TY - JOUR T1 - PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0422-17.2018 SP - ENEURO.0422-17.2018 AU - Kathrine Louise Jensen AU - Gunnar Sørensen AU - Ditte Dencker AU - William Anthony Owens AU - Troels Rahbek-Clemmensen AU - Michael Brett Lever AU - Annika H. Runegaard AU - Nikolaj Riis Christensen AU - Pia Weikop AU - Gitta Wörtwein AU - Anders Fink-Jensen AU - Kenneth L. Madsen AU - Lynette Daws AU - Ulrik Gether AU - Mattias Rickhag Y1 - 2018/05/14 UR - http://www.eneuro.org/content/early/2018/05/15/ENEURO.0422-17.2018.abstract N2 - Protein Interacting with C-Kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its 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 knockout (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 knockdown 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.Significance Statement Cocaine addiction is a major societal problem and better treatments are needed. We demonstrate here the importance of the PDZ-domain scaffold protein PICK1 for both the acute reinforcing effects of cocaine and the long-term behavioral changes seen on repeated cocaine exposure. Interestingly, our data suggest that these alterations are independent of PICK1 binding to the primary target of cocaine, DAT. Moreover, our study reveals a novel role of PICK1 in maintenance of DA homeostasis that involves negative regulation of the levels of striatal TH, the rate-limiting enzyme in DA synthesis. Summarized, these data provide an important framework for further exploring the role of PICK1 in addiction and as putative target for treatment of psychostimulant abuse. ER -