Deletion of SHATI/NAT8L increases dopamine D1 receptor on the cell surface in the nucleus accumbens, accelerating methamphetamine dependence.
In a previous report, we identified a novel molecule, SHATI/NAT8L, having an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference (CPP). SHATI/NAT8L attenuates the METH-induced increase in dopamine overflow in the nucleus accumbens (NAc) by promoting plasmalemmal and vesicular dopamine uptake. However, the biological functions of the protein remain unclear. In this study, we explored NAT8L-binding proteins using pull-down assays and identified a number of components of the adaptor protein (AP)-2 complex, which is a multimeric protein localized to the plasma membrane that functions to internalize cargo during clathrin-mediated endocytosis. To investigate whether NAT8L regulates the receptor localization to the cell surface, cell-surface dopamine D1 receptor in the NAc of Nat8l knockout (KO) mice was quantified. We found that dopamine D1 receptor on the cell surface was increased in the NAc of Nat8l KO mice compared with the wild type (WT) animals. Consistent with this finding, Nat8l KO mice showed higher basal locomotor activity and heightened sensitivity to D1 agonist compared with WT mice. In addition, METH-induced sensitization and CPP were enhanced in Nat8l KO mice. These results suggest that NAT8L might regulate the localization of cell-surface dopamine D1 receptor, thereby controlling basal behaviour and sensitivity to METH. Furthermore, we observed a single nucleotide polymorphism (SNP) in the human NAT8L gene related to reward dependence, a personality trait, and grey matter volume in the caudate nucleus in healthy subjects, suggesting that NAT8L might also affect human personality.
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Kazuya
K
Toriumi
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Mizuki
M
Kondo
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Taku
T
Nagai
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
Ryota
R
Hashimoto
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
Kazutaka
K
Ohi
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Ziyu
Z
Song
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Junko
J
Tanaka
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Akihiro
A
Mouri
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Takenao
T
Koseki
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
Hidenaga
H
Yamamori
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yoko
Y
Furukawa-Hibi
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Takayoshi
T
Mamiya
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Takeshi
T
Fukushima
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
Masatoshi
M
Takeda
Department of Pharmaceutical Therapy & Neuropharmacology, Faculty of Pharmaceutical Science, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan.
Atsumi
A
Nitta
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kiyofumi
K
Yamada
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Toshitaka
T
Nabeshima
D000123:Acetyltransferases / Q000172:deficiency* / Q000235:genetics; D000328:Adult; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003216:Conditioning, Operant / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000378:metabolism*
D001552:Benzazepines; C486562:CAPRIN1 protein, human; D018797:Cell Cycle Proteins; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D008694:Methamphetamine; C067113:SK&F 81297; D000123:Acetyltransferases; C521704:Shati protein, mouse