Thalamic microinjection of nicotine reverses sevoflurane-induced loss of righting reflex in the rat.
BACKGROUND
Neuronal nicotinic acetylcholine receptors are both potently inhibited by anesthetics and densely expressed in the thalamus. Brain imaging shows that thalamic activity suppression accompanies anesthetic-induced unconsciousness. Therefore, anesthetic-induced unconsciousness may involve direct antagonism of thalamic nicotinic receptors. The authors test this by separately attempting to block or enhance anesthetic-induced loss of righting in rats using intrathalamic microinjections of nicotine or its antagonist.


METHODS
Rats were implanted with a cannula aimed at the thalamus or control locations. A week later, loss of righting was induced using sevoflurane (1.4 +/- 0.2%). A dose-parameter study (n = 35) first identified an optimal intrathalamic nicotine dose associated with arousal. Subsequently, this dose was used to pinpoint the thalamic site mediating the arousal response (n = 107). Finally, sevoflurane righting dose and response specificity were assessed after blocking nicotinic channels with intrathalamic mecamylamine pretreatment (n = 8) before nicotine challenge.


RESULTS
Nicotine (150 microg/0.5 microl over 1 min) was the optimal arousal dose, because lower doses (75 microg) were ineffective and higher doses (300 microg) often caused seizures. Nicotine temporarily restored righting and mobility in animals when microinjections involved the central medial thalamus (P < 0.0001, chi-square). Righting occurred despite continued sevoflurane administration. Intrathalamic mecamylamine pretreatment did not lower the sevoflurane dose associated with loss of righting, but prevented the nicotine arousal response.


CONCLUSIONS
The reversal of unconsciousness found here with intrathalamic microinfusion of nicotine suggests that suppression of the midline thalamic cholinergic arousal system is part of the mechanism by which anesthetics produce unconsciousness.
Alkire
Michael T
MT
Department of Anesthesiology, Center for the Neurobiology of Learning and Memory, University of California, Irvine, California, USA.
McReynolds
Jayme R
JR
Hahn
Emily L
EL
Trivedi
Akash N
AN
D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003243:Consciousness / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005730:Ganglionic Blockers / Q000008:administration & dosage; D005731:Ganglionic Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D008464:Mecamylamine / Q000008:administration & dosage; D008738:Methyl Ethers / Q000008:administration & dosage / Q000009:adverse effects*; D008845:Microinjections; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012021:Reflex, Abnormal / Q000187:drug effects*; D000077149:Sevoflurane; D013788:Thalamus / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D005730:Ganglionic Blockers; D005731:Ganglionic Stimulants; D008738:Methyl Ethers; D000077149:Sevoflurane; D008464:Mecamylamine; D009538:Nicotine