A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking

Samantha L. White, Pavel I. Ortinski, Shayna H. Friedman, Lei Zhang, Rachael L. Neve, Robert G. Kalb, Heath D. Schmidt, R. Christopher Pierce*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

A growing body of evidence indicates that the transport of GluA1 subunit-containing calcium-permeable AMPA receptors (CP-AMPARs) to synapses in subregions of the nucleus accumbens promotes cocaine seeking. Consistent with these findings, the present results show that administration of the CP-AMPAR antagonist, Naspm, into the caudal lateral core or caudal medial shell of the nucleus accumbens attenuated cocaine priming-induced reinstatement of drug seeking. Moreover, viral-mediated overexpression of 'pore dead' GluA1 subunits (via herpes simplex virus (HSV) GluA1-Q582E) in the lateral core or medial shell attenuated the reinstatement of cocaine seeking. The overexpression of wild-type GluA1 subunits (via HSV GluA1-WT) in the medial shell, but not the lateral core, enhanced the reinstatement of cocaine seeking. These results indicate that activation of GluA1-containing AMPARs in subregions of the nucleus accumbens reinstates cocaine seeking. SAP97 and 4.1N are proteins involved in GluA1 trafficking to and stabilization in synapses; SAP97-GluA1 interactions also influence dendritic growth. We next examined potential roles of SAP97 and 4.1N in cocaine seeking. Viral-mediated expression of a microRNA that reduces SAP97 protein expression (HSV miSAP97) in the medial accumbens shell attenuated cocaine seeking. In contrast, a virus that overexpressed a dominant-negative form of a 4.1N C-terminal domain (HSV 4.1N-CTD), which prevents endogenous 4.1N binding to GluA1 subunits, had no effect on cocaine seeking. These results indicate that the GluA1 subunit accessory protein SAP97 may represent a novel target for pharmacotherapeutic intervention in the treatment of cocaine craving.

Original languageEnglish (US)
Pages (from-to)736-750
Number of pages15
JournalNeuropsychopharmacology
Volume41
Issue number3
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    White, S. L., Ortinski, P. I., Friedman, S. H., Zhang, L., Neve, R. L., Kalb, R. G., Schmidt, H. D., & Pierce, R. C. (2016). A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking. Neuropsychopharmacology, 41(3), 736-750. https://doi.org/10.1038/npp.2015.199