. PNAS 85(14):5274–5278

    Article  Google Scholar 

  • Dluzen DE, McDermott JL (2008) Sex differences in dopamine- and vesicular monoamine-transporter functions. Ann N Y Acad Sci 1139:140–150. https://doi.org/10.1196/annals.1432.010

    Article  CAS  PubMed  Google Scholar 

  • Dluzen DE, Bhatt S, McDermott JL (2008) Differences in reserpine-induced striatal dopamine output and content between female and male mice: implications for sex differences in vesicular monoamine transporter 2 function. Neuroscience 154(4):1488–1496

    Article  CAS  Google Scholar 

  • Esposito RU, Perry W, Kornetsky C (1980) Effects of d-amphetamine and naloxone on brain stimulation reward. Psychopharmacology 69(2):187–191. https://doi.org/10.1007/BF00427648

    Article  CAS  PubMed  Google Scholar 

  • Fiorino DF, Coury A, Fibiger HC et al (1993) Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat. Behav Brain Res 55(2):131–141

    Article  CAS  Google Scholar 

  • Fish EW, Robinson JE, Krouse MC, Hodge CW, Reed C, Phillips TJ, Malanga CJ (2012) Intracranial self-stimulation in FAST and SLOW mice: effects of alcohol and cocaine. Psychopharmacology 220(4):719–730. https://doi.org/10.1007/s00213-011-2523-x

    Article  CAS  PubMed  Google Scholar 

  • Flint J, Valdar W, Shifman S, Mott R (2005) Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6:271–286

    Article  CAS  Google Scholar 

  • Garris PA, Kilpatrick M, Bunin MA, Michael D, Walker QD, Wightman RM (1999) Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation. Nature 398(6722):67–69. https://doi.org/10.1038/18019

    Article  CAS  PubMed  Google Scholar 

  • Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532

    Article  CAS  Google Scholar 

  • Han SP, Tang YH, Smith R (2010) Functional diversity of the hnRNPs: past, present and perspectives. Biochem J 430(3):379–392. https://doi.org/10.1042/BJ20100396

    Article  CAS  PubMed  Google Scholar 

  • Hancock DB, Markunas CA, Bierut LJ, Johnson EO (2018) Human genetics of addiction: new insights and future directions. Curr Psychiatry Rep 20(2):8. https://doi.org/10.1007/s11920-018-0873-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Ikeda M, Okahisa Y, Aleksic B, Won M, Kondo N, Naruse N, Aoyama-Uehara K, Sora I, Iyo M, Hashimoto R, Kawamura Y, Nishida N, Miyagawa T, Takeda M, Sasaki T, Tokunaga K, Ozaki N, Ujike H, Iwata N (2013) Evidence for shared genetic risk between methamphetamine-induced psychosis and schizophrenia. Neuropsychopharmacology 38:1864–1870

    Article  CAS  Google Scholar 

  • Jensen KP (2016) A review of genome-wide association studies of stimulant and opioid use disorders. Mol Neuropsychiatry 2(1):37–45. https://doi.org/10.1159/000444755

    Article  PubMed  PubMed Central  Google Scholar 

  • Johnson AR, Banks ML, Selley DE, Negus SS (2018) Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 43(8):1753–1762. https://doi.org/10.1038/s41386-018-0071-3

    Article  CAS  Google Scholar 

  • Kesby JP, Chang A, Markou A, Semenova S (2018) Modeling human methamphetamine use patterns in mice: chronic and binge methamphetamine exposure, reward function and neurochemistry. Addict Biol 23(1):206–218. https://doi.org/10.1111/adb.12502

    Article  CAS  PubMed  Google Scholar 

  • Kim VN, Kataoka N, Dreyfuss G (2002) Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3(3):195–205. https://doi.org/10.1038/nrm760

    Article  CAS  PubMed  Google Scholar 

  • Koshikawa N, Mori E, Oka K et al (1989) Effects of SCH23390 injection into the dorsal striatum and nucleus accumbens on methamphetamine-induced gnawing and hyperlocomotion in rats. J Nihon Univ Sch Dent 31(2):451–457

