Glutamate receptor interacting protein acts within the prefrontal cortex to blunt cocaine seeking.

Glutamate receptor interacting protein (GRIP) is a neuronal scaffolding protein that anchors GluA2-containing AMPA receptors to the cell membrane. GRIP plays a critical role in activity-dependent synaptic plasticity, including that which occurs after drug exposure. Given that cocaine administration alters glutamate receptor trafficking within the prefrontal cortex (PFC), a better understanding of the role of receptor trafficking proteins could lead to a more complete understanding of addictive phenotypes. AMPA receptor trafficking in general, and GRIP specifically, is known to play a role in cocaine seeking and conditioned reward in the nucleus accumbens, but its role in the PFC has not been characterized. The current study demonstrates that conditional deletion of GRIP1 in the medial prefrontal cortex increases the motivation for cocaine and potentiates cue-induced reinstatement of cocaine seeking in male and female mice. As no effects of PFC GRIP1 deletion were seen in reinstatement of food seeking, strategy set-shifting, or reversal learning the effects on cocaine seeking are not related to generalized alterations in cognitive function. While disrupting GRIP1 might be expected to lead to decreased AMPA transmission, our electrophysiological data indicate an increase in sEPSC amplitude in the prefrontal cortex and a corresponding decrease in paired pulse facilitation in the nucleus accumbens. Taken together this suggests a strengthening of the PFC to NAc input following prefrontal GRIP1 deletion that may mediate the enhanced drug seeking behavior.

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