Nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes inhibit alpha(4)beta(2) neuronal nicotinic acetylcholine receptors.
The nonhalogenated anesthetic alkanes, cyclopropane and butane, do not enhance gamma-aminobutyric acid-elicited GABAergic currents, suggesting that these agents produce anesthesia via interactions with other molecular targets. Perhalogenated nonimmobilizing alkanes, such as 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane, also fail to enhance GABAergic currents, but display specific behavioral effects that are distinct from those of structurally similar anesthetics. At concentrations predicted to be anesthetic, 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane produce amnesia but fail to produce immobility. Neuronal nicotinic acetylcholine (nACh) receptors are sensitive to many anesthetics and are thought to have an important role in learning and memory. We postulated that neuronal nACh receptors might mediate the common amnestic action of nonhalogenated and perhalogenated alkanes. To test the hypothesis that neuronal nACh receptors have a role in mediating the behavioral effects of general anesthetics and nonimmobilizers, we quantified the inhibitory potencies of nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes on currents mediated by alpha(4)beta(2) neuronal nACh receptors. Our studies reveal that anesthetics and nonimmobilizers significantly inhibit alpha(4)beta(2) neuronal nACh receptors at concentrations that suppress learning and with potencies that correlate with their hydrophobicities. These results support the hypothesis that alpha(4)beta(2) neuronal nACh receptors mediate the amnestic actions of alkanes but not their immobilizing actions.


CONCLUSIONS
The results of this study suggest that the immobilizing actions of general anesthetics do not result from the inhibition of alpha(4beta2) neuronal nicotinic acetylcholine receptors. However, the inhibition of neuronal nicotinic acetylcholine receptors may account for the amnestic activities of general anesthetics and nonimmobilizers.
Raines
Douglas E
DE
Department of Anesthesia, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA. draines@partners.org
Claycomb
Robert J
RJ
Forman
Stuart A
SA
D000465:Algorithms; D000473:Alkanes / Q000494:pharmacology*; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004594:Electrophysiology; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014981:Xenopus
D000473:Alkanes; D000777:Anesthetics; D006846:Hydrocarbons, Halogenated; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2