Original Article

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

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Abstract

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.

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References

  1. , , , , , et al (2006). Interaction of riluzole with the closed inactivated state of Kv4.3 channels. J Pharmacol Exp Ther 319: 323–331.

  2. , , , , , et al (2010). Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15: 501–511.

  3. (2007). The action potential in mammalian central neurons. Nat Rev Neurosci 8: 451–465.

  4. , , (2010). AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron 67: 11–24.

  5. , , , , , et al (2013). Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory. J Neuroimmune Pharmacol 8: 1098–1105.

  6. , (eds) (2015) Cocaine Self-Administration and Cue-Reinstatement Disrupt Kv7 (KCNQ) Channel Inhibition in the Prefrontal Cortex. Society for Neuroscience: Chicago, IL.

  7. , , , (2002). Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole. Eur J Pharmacol 449: 47–54.

  8. , , (2012). Riluzole elevates GLT-1 activity and levels in striatal astrocytes. Neurochem Int 60: 31–38.

  9. , , , (2010). Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr Med Chem 17: 1942–1199.

  10. , , , , , et al (2013). Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496: 359–362.

  11. , , , , , et al (2005). Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence. Addiction 100((Suppl 1)): 12–22.

  12. (2001). Glutamate uptake. Prog Neurobiol 65: 1–105.

  13. , , , , , et al (2005). Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: adaptations in potassium currents. J Neurosci 25: 936–940.

  14. , , , , , et al (2007). The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 32: 793–802.

  15. , , , , , (2000). The neuroprotective agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK. Mol Pharmacol 57: 906–912.

  16. , (2007). Glucocorticoids enhance the excitability of principal basolateral amygdala neurons. J Neurosci 27: 4482–4491.

  17. , (2002). Physiological role of calcium-activated potassium currents in the rat lateral amygdala. J Neurosci 22: 1618–1628.

  18. , (2003). Calcium-activated potassium channels: multiple contributions to neuronal function. Neuroscientist 9: 181–194.

  19. , , (2013). Role of the major glutamate transporter GLT1 in nucleus accumbens core versus shell in cue-induced cocaine-seeking behavior. J Neurosci 33: 9319–9327.

  20. , , (2012). Differential effects of cocaine access and withdrawal on glutamate type 1 transporter expression in rat nucleus accumbens core and shell. Neuroscience 210: 333–339.

  21. , , , (2004). Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol 24: 123–128.

  22. , , , , (2008). Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol 578: 171–176.

  23. , , , , , (2013). Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron 77: 867–872.

  24. , , , (2012). Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice. Psychopharmacology 219: 805–814.

  25. , (2016). Going and stopping: dichotomies in behavioral control by the prefrontal cortex. Nat Neurosci 19: 656–664.

  26. , , , (2017). Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine. Biol Open 6: 8–16.

  27. , , , , , et al (2013). Repeated cocaine weakens GABA(B)-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron 80: 159–170.

  28. , , , , , et al (2011). Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3: 102mr102.

  29. , (2011). New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16: 974–986.

  30. , , , , , (2015). Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior. Eur J Neurosci 41: 1126–1138.

  31. , , (2010). Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67: 81–84.

  32. , , , , , et al (2015). Mechanisms of action and persistent neuroplasticity by drugs of abuse. Pharmacol Rev 67: 872–1004.

  33. , , (2015). Intrinsic plasticity: an emerging player in addiction. Nat Rev Neurosci 16: 173–184.

  34. , , (2010). The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn Mem 17: 168–175.

  35. , (2008). Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci 27: 2501–2514.

  36. , , , , , (2011). Neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. J Biol Chem 286: 2785–2794.

  37. , , , , , (2003). Effect of riluzole on MK-801 and amphetamine-induced hyperlocomotion. Neuropsychobiology 48: 27–30.

  38. , (2011). Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69: 650–663.

  39. , , , , (2009). Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 15: 1595–1611.

  40. , (2015). Regulation of extrasynaptic glutamate levels as a pathophysiological mechanism in disorders of motivation and addiction. Neuropsychopharmacology 40: 254–255.

  41. , (2001). The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21: 8655–8663.

