Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly

Karen K. Szumlinski, Kevin D. Lominac, Rianne R. Campbell, Matan Cohen, Elissa K. Fultz, Chelsea N. Brown, Bailey W. Miller, Sema G. Quadir, Douglas Martin, Andrew B. Thompson, Georg von Jonquieres, Matthias Klugmann, Tamara J. Phillips, Tod E. Kippin

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)959-970
Number of pages12
JournalBiological Psychiatry
Volume81
Issue number11
DOIs
StatePublished - Jun 1 2017

Keywords

  • Conditioned place preference
  • Glutamate
  • Homer proteins
  • MAHDR
  • Metabotropic glutamate receptor
  • NMDA receptor
  • Nucleus accumbens

ASJC Scopus subject areas

  • Biological Psychiatry

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