Pick1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis

Kathrine Louise Jensen, Gunnar Sørensen, Ditte Dencker, William Anthony Owens, Troels Rahbek-Clemmensen, Michael Brett Lever, Annika H. Runegaard, Nikolaj Riis Christensen, Pia Weikop, Gitta Wörtwein, Anders Fink-Jensen, Kenneth L. Madsen, Lynette C Daws, Ulrik Gether, Mattias Rickhag

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article numberENEURO.0422-17.2018
JournaleNeuro
Volume5
Issue number3
DOIs
StatePublished - May 1 2018

Fingerprint

Cocaine
Dopamine
Homeostasis
Phosphotransferases
Corpus Striatum
Proteins
Knockout Mice
Tyrosine 3-Monooxygenase
Dopamine Plasma Membrane Transport Proteins
Self Administration
Dopaminergic Neurons
Dopamine Agonists
Dopamine Receptors
Membrane Proteins

Keywords

  • Cocaine
  • Dopamine homeostasis
  • Drug addiction
  • Protein interacting with C-kinase 1
  • Striatum
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Jensen, K. L., Sørensen, G., Dencker, D., Owens, W. A., Rahbek-Clemmensen, T., Lever, M. B., ... Rickhag, M. (2018). Pick1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis. eNeuro, 5(3), [ENEURO.0422-17.2018]. https://doi.org/10.1523/ENEURO.0422-17.2018

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; Lever, Michael Brett; Runegaard, Annika H.; Christensen, Nikolaj Riis; Weikop, Pia; Wörtwein, Gitta; Fink-Jensen, Anders; Madsen, Kenneth L.; Daws, Lynette C; Gether, Ulrik; Rickhag, Mattias.

In: eNeuro, Vol. 5, No. 3, ENEURO.0422-17.2018, 01.05.2018.

Research output: Contribution to journalArticle

Jensen, KL, Sørensen, G, Dencker, D, Owens, WA, Rahbek-Clemmensen, T, Lever, MB, Runegaard, AH, Christensen, NR, Weikop, P, Wörtwein, G, Fink-Jensen, A, Madsen, KL, Daws, LC, Gether, U & Rickhag, M 2018, 'Pick1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis', eNeuro, vol. 5, no. 3, ENEURO.0422-17.2018. https://doi.org/10.1523/ENEURO.0422-17.2018
Jensen KL, Sørensen G, Dencker D, Owens WA, Rahbek-Clemmensen T, Lever MB et al. Pick1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis. eNeuro. 2018 May 1;5(3). ENEURO.0422-17.2018. https://doi.org/10.1523/ENEURO.0422-17.2018
Jensen, Kathrine Louise ; Sørensen, Gunnar ; Dencker, Ditte ; Owens, William Anthony ; Rahbek-Clemmensen, Troels ; Lever, Michael Brett ; Runegaard, Annika H. ; Christensen, Nikolaj Riis ; Weikop, Pia ; Wörtwein, Gitta ; Fink-Jensen, Anders ; Madsen, Kenneth L. ; Daws, Lynette C ; Gether, Ulrik ; Rickhag, Mattias. / Pick1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis. In: eNeuro. 2018 ; Vol. 5, No. 3.
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AU - Lever, Michael Brett

AU - Runegaard, Annika H.

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