Karen K Szumlinski1, Kevin D Lominac2, Rianne R Campbell2, Matan Cohen2, Elissa K Fultz2, Chelsea N Brown2, Bailey W Miller2, Sema G Quadir2, Douglas Martin2, Andrew B Thompson2, Georg von Jonquieres3, Matthias Klugmann3, Tamara J Phillips4, Tod E Kippin5. 1. Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California; Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California. Electronic address: karen.szumlinski@psych.ucsb.edu. 2. Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California. 3. Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales, Australia. 4. Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University; VA Portland Health Care System, Portland, Oregon. 5. Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California; Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California; Neuroscience Research Institute, and Institute for Collaborative Biotechnology, University of California at Santa Barbara, Santa Barbara, California.
Abstract
BACKGROUND: The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology. METHODS: We conducted immunoblotting and in vivo microdialysis procedures in MA high/low drinking mice, as well as in isogenic C57BL/6J mice that varied in their MA preference/taking, to examine the glutamate underpinnings of MA abuse vulnerability. Neuropharmacological and Homer2 knockdown approaches were also used in C57BL/6J mice to confirm the role for nucleus accumbens (NAC) glutamate/Homer2 expression in MA preference/aversion. RESULTS: We identified a hyperglutamatergic state within the NAC as a biochemical trait corresponding with both genetic and idiopathic vulnerability for high MA preference and taking. We also confirmed that subchronic subtoxic MA experience elicits a hyperglutamatergic state within the NAC during protracted withdrawal, characterized by elevated metabotropic glutamate 1/5 receptor function and Homer2 receptor-scaffolding protein expression. A high MA-preferring phenotype was recapitulated by elevating endogenous glutamate within the NAC shell of mice and we reversed MA preference/taking by lowering endogenous glutamate and/or Homer2 expression within this subregion. CONCLUSIONS: Our data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.
BACKGROUND: The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology. METHODS: We conducted immunoblotting and in vivo microdialysis procedures in MA high/low drinking mice, as well as in isogenic C57BL/6J mice that varied in their MA preference/taking, to examine the glutamate underpinnings of MA abuse vulnerability. Neuropharmacological and Homer2 knockdown approaches were also used in C57BL/6J mice to confirm the role for nucleus accumbens (NAC) glutamate/Homer2 expression in MA preference/aversion. RESULTS: We identified a hyperglutamatergic state within the NAC as a biochemical trait corresponding with both genetic and idiopathic vulnerability for high MA preference and taking. We also confirmed that subchronic subtoxic MA experience elicits a hyperglutamatergic state within the NAC during protracted withdrawal, characterized by elevated metabotropic glutamate 1/5 receptor function and Homer2 receptor-scaffolding protein expression. A high MA-preferring phenotype was recapitulated by elevating endogenous glutamate within the NAC shell of mice and we reversed MA preference/taking by lowering endogenous glutamate and/or Homer2 expression within this subregion. CONCLUSIONS: Our data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.
Authors: J M Wheeler; C Reed; S Burkhart-Kasch; N Li; C L Cunningham; A Janowsky; F H Franken; K M Wiren; J G Hashimoto; A C Scibelli; T J Phillips Journal: Genes Brain Behav Date: 2009-07-21 Impact factor: 3.449
Authors: Karen K Szumlinski; Kevin D Lominac; Erik B Oleson; Jennifer K Walker; Ashley Mason; Marlin H Dehoff; Matthias Klugmann; Matthias Klugman; Stephanie Cagle; Kristine Welt; Matthew During; Paul F Worley; Lawrence D Middaugh; Peter W Kalivas Journal: J Neurosci Date: 2005-07-27 Impact factor: 6.167
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Authors: Zachary R Harmony; Erin M Alderson; Israel Garcia-Carachure; Laurence D Bituin; Cynthia A Crawford Journal: Drug Alcohol Depend Date: 2020-02-19 Impact factor: 4.492
Authors: Elissa K Fultz; Douglas L Martin; Courtney N Hudson; Tod E Kippin; Karen K Szumlinski Journal: Drug Alcohol Depend Date: 2017-05-24 Impact factor: 4.492
Authors: Karen K Szumlinski; Alexis W Ary; Christina B Shin; Melissa G Wroten; Justin Courson; Bailey W Miller; Micaela Ruppert-Majer; John W Hiller; John R Shahin; Osnat Ben-Shahar; Tod E Kippin Journal: Addict Biol Date: 2018-11-18 Impact factor: 4.280
Authors: Gabriella Shab; Elissa K Fultz; Ariana Page; Michal A Coelho; Lindsey W Brewin; Nicholas Stailey; Chelsea N Brown; Camron D Bryant; Tod E Kippin; Karen K Szumlinski Journal: Behav Brain Res Date: 2020-10-11 Impact factor: 3.332