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Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression.
Neuropsychopharmacology 2018; 43(6):1212-1223N

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28990593

Citation

Sepulveda-Orengo, Marian T., et al. "Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 43, no. 6, 2018, pp. 1212-1223.
Sepulveda-Orengo MT, Healey KL, Kim R, et al. Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression. Neuropsychopharmacology. 2018;43(6):1212-1223.
Sepulveda-Orengo, M. T., Healey, K. L., Kim, R., Auriemma, A. C., Rojas, J., Woronoff, N., ... Reissner, K. J. (2018). Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 43(6), pp. 1212-1223. doi:10.1038/npp.2017.244.
Sepulveda-Orengo MT, et al. Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression. Neuropsychopharmacology. 2018;43(6):1212-1223. PubMed PMID: 28990593.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression. AU - Sepulveda-Orengo,Marian T, AU - Healey,Kati L, AU - Kim,Ronald, AU - Auriemma,Alyson C, AU - Rojas,Jennifer, AU - Woronoff,Nicholas, AU - Hyppolite,Rachel, AU - Reissner,Kathryn J, Y1 - 2017/10/09/ PY - 2017/05/17/received PY - 2017/09/29/revised PY - 2017/10/01/accepted PY - 2017/10/11/pubmed PY - 2019/3/5/medline PY - 2017/10/10/entrez SP - 1212 EP - 1223 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 43 IS - 6 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/28990593/Riluzole_Impairs_Cocaine_Reinstatement_and_Restores_Adaptations_in_Intrinsic_Excitability_and_GLT-1_Expression L2 - http://dx.doi.org/10.1038/npp.2017.244 DB - PRIME DP - Unbound Medicine ER -