Up-regulation of gamma-aminobutyric acid transporter I mediates ethanol sensitivity in mice.
Ethanol is among the most widely abused drugs in the world. Chronic ethanol consumption leads to ethanol tolerance and addiction, and impairs learning and memory. Na+/Cl- dependent GABA transporters play an important role in controlling the concentration of GABA in the synaptic cleft, and thus they control the intensity and duration of synaptic transmission of GABA. It has been suggested that GABAergic system is involved in ethanol consumption, tolerance and addiction, because chronic ethanol consumption alters the expression of GABAA receptors and drugs on GABA receptors affect ethanol actions. The results of the present study reveal that that activity of GABA transporters in mouse brain after 15-min acute ethanol injection or after chronic ethanol consumption is increased. Moreover, mice pre-injected with a competitive or a noncompetitive antagonist of gamma-aminobutyric acid transporter subtype 1 (GAT1) showed high sensitivity to the sedative/hypnotic effects of ethanol. In contrast, transgenic mice overexpressing GAT1 displayed low sensitivity to ethanol, as shown by the righting reflex test. Mice overexpressing GAT1 survived a lethal dose of ethanol (9 g/kg, i.p.) longer, maintained locomotor activity longer after a sub-lethal dose (1.75 g/kg, i.p.) and exhibited a higher median lethal dose than wild-type littermates. These results suggest that GAT1 plays an important role in sensitivity to ethanol, and might be a therapeutic target for alcoholism prevention and treatment. Acute and chronic ethanol administration resulted in the increase of GABA transporter function. Use of GAT1 selective inhibitors and GAT1 overexpressing mice thus demonstrate that GAT1 should be an important protein mediating sensitivity to ethanol in mice.
Hu
J-H
JH
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, People's Republic of China.
Ma
Y-H
YH
Yang
N
N
Mei
Z-T
ZT
Zhang
M-H
MH
Fei
J
J
Guo
L-H
LH
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D007700:Kinetics; D008565:Membrane Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009557:Nipecotic Acids / Q000494:pharmacology; D027361:Organic Anion Transporters; D010091:Oximes / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012890:Sleep / Q000187:drug effects; D013534:Survival; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002352:Carrier Proteins; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; D012333:RNA, Messenger; C493414:Slc6a1 protein, mouse; D014316:Tritium; C078793:NNC 711; D000431:Ethanol; C038002:nipecotic acid ethyl ester; D005680:gamma-Aminobutyric Acid