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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis. / Jensen, Kathrine Louise; Sørensen, Gunnar; Dencker, Ditte; Owens, William Anthony; Rahbek-Clemmensen, Troels; Brett Lever, Michael; Runegaard, Annika H; Riis Christensen, Nikolaj; Weikop, Pia; Wörtwein, Gitta; Fink-Jensen, Anders; Madsen, Kenneth L; Daws, Lynette; Gether, Ulrik; Rickhag, Mattias.

In: eNeuro, Vol. 5, No. 3, 2018.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Jensen, KL, Sørensen, G, Dencker, D, Owens, WA, Rahbek-Clemmensen, T, Brett Lever, M, Runegaard, AH, Riis Christensen, N, Weikop, P, Wörtwein, G, Fink-Jensen, A, Madsen, KL, Daws, L, Gether, U & Rickhag, M 2018, 'PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis', eNeuro, vol. 5, no. 3. https://doi.org/10.1523/ENEURO.0422-17.2018

APA

Jensen, K. L., Sørensen, G., Dencker, D., Owens, W. A., Rahbek-Clemmensen, T., Brett Lever, M., ... Rickhag, M. (2018). PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis. eNeuro, 5(3). https://doi.org/10.1523/ENEURO.0422-17.2018

Vancouver

Jensen KL, Sørensen G, Dencker D, Owens WA, Rahbek-Clemmensen T, Brett Lever M et al. PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis. eNeuro. 2018;5(3). https://doi.org/10.1523/ENEURO.0422-17.2018

Author

Jensen, Kathrine Louise ; Sørensen, Gunnar ; Dencker, Ditte ; Owens, William Anthony ; Rahbek-Clemmensen, Troels ; Brett Lever, Michael ; Runegaard, Annika H ; Riis Christensen, Nikolaj ; Weikop, Pia ; Wörtwein, Gitta ; Fink-Jensen, Anders ; Madsen, Kenneth L ; Daws, Lynette ; Gether, Ulrik ; Rickhag, Mattias. / PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis. In: eNeuro. 2018 ; Vol. 5, No. 3.

Bibtex

@article{06b1a5f5313d42eebd90c4fa90cc4eb2,
title = "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.",
author = "Jensen, {Kathrine Louise} and Gunnar S{\o}rensen and Ditte Dencker and Owens, {William Anthony} and Troels Rahbek-Clemmensen and {Brett Lever}, Michael and Runegaard, {Annika H} and {Riis Christensen}, Nikolaj and Pia Weikop and Gitta W{\"o}rtwein and Anders Fink-Jensen and Madsen, {Kenneth L} and Lynette Daws and Ulrik Gether and Mattias Rickhag",
year = "2018",
doi = "10.1523/ENEURO.0422-17.2018",
language = "English",
volume = "5",
journal = "eNeuro",
issn = "2373-2822",
publisher = "Society for Neuroscience",
number = "3",

}

RIS

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 - Brett Lever, Michael

AU - Runegaard, Annika H

AU - Riis Christensen, Nikolaj

AU - Weikop, Pia

AU - Wörtwein, Gitta

AU - Fink-Jensen, Anders

AU - Madsen, Kenneth L

AU - Daws, Lynette

AU - Gether, Ulrik

AU - Rickhag, Mattias

PY - 2018

Y1 - 2018

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.

U2 - 10.1523/ENEURO.0422-17.2018

DO - 10.1523/ENEURO.0422-17.2018

M3 - Journal article

VL - 5

JO - eNeuro

JF - eNeuro

SN - 2373-2822

IS - 3

ER -

ID: 202778244