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

Overview

Journal Biol Psychiatry

Publisher Elsevier

Specialty Psychiatry

Date 2016 Nov 29

PMID 27890469

Citations 41

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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Locomotion changes in methamphetamine and amphetamine withdrawal: a systematic review.

Kumar J, Naina Mohamed I, Mohamed R, Ugusman A, Muzaimi M, Mohamed W Front Pharmacol. 2024; 15:1428492.

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Modeling methamphetamine use disorder and relapse in animals: short- and long-term epigenetic, transcriptional., and biochemical consequences in the rat brain.

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Effects of systemic pretreatment with the NAALADase inhibitor 2-PMPA on oral methamphetamine reinforcement in C57BL/6J mice.

Fultz E, Nei A, Chi J, Lichter J, Szumlinski K Front Psychiatry. 2024; 15:1297275.

PMID: 38638417 PMC: 11024460. DOI: 10.3389/fpsyt.2024.1297275.

Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice.

Denning C, Madory L, Herbert J, Cabrera R, Szumlinski K Int J Mol Sci. 2024; 25(3).

PMID: 38339206 PMC: 10856401. DOI: 10.3390/ijms25031928.

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