Effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine by their transporters heterologously expressed in COS cells and in rat brain synaptosomes.
Although the neurotransmitter uptake system is considered a possible target for the presynaptic action of anesthetic agents, observations are inconsistent concerning effects on the transporter and their clinical relevance. The present study examined the effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine in COS cells heterologously expressing the transporters for these neurotransmitters and in the rat brain synaptosomes. Halothane and isoflurane, but not thiamylal or thiopental, significantly inhibited uptake by COS cell systems of GABA, dopamine and glutamic acid in a concentration-dependent manner within clinically relevant ranges for anesthesia induced by these agents. Similarly, in synaptosomes halothane and isoflurane but not thiopental significantly suppressed the uptake of GABA and glutamic acid, respectively. These results do not support the hypothesis that volatile and intravenous anesthetics exert their action via specific inhibition of GABA uptake to enhance inhibitory GABAergic neuronal activity. Rather, they suggest that presynaptic uptake systems for various neurotransmitters including GABA may be the molecular targets for volatile anesthetic agents.
Sugimura
M
M
Department of Anesthesiology, Faculty of Dentistry, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Japan.
Kitayama
S
S
Morita
K
K
Irifune
M
M
Takarada
T
T
Kawahara
M
M
Dohi
T
T
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D050485:GABA Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000493:pharmacokinetics; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents / Q000493:pharmacokinetics*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D027361:Organic Anion Transporters; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D002352:Carrier Proteins; D018076:DNA, Complementary; D050483:Dopamine Plasma Membrane Transport Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D014179:Neurotransmitter Uptake Inhibitors; D027361:Organic Anion Transporters; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine