Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression

Neuropsychopharmacology. 2018 May;43(6):1212-1223. doi: 10.1038/npp.2017.244. Epub 2017 Oct 9.


Adaptations in glutamate signaling within the brain's reward circuitry are observed following withdrawal from several abused drugs, including cocaine. These include changes in intrinsic cellular excitability, glutamate release, and glutamate uptake. Pharmacological or optogenetic reversal of these adaptations have been shown to reduce measures of cocaine craving and seeking, raising the hypothesis that regulation of glutamatergic signaling represents a viable target for the treatment of substance use disorders. Here, we tested the hypothesis that administration of the compound riluzole, which regulates glutamate dynamics in several ways, would reduce cocaine seeking in the rat self-administration and reinstatement model of addiction. Riluzole dose-dependently inhibited cue- and cocaine-primed reinstatement to cocaine, but did not affect locomotor activity or reinstatement to sucrose seeking. Moreover, riluzole reversed bidirectional cocaine-induced adaptations in intrinsic excitability of prelimbic (PL) and infralimbic (IL) pyramidal neurons; a cocaine-induced increase in PL excitability was decreased by riluzole, and a cocaine-induced decrease in IL excitability was increased to normal levels. Riluzole also reversed the cocaine-induced suppression of the high-affinity glutamate transporter 1 (EAAT2/GLT-1) in the nucleus accumbens (NAc). GLT-1 is responsible for the majority of glutamate uptake in the brain, and has been previously reported to be downregulated by cocaine. These results demonstrate that riluzole impairs cocaine reinstatement while rectifying several cellular adaptations in glutamatergic signaling within the brain's reward circuitry, and support the hypothesis that regulators of glutamate homeostasis represent viable candidates for pharmacotherapeutic treatment of psychostimulant relapse.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / physiopathology
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / physiopathology*
  • Dietary Sucrose
  • Dopamine Uptake Inhibitors / administration & dosage
  • Drug-Seeking Behavior / drug effects
  • Drug-Seeking Behavior / physiology
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Feeding Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Motor Activity / drug effects
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology
  • Rats, Sprague-Dawley
  • Riluzole / pharmacology*
  • Self Administration
  • Tissue Culture Techniques


  • Dietary Sucrose
  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Excitatory Amino Acid Transporter 2
  • Slc1a2 protein, rat
  • Riluzole
  • Cocaine