Quinolinic acid toxicity on orexin neurons blocked by gamma aminobutyric acid type A receptor stimulation.
Selective degeneration of hypothalamic orexin neurons, a hallmark of pathology in narcolepsy patients, is in part reproduced in hypothalamic slice cultures by application of an endogenous excitotoxin quinolinic acid. Depolarized membrane potential may be responsible for the vulnerability of orexin neurons to excitotoxicity. We show that stimulation of gamma-aminobutyric acid type A receptors, which is known to hyperpolarize orexin neurons, by muscimol or isoguvacine potently inhibits quinolinic acid cytotoxicity on orexin neurons. In addition, the protective effect of gamma-aminobutyric acid and a gamma-aminobutyric acid uptake blocker nipecotic acid is abolished by a gamma-aminobutyric acid type A antagonist picrotoxin. Norepinephrine and serotonin do not provide a neuroprotective effect. Thus, GABAergic inhibitory control may be a decisive factor regulating survival of orexin neurons under excitotoxic insults.
Katsuki
Hiroshi
H
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Akaike
Akinori
A
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D009557:Nipecotic Acids / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A / Q000502:physiology*; D018013:Receptors, Neuropeptide; D012701:Serotonin / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001640:Bicuculline; D015283:Citalopram; D005473:Fluoxetine; D018755:GABA Agonists; D018756:GABA Antagonists; D005968:Glutamate Decarboxylase; D047908:Intracellular Signaling Peptides and Proteins; D008274:Magnesium; D009479:Neuropeptides; D009557:Nipecotic Acids; D009638:Norepinephrine; D064446:Orexin Receptors; D000068797:Orexins; D009943:Organophosphorus Compounds; D010852:Picrotoxin; D017378:Quinolinic Acid; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D018013:Receptors, Neuropeptide; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; C107353:CGP 54626; C011386:nisoxetine; C030278:nipecotic acid