title: Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.
abstract: The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.
authors.affiliation: 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.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Lominac
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Rianne R
authors.initials: RR
authors.lastname: Campbell
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Matan
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Fultz
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Chelsea N
authors.initials: CN
authors.lastname: Brown
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Bailey W
authors.initials: BW
authors.lastname: Miller
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Sema G
authors.initials: SG
authors.lastname: Quadir
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Douglas
authors.initials: D
authors.lastname: Martin
authors.affiliation: Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Thompson
authors.affiliation: Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales, Australia.
authors.forename: Georg
authors.initials: G
authors.lastname: von Jonquieres
authors.affiliation: Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.affiliation: Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University; VA Portland Health Care System, Portland, Oregon.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Phillips
authors.affiliation: 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.
authors.forename: Tod E
authors.initials: TE
authors.lastname: Kippin
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology*; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D000072233:Homer Scaffolding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
chemical_list: D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D008694:Methamphetamine
keywords: Conditioned place preference; Glutamate; Homer proteins; MAHDR; Metabotropic glutamate receptor; NMDA receptor; Nucleus accumbens