TY - JOUR
T1 - Pick1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis
AU - Jensen, Kathrine Louise
AU - Sørensen, Gunnar
AU - Dencker, Ditte
AU - Owens, William Anthony
AU - Rahbek-Clemmensen, Troels
AU - Lever, Michael Brett
AU - Runegaard, Annika H.
AU - Christensen, Nikolaj Riis
AU - Weikop, Pia
AU - Wörtwein, Gitta
AU - Fink-Jensen, Anders
AU - Madsen, Kenneth L.
AU - Daws, Lynette
AU - Gether, Ulrik
AU - Rickhag, Mattias
N1 - Funding Information:
The PICK1 KO mouse strain was kindly provided by Dr. Richard Huganir (Johns Hopkins University, Baltimore, MD). The lentiviral vectors (Citri et al., 2010) were kindly provided by Prof. Robert C. Malenka at Stanford University (Palo Alto, CA). We also thank Anna Mai Jansen for providing the dual promoter lentiviral constructs used to KD PICK1 in dopaminergic cultures.
Funding Information:
9 Runegaard1, Nikolaj Riis Christensen1, Pia Weikop2, Gitta Wörtwein2, Anders Fink-Jensen2, 10 Kenneth L. Madsen1, Lynette Daws3, Ulrik Gether1 and Mattias Rickhag1 11 *equal contribution 12 13 1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, 14 Faculty of Health andMedical Sciences, University of Copenhagen,DK-2200 Copenhagen, 15 Denmark; 2Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Faculty of 16 Health andMedicalSciences, University of Copenhagen,DK-2200 Copenhagen,Denmark; 17 3Department of Cellular and Integrative Physiology, University of Texas Health Science 18 Center at San Antonio, Texas, USA 19 20 4. Author contributions: KLJ, GS, GW, AFJ, KLM, LD, UG and MR Designed research; 21 KLJ, GS, DD, WAO, TRC, MBL, AHR, NRC, PW, GW and MR Performed research; KLJ, 22 GS, DD, WAO, TRC, MBL, AHR, NRC, PW, GW, KLM, LD, UG and MR Analyzed data; KLJ, 23 GS, GW, LD, UG and MR Wrote the paper 24 25 5. Corresponding authors: 26 Mattias Rickhag, Molecular Neuropharmacology and Genetics Laboratory, Department of 27 Neuroscience, Faculty of Health andMedicalSciences, University of Copenhagen,DK-2200 28 Copenhagen N, Denmark,E-mail: rickhag@sund.ku.dk 29 or 30 Ulrik Gether, Molecular Neuropharmacology and Genetics Laboratory, Faculty of Health and 31 Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark, Tel: +45 32 2384 0089;E-mail: gether@sund.ku.dk 33 34 6. Number of Figures: 6 35 7. Number of Tables: 2 36 8. Number of Multimedia: 0 37 9. Number of words for Abstract: 239 38 10.Number of words for Significance Statement: 115 39 11. Number of words for Introduction: 630 40 12.Number of words for Discussion:1500 41 42 13. Acknowledgements: The PICK1 KO mouse strain (Gardner et al., 2005) was kindly 43 providedbyDr. Richard Huganir (Johns HopkinsUniversity, Baltimore, USA). Thelentiviral 44 vectors (Citri et al., 2010) were kindly provided by Prof. Robert C. Malenka at Stanford 45 University (Palo Alto, California, USA). We also thank Anna Mai Jansen for providing the 46 dual promoter lentiviral constructs used to knock-down PICK1 in dopaminergic cultures. 47 48 14. Conflict of interest: Author’s declare no conflict of interest 49 50 15. This work was supported by the Lundbeck Fondation (M.R.), the Danish Medical 51 Research Council (U.G., M.R., K.L.J.), University of Copenhagen BioScaRT Program of 52 Excellence (G.S., U.G.), Lundbeck Foundation Center for Biomembranes in Nanomedicine 53 (U.G.), the Weimann Foundation (M.R.), and National Institutes of Health R21 DA038504 54 (L.C.D.).
Funding Information:
This work was supported by the Lundbeck Fondation (M.R.), the Danish Medical Research Council (U.G., M.R., K.L.J.), University of Copenhagen BioScaRT Program of Excellence (G.S., U.G.), Lundbeck Foundation Center for Biomembranes in Nanomedicine (U.G.), the Weimann Foundation (M.R.), and National Institutes of Health R21 DA038504 (L.C.D.).
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
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.
KW - Cocaine
KW - Dopamine homeostasis
KW - Drug addiction
KW - Protein interacting with C-kinase 1
KW - Striatum
KW - Tyrosine hydroxylase
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U2 - 10.1523/ENEURO.0422-17.2018
DO - 10.1523/ENEURO.0422-17.2018
M3 - Article
C2 - 29911172
AN - SCOPUS:85050202309
VL - 5
JO - eNeuro
JF - eNeuro
SN - 2373-2822
IS - 3
M1 - ENEURO.0422-17.2018
ER -