    Article  CAS  Google Scholar 

  • Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chi Chin M, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Feng Yuan X, Zhang B, Zwingman TA, Jones AR (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445(7124):168–176. https://doi.org/10.1038/nature05453

    Article  CAS  PubMed  Google Scholar 

  • Lominac KD, McKenna CL, Schwartz LM et al (2014) Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation. Front Syst Neurosci 8:70. https://doi.org/10.3389/fnsys.2014.00070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Milesi-Hallé A, Hendrickson HP, Laurenzana EM, Gentry WB, Owens SM (2005) Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats. Toxicol Appl Pharmacol 209(3):203–213. https://doi.org/10.1016/j.taap.2005.04.007

    Article  CAS  PubMed  Google Scholar 

  • Miliaressis E, Rompre P, Laviolette P et al (1986) The curve-shift paradigm in self-stimulation. Physiol Behav 37(1):85–91. https://doi.org/10.1016/0031-9384(86)90388-4

    Article  CAS  PubMed  Google Scholar 

  • Miliaressis E, Emond C, Merali Z (1991) Re-evaluation of the role of dopamine in intracranial self-stimulation using in vivo microdialysis. Behav Brain Res 46(1):43–48

    Article  CAS  Google Scholar 

  • National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press (US), Washington (DC).

  • Negus SS, Miller LL (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66(3):869–917. https://doi.org/10.1124/pr.112.007419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otani K, Ujike H, Sakai A, Okahisa Y, Kotaka T, Inada T, Harano M, Komiyama T, Hori T, Yamada M, Sekine Y, Iwata N, Iyo M, Sora I, Ozaki N, Kuroda S (2008) Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence. Neurosci Lett 434(1):88–92. https://doi.org/10.1016/j.neulet.2008.01.033

    Article  CAS  PubMed  Google Scholar 

  • Owesson-White CA, Cheer JF, Beyene M, Carelli RM, Wightman MR (2008) Dynamic changes in accumbens dopamine correlate with learning during intracranial self-stimulation. Proc Natl Acad Sci U S A 105(33):11957–11962. https://doi.org/10.1073/pnas.0803896105

    Article  PubMed  PubMed Central  Google Scholar 

  • Paxinos GT, Franklin KB (2004) The mouse brain in stereotaxic coordinates, 2 edn. Academic Press, San Diego, CA

  • Phillips AG, Blaha CD, Fibiger HC (1989) Neurochemical correlates of brain-stimulation reward measured by ex vivo and in vivo analyses. Neurosci Biobehav Rev 13(2-3):99–104

    Article  CAS  Google Scholar 

  • Riday TT, Kosofsky BE, Malanga CJ (2012) The rewarding and locomotor-sensitizing effects of repeated cocaine administration are distinct and separable in mice. Neuropharmacology 62(4):1858–1866. https://doi.org/10.1016/j.neuropharm.2011.12.011

    Article  CAS  PubMed  Google Scholar 

  • Robinson JE, Agoglia AE, Fish EW, Krouse MC, Malanga CJ (2012) Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: comparison to cocaine. Behav Brain Res 234(1):76–81. https://doi.org/10.1016/j.bbr.2012.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruan QT, Yazdani N, Reed ER, Beierle JA, Peterson LP, Luttik KP, Szumlinski KK, Johnson WE, Ash PEA, Wolozin B, Bryant CD (2020a) 5′ UTR variants in the quantitative trait gene Hnrnph1 support reduced 5′ UTR usage and hnRNP H protein as a molecular mechanism underlying reduced methamphetamine sensitivity [published online ahead of print, 2020 May 13]. FASEB J 34:9223–9244. https://doi.org/10.1096/fj.202000092R

