The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway.
We investigated the role of regionally discrete GABA (gamma-aminobutyric acid) receptors in the sedative response to pharmacological agents that act on GABA(A) receptors (muscimol, propofol and pentobarbital; 'GABAergic agents') and to ketamine, a general anesthetic that does not affect GABA(A) receptors. Behavioral studies in rats showed that the sedative response to centrally administered GABAergic agents was attenuated by the GABA(A) receptor antagonist gabazine (systemically administered). The sedative response to ketamine, by contrast, was unaffected by gabazine. Using c-Fos as a marker of neuronal activation, we identified a possible role for the tuberomammillary nucleus (TMN): when gabazine was microinjected directly into the TMN, it attenuated the sedative response to GABAergic agents. Furthermore, the GABA(A) receptor agonist muscimol produced a dose-dependent sedation when it was administered into the TMN. We conclude that the TMN is a discrete neural locus that has a key role in the sedative response to GABAergic anesthetics.
Department of Anaesthetics & Intensive Care, Chelsea & Westminster Hospital, Imperial College School of Medicine, London SW10 9NH, UK.
L E
LE
Nelson
T Z
TZ
Guo
J
J
Lu
C B
CB
Saper
N P
NP
Franks
M
M
Maze
D000758:Anesthesia / Q000379:methods; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000502:physiology*; D012890:Sleep / Q000187:drug effects / Q000502:physiology*
D000777:Anesthetics; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A