Administration of a novel high affinity PICK1 PDZ domain inhibitor attenuates cocaine seeking in rats

Protein interacting with C kinase-1 (PICK1) regulates intra-cellular trafficking of GluA2-containing AMPA receptors, a process known to play a critical role in cocaine-seeking behavior. This suggests that PICK1 may represent a molecular target for developing novel pharmacotherapies to treat cocaine craving-induced relapse. Emerging evidence indicates that inhibition of PICK1 attenuates the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we show that systemic administration of TAT-P₄-(DATC5)₂, a novel high-affinity peptide inhibitor of the PICK1 PDZ domain, dose-dependently attenuated the reinstatement of cocaine seeking in rats at doses that did not produce operant learning deficits or suppress locomotor activity. We also show that systemic TAT-P₄-(DATC5)₂ penetrated the brain where it was visualized in the nucleus accumbens shell. Consistent with these effects, infusions of TAT-P₄-(DATC5)₂ directly into the accumbens shell reduced cocaine, but not sucrose, seeking. The effects of TAT-P₄-(DATC5)₂ on cocaine seeking are likely due, in part, to inhibition of PICK1 in medium spiny neurons (MSNs) of the accumbens shell as TAT-P₄-(DATC5)₂ was shown to accumulate in striatal neurons and bind PICK1. Taken together, these findings highlight a novel role for PICK1 in the reinstatement of cocaine seeking and support future studies examining the efficacy of peptide inhibitors of PICK1 in animal and human models of cocaine relapse.