PMID- 29911172 OWN - NLM STAT- MEDLINE DCOM- 20190125 LR - 20230819 IS - 2373-2822 (Electronic) IS - 2373-2822 (Linking) VI - 5 IP - 3 DP - 2018 May-Jun TI - PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis. LID - 10.1523/ENEURO.0422-17.2018 [doi] LID - ENEURO.0422-17.2018 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 approximately 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. FAU - Jensen, Kathrine Louise AU - Jensen KL AUID- ORCID: 0000-0001-8985-9126 AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Sorensen, Gunnar AU - Sorensen G AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. AD - Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Dencker, Ditte AU - Dencker D AUID- ORCID: 0000-0002-4829-439X AD - Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Owens, William Anthony AU - Owens WA AD - Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, TX 78229. FAU - Rahbek-Clemmensen, Troels AU - Rahbek-Clemmensen T AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Brett Lever, Michael AU - Brett Lever M AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Runegaard, Annika H AU - Runegaard AH AUID- ORCID: 0000-0001-7659-5539 AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Riis Christensen, Nikolaj AU - Riis Christensen N AUID- ORCID: 0000-0003-3307-2839 AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Weikop, Pia AU - Weikop P AD - Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Wortwein, Gitta AU - Wortwein G AD - Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Fink-Jensen, Anders AU - Fink-Jensen A AD - Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Madsen, Kenneth L AU - Madsen KL AUID- ORCID: 0000-0001-9274-6691 AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Daws, Lynette AU - Daws L AD - Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, TX 78229. FAU - Gether, Ulrik AU - Gether U AUID- ORCID: 0000-0002-0020-3807 AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. FAU - Rickhag, Mattias AU - Rickhag M AD - Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark. LA - eng GR - R21 DA038504/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180611 PL - United States TA - eNeuro JT - eNeuro JID - 101647362 RN - 0 (Carrier Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (Dopamine Plasma Membrane Transport Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Prkcabp protein, mouse) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - I5Y540LHVR (Cocaine) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Carrier Proteins/genetics/*metabolism MH - Cell Cycle Proteins MH - Cocaine/*administration & dosage MH - Corpus Striatum/drug effects/metabolism MH - Dopamine/*metabolism MH - Dopamine Plasma Membrane Transport Proteins/metabolism MH - Dopaminergic Neurons/*drug effects/*metabolism MH - Homeostasis/*drug effects MH - Locomotion/drug effects MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nuclear Proteins/genetics/*metabolism MH - Reinforcement, Psychology MH - Signal Transduction/drug effects MH - Tyrosine 3-Monooxygenase/metabolism PMC - PMC6001137 OTO - NOTNLM OT - cocaine OT - dopamine homeostasis OT - drug addiction OT - protein interacting with C-kinase 1 OT - striatum OT - tyrosine hydroxylase EDAT- 2018/06/19 06:00 MHDA- 2019/01/27 06:00 PMCR- 2018/06/11 CRDT- 2018/06/19 06:00 PHST- 2017/12/05 00:00 [received] PHST- 2018/04/18 00:00 [revised] PHST- 2018/04/27 00:00 [accepted] PHST- 2018/06/19 06:00 [entrez] PHST- 2018/06/19 06:00 [pubmed] PHST- 2019/01/27 06:00 [medline] PHST- 2018/06/11 00:00 [pmc-release] AID - eN-NWR-0422-17 [pii] AID - 10.1523/ENEURO.0422-17.2018 [doi] PST - epublish SO - eNeuro. 2018 Jun 11;5(3):ENEURO.0422-17.2018. doi: 10.1523/ENEURO.0422-17.2018. eCollection 2018 May-Jun.