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

NEUROPHARMACOLOGY

卷:164

Article

Turner, Christopher¹  De Luca, Marta²  Wolfheimer, Jordan¹  Hernandez, Nicole³  Madsen, Kenneth Lindegaard²  Schmidt, Heath D.^1,4 

[1] Univ Penn, Sch Nursing, Dept Biobehav Hlth Sci, 125 South 31st St, Philadelphia, PA 19104 USA

[2] Univ Copenhagen, Fac Hlth Sci, Dept Neurosci, Blegdamsvej 3, DK-2200 Copenhagen, Denmark

[3] Univ Penn, Perelman Sch Med, Neurosci Grad Grp, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA

关键词: Relapse;    Addiction;    Nucleus accumbens;    Self-administration;    Reinstatement;    Medium spiny neurons;   

DOI  :  10.1016/j.neuropharm.2019.107901

来源: Elsevier

【 摘 要 】

Protein interacting with C kinase-1 (PICK1) regulates intra-cellular trafficking of GIuA2-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-P-4-(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-P-4 -(DATC5)(2) penetrated the brain where it was visualized in the nucleus accumbens shell. Consistent with these effects, infusions of TAT-P-4-(DATC5)(2) directly into the accumbens shell reduced cocaine, but not sucrose, seeking. The effects of TAT-P-4-(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-P-4-(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.

【 授权许可】

Free