Elsevier

Biological Psychiatry

Volume 81, Issue 11, 1 June 2017, Pages 959-970
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2016.10.005Get rights and content

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.

Section snippets

Experimental Overview

To test the hypothesis that NAC glutamate anomalies accompany genetic predisposition to consume MA, we conducted in vivo microdialysis and immunoblotting procedures on mouse lines selectively bred to exhibit MA high drinking (MAHDR) and MA low drinking (MALDR) (14, 15). We next examined whether individual variance in MA preference/taking might correlate with indices of NAC glutamate transmission in an isogenic model that involved screening a large (N = 186) group of inbred C57BL/6J (B6) mice

Elevated Indices of NAC Glutamate Transmission Correspond With High MA Taking in a Genetic Model of Addiction Vulnerability/Resiliency

Using no net-flux in vivo microdialysis procedures, we established that basal extracellular glutamate content within the NAC of MAHDR mice was more than twice that of MALDR mice (Figure 1A, B); this line difference was replicated using conventional microdialysis procedures (MAHDR = 4.17 ± 1.12 pg/sample; MALDR = 1.42 ± 0.17 pg/sample; t13 = 2.27, p = .04). Despite this, acute MA elicited a robust increase in NAC glutamate levels only in MAHDR mice (Figure 1C). These data served as our first

Discussion

Through study of both genetic (selective breeding) and inbred murine models of MA abuse and reward vulnerability, we discovered that a hyperglutamatergic state within the NAC is a biochemical trait corresponding to a high MA-preferring/taking/seeking phenotype, largely resembling that produced by subchronic MA experience. Causal relations between high MA preference and glutamate hyperactivity within the NACs were established by bidirectional neuropharmacological manipulations of endogenous

Acknowledgments and Disclosures

This work was supported by the National Institute on Drug Abuse (Grant Nos. DA024038 and DA039168 to KKS, Grant No. P50 DA018165 to TJP, and Grant No. DA027525 to TEK); the Department of Veterans Affairs (to TJP), the W.M. Keck Foundation (to TEK), and funds from the Australian Research Council (to MK). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

KKS, KDL, RRC, MC, CNB, TEK, and TJP designed the studies. KKS, KDL, RRC, MC,

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