    Article  CAS  PubMed  Google Scholar 

  • Ruan QT, Yazdani N, Blum BC, Beierle JA, Lin W, Coelho MA, Fultz EK, Healy AF, Shahin JR, Kandola AK, Luttik KP, Zheng K, Smith NJ, Cheung J, Mortazavi F, Apicco DJ, Ragu Varman D, Ramamoorthy S, Ash PEA, Rosene DL, Emili A, Wolozin B, Szumlinski KK, Bryant CD (2020b) A mutation in Hnrnph1 that decreases methamphetamine-induced reinforcement, reward, and dopamine release and increases synaptosomal hnRNP H and mitochondrial proteins. J Neurosci 40(1):107–130

    Article  CAS  Google Scholar 

  • Schultz W (2000) Multiple reward signals in the brain. Nat Rev Neurosci 1(3):199–207. https://doi.org/10.1038/35044563

    Article  CAS  PubMed  Google Scholar 

  • Seth P, Scholl L, Rudd RA et al (2018) Overdose deaths involving opioids, cocaine, and psychostimulants – United States, 2015–2016. MMWR Morb Mortal Wkly Rep 67(12):349–358. https://doi.org/10.15585/mmwr.mm6712a1

    Article  PubMed  PubMed Central  Google Scholar 

  • Spanagel R (2013) Convergent functional genomics in addiction research – a translational approach to study candidate genes and gene networks. Silico Pharmacol 1(1):1–9. https://doi.org/10.1186/2193-9616-1-18

    Article  Google Scholar 

  • Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75(6):406–433. https://doi.org/10.1016/j.pneurobio.2005.04.003

    Article  CAS  PubMed  Google Scholar 

  • Uhl GR, Drgon T, Liu Q et al (2008) Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry 65(3):345–355. https://doi.org/10.1001/archpsyc.65.3.345

    Article  CAS  PubMed  Google Scholar 

  • Yazdani N, Parker CC, Shen Y, Reed ER, Guido MA, Kole LA, Kirkpatrick SL, Lim JE, Sokoloff G, Cheng R, Johnson WE, Palmer AA, Bryant CD (2015) Hnrnph1 is a quantitative trait gene for methamphetamine sensitivity. PLoS Genet 11(12):e1005713

    Article  Google Scholar 

  • Zocchi A, Orsini C, Cabib S, Puglisi-Allegra S (1997) Parallel strain-dependent effect of amphetamine on locomotor activity and dopamine release in the nucleus accumbens: an in vivo study in mice. Neuroscience 82(2):521–528. https://doi.org/10.1016/S0306-4522(97)00276-5

    Article  Google Scholar 

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Acknowledgments

We thank Julia L. Scotellaro for assistance with genotyping, histology, and behavioral training. W.A.C. discloses that he has served as a paid consultant for Psy Therapeutics within the past 2 years.

Funding

This work was funded by R01DA039168 (C.D.B.), U01DA050243 (C.D.B.), NIGMS T32 Biomolecular Pharmacology Training Grant GM008541 (K.N.B.), and Boston University’s Transformative Training Program in Addiction Science (TTPAS Burroughs Wellcome Fund #1011479; K.N.B.).

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Authors and Affiliations

  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

    Kristyn N. Borrelli, Carly R. Langan, Kyra R. Dubinsky & Camron D. Bryant

  2. Ph.D. Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA

    Kristyn N. Borrelli

  3. Graduate Program for Neuroscience, Boston University, Boston, MA, USA

    Kristyn N. Borrelli

  4. Transformative Training Program in Addiction Science, Boston University, Boston, MA, USA

    Kristyn N. Borrelli

  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

    Karen K. Szumlinski

  6. Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA

    William A. Carlezon Jr & Elena H. Chartoff

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  1. Kristyn N. Borrelli
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  2. Carly R. Langan
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Correspondence to Camron D. Bryant.

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Borrelli, K.N., Langan, C.R., Dubinsky, K.R. et al. Intracranial self-stimulation and concomitant behaviors following systemic methamphetamine administration in Hnrnph1 mutant mice. Psychopharmacology 238, 2031–2041 (2021). https://doi.org/10.1007/s00213-021-05829-4

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