title: α2δ-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse.
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.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, spences@musc.edu.
authors.forename: Sade
authors.identifier: http://orcid.org/0000-0001-8663-9056
authors.initials: S
authors.lastname: Spencer
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia, and.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Brown
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, Florida State University-Panama, Clayton, Republic of Panama, Institute of Scientific Research and High Technology Services, Center for Neurosciences, Clayton, Republic of Panama.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Quintero
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Yonatan M
authors.initials: YM
authors.lastname: Kupchik
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thomas
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-9100.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Reissner
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012646:Self Administration; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003042:Cocaine
keywords: cocaine self-administration; gabapentin; nucleus accumbens; relapse; thrombospondin; α2δ-1