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Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly
Karen K Szumlinski1, Kevin D Lominac2, Rianne R Campbell2
1Department 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.
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.