Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors

Stephen V Mahler; Megan Hensley-Simon; Pouya Tahsili-Fahadan; Ryan T LaLumiere; Charles Thomas; Rebecca V Fallon; Peter W Kalivas; Gary Aston-Jones

doi:10.1111/j.1369-1600.2012.00506.x

Back

Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors

Journal article

Peer reviewed

Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors

Stephen V Mahler, Megan Hensley-Simon, Pouya Tahsili-Fahadan, Ryan T LaLumiere, Charles Thomas, Rebecca V Fallon, Peter W Kalivas and Gary Aston-Jones

Addiction biology, Vol.19(1), pp.49-60

01/2014

DOI: 10.1111/j.1369-1600.2012.00506.x

PMCID: PMC3535502

PMID: 23017017

View Online

Abstract

Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties.

Microdialysis - methods

Benzhydryl Compounds - administration & dosage

Nucleus Accumbens - metabolism

Extinction, Psychological - drug effects

Glutamates - metabolism

Male

Receptors, Metabotropic Glutamate - metabolism

Secondary Prevention

Amino Acids - administration & dosage

Amino Acids - pharmacology

Cocaine-Related Disorders - metabolism

Amino Acid Transport System y+ - antagonists & inhibitors

Self Administration - statistics & numerical data

Wakefulness-Promoting Agents - administration & dosage

Xanthenes - pharmacology

Disease Models, Animal

Microinjections

Excitatory Amino Acid Antagonists - administration & dosage

Rats

Excitatory Amino Acid Antagonists - pharmacology

Rats, Sprague-Dawley

Drug-Seeking Behavior - drug effects

Dopamine Uptake Inhibitors - administration & dosage

Cocaine - administration & dosage

Animals

Xanthenes - administration & dosage

Analysis of Variance

Benzhydryl Compounds - pharmacology

Nucleus Accumbens - drug effects

Glutamates - drug effects

Receptors, Metabotropic Glutamate - antagonists & inhibitors

Wakefulness-Promoting Agents - pharmacology

Details

Title: Subtitle: Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors
Creators: Stephen V Mahler - Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
Megan Hensley-Simon
Pouya Tahsili-Fahadan
Ryan T LaLumiere
Charles Thomas
Rebecca V Fallon
Peter W Kalivas
Gary Aston-Jones
Resource Type: Journal article
Publication Details: Addiction biology, Vol.19(1), pp.49-60
Publisher: United States
DOI: 10.1111/j.1369-1600.2012.00506.x
PMID: 23017017
PMCID: PMC3535502
ISSN: 1355-6215
eISSN: 1369-1600
Grant note: K99 DA035251 / NIDA NIH HHS\nR01 DA006214 / NIDA NIH HHS\nR01 DA012513 / NIDA NIH HHS\nDA003906 / NIDA NIH HHS\nP50 DA015369 / NIDA NIH HHS\nDA026692 / NIDA NIH HHS\nDA015369 / NIDA NIH HHS\nDA06214 / NIDA NIH HHS\nF32 DA026692 / NIDA NIH HHS\nR37 DA003906 / NIDA NIH HHS\nR01 DA003906 / NIDA NIH HHS\nR37 DA006214 / NIDA NIH HHS
Language: English
Date published: 01/2014
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute
Record Identifier: 9984070265702771

Metrics

20 Record Views

37 Times Cited - Web of Science