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 language | English (US) |
|---|---|
| Article number | ENEURO.0422-17.2018 |
| Journal | eNeuro |
| Volume | 5 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 1 2018 |
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Keywords
- Cocaine
- Dopamine homeostasis
- Drug addiction
- Protein interacting with C-kinase 1
- Striatum
- Tyrosine hydroxylase
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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 journal › Article
}
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 C
AU - Gether, Ulrik
AU - Rickhag, Mattias
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
UR - http://www.scopus.com/inward/record.url?scp=85050202309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050202309&partnerID=8YFLogxK
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 -