Methamphetamine Addiction Vulnerability

The Glutamate, the Bad, and the Ugly

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 Phillips, Tod E. Kippin

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Jul 22 2016

Fingerprint

Methamphetamine
Glutamic Acid
Nucleus Accumbens
Inbred C57BL Mouse
Metabotropic Glutamate 5 Receptor
Microdialysis
Immunoblotting
Drinking
Phenotype

Keywords

  • Conditioned place preference
  • Glutamate
  • Homer proteins
  • MAHDR
  • Metabotropic glutamate receptor
  • NMDA receptor
  • Nucleus accumbens

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Szumlinski, K. K., Lominac, K. D., Campbell, R. R., Cohen, M., Fultz, E. K., Brown, C. N., ... Kippin, T. E. (Accepted/In press). Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2016.10.005

Methamphetamine Addiction Vulnerability : The Glutamate, the Bad, and the Ugly. / Szumlinski, Karen K.; Lominac, Kevin D.; Campbell, Rianne R.; Cohen, Matan; Fultz, Elissa K.; Brown, Chelsea N.; Miller, Bailey W.; Quadir, Sema G.; Martin, Douglas; Thompson, Andrew B.; von Jonquieres, Georg; Klugmann, Matthias; Phillips, Tamara; Kippin, Tod E.

In: Biological Psychiatry, 22.07.2016.

Research output: Contribution to journalArticle

Szumlinski, KK, Lominac, KD, Campbell, RR, Cohen, M, Fultz, EK, Brown, CN, Miller, BW, Quadir, SG, Martin, D, Thompson, AB, von Jonquieres, G, Klugmann, M, Phillips, T & Kippin, TE 2016, 'Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2016.10.005
Szumlinski, Karen K. ; Lominac, Kevin D. ; Campbell, Rianne R. ; Cohen, Matan ; Fultz, Elissa K. ; Brown, Chelsea N. ; Miller, Bailey W. ; Quadir, Sema G. ; Martin, Douglas ; Thompson, Andrew B. ; von Jonquieres, Georg ; Klugmann, Matthias ; Phillips, Tamara ; Kippin, Tod E. / Methamphetamine Addiction Vulnerability : The Glutamate, the Bad, and the Ugly. In: Biological Psychiatry. 2016.
@article{b2ff5b63466c407a9f09f9248a69453c,
title = "Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly",
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.",
keywords = "Conditioned place preference, Glutamate, Homer proteins, MAHDR, Metabotropic glutamate receptor, NMDA receptor, Nucleus accumbens",
author = "Szumlinski, {Karen K.} and Lominac, {Kevin D.} and Campbell, {Rianne R.} and Matan Cohen and Fultz, {Elissa K.} and Brown, {Chelsea N.} and Miller, {Bailey W.} and Quadir, {Sema G.} and Douglas Martin and Thompson, {Andrew B.} and {von Jonquieres}, Georg and Matthias Klugmann and Tamara Phillips and Kippin, {Tod E.}",
year = "2016",
month = "7",
day = "22",
doi = "10.1016/j.biopsych.2016.10.005",
language = "English (US)",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

}

TY - JOUR

T1 - Methamphetamine Addiction Vulnerability

T2 - The Glutamate, the Bad, and the Ugly

AU - Szumlinski, Karen K.

AU - Lominac, Kevin D.

AU - Campbell, Rianne R.

AU - Cohen, Matan

AU - Fultz, Elissa K.

AU - Brown, Chelsea N.

AU - Miller, Bailey W.

AU - Quadir, Sema G.

AU - Martin, Douglas

AU - Thompson, Andrew B.

AU - von Jonquieres, Georg

AU - Klugmann, Matthias

AU - Phillips, Tamara

AU - Kippin, Tod E.

PY - 2016/7/22

Y1 - 2016/7/22

N2 - 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.

AB - 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.

KW - Conditioned place preference

KW - Glutamate

KW - Homer proteins

KW - MAHDR

KW - Metabotropic glutamate receptor

KW - NMDA receptor

KW - Nucleus accumbens

UR - http://www.scopus.com/inward/record.url?scp=85007228610&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007228610&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2016.10.005

DO - 10.1016/j.biopsych.2016.10.005

M3 - Article

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -