title: Prefrontal glutamate correlates of methamphetamine sensitization and preference.
abstract: Methamphetamine (MA) is a widely misused, highly addictive psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated MA impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relationship between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of MA (ten injections of 2 mg/kg, i.p.) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high vs. low MA-drinking selectively bred mouse lines (MAHDR vs. MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated MA sensitized drug-induced glutamate release and lowered indices of N-methyl-d-aspartate receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. Elevated basal glutamate, blunted MA-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high vs. low MA drinking, and Homer2a/b levels were inversely correlated with the motivational valence of MA in C57BL/6J mice. These data provide novel evidence that repeated, low-dose MA is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in MA addiction vulnerability/resiliency.
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Lominac
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Sema G
authors.initials: SG
authors.lastname: Quadir
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Barrett
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: McKenna
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schwartz
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Paige N
authors.initials: PN
authors.lastname: Ruiz
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Wroten
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Rianne R
authors.initials: RR
authors.lastname: Campbell
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Bailey W
authors.initials: BW
authors.lastname: Miller
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Holloway
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Katherine O
authors.initials: KO
authors.lastname: Travis
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rajasekar
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Maliniak
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Thompson
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Urman
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Tod E
authors.initials: TE
authors.lastname: Kippin
authors.affiliation: Behavioral Neuroscience and Methamphetamine Abuse Research Center, VA Portland Health Care System, Oregon Health & Science University, Portland, OR, 97239, USA.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Phillips
authors.affiliation: Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-9660, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000818:Animals; D059333:Central Nervous System Sensitization; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003214:Conditioning, Classical; D018698:Glutamic Acid / Q000378:metabolism*; D000072233:Homer Scaffolding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000502:physiology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012646:Self Administration; D009435:Synaptic Transmission
chemical_list: D027322:Amino Acid Transport System X-AG; D000697:Central Nervous System Stimulants; D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008694:Methamphetamine
keywords: Homer proteins; NMDA receptor; addiction vulnerability; metabotropic glutamate receptor; methamphetamine; prefrontal cortex