Trafficking and stabilization of AMPA receptors at synapses in response to cocaine exposure is thought to be critical for expression of cocaine addiction and relapse. Glutamate receptor-interacting protein (GRIP) is a neuronal scaffolding protein that stabilizes GluA2 AMPARs at synapses but its role in cocaine addiction has not been examined. The current study demonstrates that conditional deletion of GRIP within the nucleus accumbens potentiates cue-induced reinstatement of cocaine seeking without affecting operant learning, locomotor activity, or reinstatement of natural reward seeking. This is the first study to demonstrate a role for accumbal GRIP in behavior. Electrophysiological recordings revealed increased rectification of AMPAR-mediated currents in the nucleus accumbens and increased AMPAR sensitivity to the GluA2-lacking AMPAR antagonist, 1-naphthylacetyl spermine, indicative of an increased contribution of GluA2-lacking calcium-permeable AMPARs. In addition, accumbal GRIP deletion was associated with blunted long-term depression, similar to what is seen following cocaine self-administration. Taken together, these results indicate that GRIP may modulate addictive phenotypes through its regulation of synaptic AMPARs by controlling their subunit composition and susceptibility to LTD. These effects are associated with changes in vulnerability to cocaine relapse and highlight GRIP as a novel target for the development of cocaine addiction therapeutics.
|Number of pages||11|
|State||Published - Feb 2014|
Bibliographical noteFunding Information:
This work was supported by National Institute on Drug Abuse (NIDA) Grant K99 DA033372 (LAB), K01 DA031747 (PIO), R01 DA015214 (RCP.), R01 DA022339 (RCP), and K02 DA018678 (RCP).
- synaptic plasticity
ASJC Scopus subject areas
- Psychiatry and Mental health