Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization.
Dopamine transporter (DAT) internalization is a mechanism underlying the decreased dopamine reuptake caused by addictive drugs like methamphetamine (METH). We found that Piccolo, a presynaptic scaffolding protein, was overexpressed in the nucleus accumbens (NAc) of the mice repeatedly administrated with METH. Piccolo downexpression by antisense technique augmented METH-induced behavioral sensitization, conditioned reward and synaptic dopamine accumulation in NAc. Expression of Piccolo C2A domain attenuated METH-induced inhibition of dopamine uptake in PC12 cells expressing human DAT. Consistent with this, it slowed down the accelerated DAT internalization induced by METH, thus maintaining the presentation of plasmalemmal DAT. In immunostaining and structural modeling Piccolo C2A domain displays an unusual feature of sequestering membrane phosphatidylinositol 4,5-bisphosphate, which may underlie its role in modulating DAT internalization. Together, our results indicate that Piccolo upregulation induced by METH represents a homeostatic response in the NAc to excessive dopaminergic transmission. Piccolo C2A domain may act as a cytoskeletal regulator for plasmalemmal DAT internalization, which may underlie its contributions in behavioral plasticity.
Cen
X
X
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Nitta
A
A
Ibi
D
D
Zhao
Y
Y
Niwa
M
M
Taguchi
K
K
Hamada
M
M
Ito
Y
Y
Ito
Y
Y
Wang
L
L
Nabeshima
T
T
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D016716:PC12 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D014162:Transfection
D003598:Cytoskeletal Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D009479:Neuropeptides; D020319:Oligodeoxyribonucleotides, Antisense; C498631:Pclo protein, mouse; D019269:Phosphatidylinositol 4,5-Diphosphate; D008694:Methamphetamine; D004298:Dopamine