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

Biol Psychiatry. 2017 Jun 1;81(11):959-970. doi: 10.1016/j.biopsych.2016.10.005. Epub 2016 Oct 13.


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.

Keywords: Conditioned place preference; Glutamate; Homer proteins; MAHDR; Metabotropic glutamate receptor; NMDA receptor; Nucleus accumbens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Behavior, Addictive / physiopathology*
  • Gene Knockdown Techniques
  • Glutamic Acid / metabolism
  • Glutamic Acid / physiology*
  • Homer Scaffolding Proteins / genetics
  • Homer Scaffolding Proteins / metabolism
  • Homer Scaffolding Proteins / physiology
  • Male
  • Methamphetamine / adverse effects
  • Methamphetamine / pharmacology*
  • Mice
  • Mice, Inbred Strains
  • Microdialysis
  • Nucleus Accumbens / physiology
  • Receptor, Metabotropic Glutamate 5 / physiology*
  • Receptors, Metabotropic Glutamate / physiology
  • Self Administration
  • Substance Withdrawal Syndrome / physiopathology*


  • Homer Scaffolding Proteins
  • Homer2 protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Glutamic Acid
  • Methamphetamine