GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and enhances non-rapid eye movement sleep during the active phase in mice.
GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergic transmission. Compounds that inhibit GAT1 are targets often used for the treatment of epilepsy; however sedation has been reported as a side effect of these agents, indicating potential sedative and/or hypnotic uses for these compounds. In the current study, we observed the sleep behaviors of mice treated with NO-711, a selective GAT1 inhibitor, in order to elucidate the role of GAT1 in sleep-wake regulation during the active phase. The data revealed that NO-711 at a high dose of 10 mg/kg caused a marked enhancement of EEG activity in the frequency ranges of 3-25 Hz during wakefulness as well as rapid eye movement (REM) sleep. During the non-REM (NREM) sleep, NO-711 (10 mg/kg) elevated EEG activity in the frequency ranges of 1.5-6.75 Hz. Similar changes were found in mice treated with a low dose of 3 mg/kg. NO-711 administered i.p. at a dose of 1, 3 or 10 mg/kg significantly shortened the sleep latency of NREM sleep, increased the amount of NREM sleep and the number of NREM sleep episodes. NO-711 did not affect the sleep latency and the amount of REM sleep. NO-711 dose-dependently increased c-Fos expression in sleep-promoting nucleus of the ventrolateral preoptic area and median preoptic area. However, c-Fos expression was decreased in the wake-promoting nuclei, tuberomammillary nucleus and lateral hypothalamus. These results indicate that NO-711 can increase NREM sleep in mice.
Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, China.
Xin-Hong
XH
Xu
State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Mei-Hong
MH
Qiu
State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Hui
H
Dong
Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: quweimin@fudan.edu.cn.
Wei-Min
WM
Qu
Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, Japan.
Yoshihiro
Y
Urade
Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China; Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: huangzl@fudan.edu.cn.
Zhi-Li
ZL
Huang
D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D009928:Organ Specificity; D010091:Oximes / Q000008:administration & dosage / Q000494:pharmacology*; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012894:Sleep Stages / Q000187:drug effects*
D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D006993:Hypnotics and Sedatives; D009419:Nerve Tissue Proteins; D009557:Nipecotic Acids; D010091:Oximes; D016760:Proto-Oncogene Proteins c-fos; C493414:Slc6a1 protein, mouse; C078793:NNC 711
EEG power density; GABA transport subtype 1; NO-711; Sleep; c-Fos