α2δ-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse

Sade Spencer, Robyn M. Brown, Gabriel C. Quintero, Yonatan M. Kupchik, Charles A. Thomas, Kathryn J. Reissner, Peter W. Kalivas

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. α2δ-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates α2δ-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that α2δ-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the α2δ-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific α2δ-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that α2δ-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy.

Original languageEnglish (US)
Pages (from-to)8605-8611
Number of pages7
JournalJournal of Neuroscience
Volume34
Issue number25
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Cocaine self-administration
  • Gabapentin
  • Nucleus accumbens
  • Relapse
  • Thrombospondin
  • α-δ1

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