Format

Send to

Choose Destination
J Neurosci. 2014 Jun 18;34(25):8605-11. doi: 10.1523/JNEUROSCI.1204-13.2014.

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

Author information

1
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, spences@musc.edu.
2
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.
3
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.
4
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425.
5
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.

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.

KEYWORDS:

cocaine self-administration; gabapentin; nucleus accumbens; relapse; thrombospondin; α2δ-1

PMID:
24948814
PMCID:
PMC4061396
DOI:
10.1523/JNEUROSCI.1204-13.2014
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center