  42. , , (2003). Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23: 3531–3537.

  43. , , (2000). What has changed with riluzole? J Neurol 247: 19–22.

  44. , , , (2014). Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res 1628(Pt A): 130–146.

  45. , , , (2017). Astroglial glutamate transporters in the brain: Regulating neurotransmitter homeostasis and synaptic transmission. J Neurosci Res 95: 2140–2151.

  46. , , (2005a). Repeated cocaine administration increases voltage-sensitive calcium currents in response to membrane depolarization in medial prefrontal cortex pyramidal neurons. J Neurosci 25: 3674–3679.

  47. , , , (2005b). Repeated cocaine administration increases membrane excitability of pyramidal neurons in the rat medial prefrontal cortex. J Pharmacol Exp Ther 312: 1305–1313.

  48. , , (2010). Learning and aging related changes in intrinsic neuronal excitability. Front Aging Neurosci 2: 2.

  49. , (2017). Reversal of cocaine-associated synaptic plasticity in prefrontal cortex. Neuropsychopharmacology 42: 2000–2010.

  50. , , , , , (2008). Riluzole in the treatment of mood and anxiety disorders. CNS Drugs 22: 761–786.

  51. , , (2001). Diverse types of interneurons generate thalamus-evoked feedforward inhibition in the mouse barrel cortex. J Neurosci 21: 2699–2710.

  52. , , , , , (2014). Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology 39: 499–506.

  53. , , , , , (2015). Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Addict Biol 20: 316–323.

  54. , (2015). Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets 14: 745–756.

  55. , (2016). Astroglial glutamate transporters coordinate excitatory signaling and brain energetics. Neurochem Int 98: 56–71.

  56. , , , (2014). Hippocampal—prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology 39: 2161–2169.

  57. , , (2008). Fear conditioning and extinction differentially modify the intrinsic excitability of infralimbic neurons. J Neurosci 28: 4028–4036.

  58. , , , (2009). Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J Neurosci 29: 9239–9243.

  59. , , , , , et al (2016). Cocaine self-administration and extinction leads to reduced glial fibrillary acidic protein expression and morphometric features of astrocytes in the nucleus accumbens core. Biol Psychiatry 80: 207–215.

  60. , , , (2013). Fear extinction induces mGluR5-mediated synaptic and intrinsic plasticity in infralimbic neurons. J Neurosci 33: 7184–7193.

  61. , , , (1997). Effects of riluzole on rat cortical neurones: an in vitro electrophysiological study. Br J Pharmacol 120: 225–230.

  62. , (2017). Glutamate transport: a new bench to bedside mechanism for treating drug abuse. Int J Neuropsychopharmacol 20: 797–812.

  63. , , , , , et al (2012). Riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines. Neuropharmacology 62: 2489–2498.

  64. , , , (2014). Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol Biol 1183: 221–242.

  65. , , , , , et al (2006). Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology 67: 20–27.

  66. , (2007). Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 8: 935–947.

  67. , (2011). Glutamatergic neuroplasticity in cocaine addiction. Prog Mol Biol Transl Sci 98: 367–400.

  68. (2016). Synaptic mechanisms underlying persistent cocaine craving. Nat Rev Neurosci 17: 351–365.

  69. , , (2001). Neuroprotective agent riluzole dramatically slows inactivation of Kv1.4 potassium channels by a voltage-dependent oxidative mechanism. J Pharmacol Exp Ther 299: 227–237.

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Acknowledgements

This work was supported by R00DA031790 (to KJR), R01DA041455 (to KJR), and T32DA007244 (to KLH). We thank Mounira Banasr for consultation on riluzole preparation, and members of the Reissner lab for constructive criticisms on a previous version of this manuscript.

Author information

Affiliations

  1. Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, USA

    • Marian T Sepulveda-Orengo
    • , Kati L Healey
    • , Ronald Kim
    • , Alyson C Auriemma
    • , Jennifer Rojas
    • , Nicholas Woronoff
    • , Rachel Hyppolite
    •  & Kathryn J Reissner
  2. Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA

    • Kathryn J Reissner

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Correspondence to Kathryn J Reissner.