RT Journal Article
SR Electronic
T1 PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0422-17.2018
DO 10.1523/ENEURO.0422-17.2018
VO 5
IS 3
A1 Kathrine Louise Jensen
A1 Gunnar Sørensen
A1 Ditte Dencker
A1 William Anthony Owens
A1 Troels Rahbek-Clemmensen
A1 Michael Brett Lever
A1 Annika H. Runegaard
A1 Nikolaj Riis Christensen
A1 Pia Weikop
A1 Gitta Wörtwein
A1 Anders Fink-Jensen
A1 Kenneth L. Madsen
A1 Lynette Daws
A1 Ulrik Gether
A1 Mattias Rickhag
YR 2018
UL http://www.eneuro.org/content/5/3/ENEURO.0422-17.2018.abstract
AB 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.