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

Addict Biol. 2014 Jan;19(1):49-60. doi: 10.1111/j.1369-1600.2012.00506.x. Epub 2012 Sep 27.


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.

Keywords: Microdialysis; nucleus accumbens; self-administration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport System y+ / antagonists & inhibitors
  • Amino Acids / administration & dosage
  • Amino Acids / pharmacology
  • Analysis of Variance
  • Animals
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / pharmacology*
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / metabolism*
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / administration & dosage
  • Drug-Seeking Behavior / drug effects*
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extinction, Psychological / drug effects
  • Glutamates / drug effects*
  • Glutamates / metabolism
  • Male
  • Microdialysis / methods
  • Microinjections
  • Modafinil
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • Secondary Prevention
  • Self Administration / statistics & numerical data
  • Wakefulness-Promoting Agents / administration & dosage
  • Wakefulness-Promoting Agents / pharmacology*
  • Xanthenes / administration & dosage
  • Xanthenes / pharmacology


  • Amino Acid Transport System y+
  • Amino Acids
  • Benzhydryl Compounds
  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Glutamates
  • LY 341495
  • Receptors, Metabotropic Glutamate
  • Wakefulness-Promoting Agents
  • Xanthenes
  • Cocaine
  • Modafinil