PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis

Abstract

Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine’s reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of a role for PICK1 in neuroadaptive changes induced by cocaine, we observed diminished cocaine intake in a self-administration paradigm. Reduced behavioral effects of cocaine were not associated with decreased striatal DAT distribution and most likely not caused by the ∼30% reduction in synaptosomal DA uptake observed in PICK1 KO mice. The PICK1 KO mice demonstrated preserved behavioral responses to DA receptor agonists supporting intact downstream DA receptor signaling. Unexpectedly, we found a prominent increase in striatal DA content and levels of striatal tyrosine hydroxylase (TH) in PICK1 KO mice. Chronoamperometric recordings showed enhanced DA release in PICK1 KO mice, consistent with increased striatal DA pools. Viral-mediated knock-down (KD) of PICK1 in cultured dopaminergic neurons increased TH expression, supporting a direct cellular effect of PICK1. In summary, in addition to demonstrating a key role of PICK1 in mediating behavioral effects of cocaine, our data reveal a so far unappreciated role of PICK1 in DA homeostasis that possibly involves negative regulation of striatal TH levels.

PDZ Domains as Drug Targets

“…[146,147] It is highly evolutionarily conserved from invertebrates to humans, which suggests that PICK1 has important biological functions. [158][159][160] The BAR domain of PICK1 is a domain that facilitates dimerization of PICK1. [158][159][160] The BAR domain of PICK1 is a domain that facilitates dimerization of PICK1.…”

“…[173] Both peptides could efficiently displace the interaction between PICK1 and GluA2 in COS7 cells, but while Pep2-SVKI was found to inhibit LTD, Pep2-EVKI did not show an effect on LTD. [158,176] To elucidate the importance of the interaction between PICK1 and DAT, the 24 C-terminal residues of DAT, which contains both a PICK1 binding site at the extreme C-terminal and a Ca 2+ /calmodulin-dependent protein kinase IIα (CamKIIα) binding site upstream of the PICK1 binding site, was fused to the Tat CPP motif to render the peptide cell permeable (Tat-DATC24). [173] Later studies have shown that Pep2-EVKI could reduce the reinstatement of cocaine seeking through decoupling of the AMPAR C-terminal/PICK1-PDZ interaction after intra-accumbal shell administration.…”

“…It is highly evolutionarily conserved from invertebrates to humans, which suggests that PICK1 has important biological functions. Through the PDZ domain, PICK1 interacts with a number of neurotransmitter receptors, transporters, and enzymes (Figure f), where in particular the interactions with the AMPAR and the dopamine transporter (DAT) have received particular attention . The BAR domain of PICK1 is a domain that facilitates dimerization of PICK1.…”

“…administration of myr‐Pep2‐EVKI, which showed a significant effect in thermal hyperalgesia and mechanical allodynia following CCI . PICK1 has also been implicated in trafficking of DAT and is thereby implicated in maintaining the dopamine homeostasis …”

The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

“…15–17,19,20 Furthermore, the disruption of PICK1-DAT interactions impairs the behavioral effects of cocaine in mice. 21 With this, PICK1 has been identified as an integral player in drug addiction. 22 Consequently, efforts have been made to identify small molecules with the potential to inhibit the function of PICK1.…”