期刊
BIOLOGICAL PSYCHIATRY
卷 81, 期 11, 页码 959-970出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2016.10.005
关键词
Conditioned place preference; Glutamate; Homer proteins; MAHDR; Metabotropic glutamate receptor; NMDA receptor; Nucleus accumbens
资金
- National Institute on Drug Abuse [DA024038, DA039168, P50 DA018165, DA027525]
- Department of Veterans Affairs
- W.M. Keck Foundation
- Australian Research Council
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.
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