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Identification of a Molecular Target Mediating the General Anesthetic Actions of Pentobarbital

Institute of Pharmacology and Toxicology (A.Z., R.J., U.R.) and Institute of Laboratory Animal Science (M.A.), University of Zürich, Zürich, Switzerland; and Laboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts (U.R.)

Barbiturates were introduced into medical practice in 1934. They are widely used today as general anesthetics. Although in vitro studies revealed that the activity of a variety of ligandgated channels is modulated by barbiturates, the target(s) mediating the anesthetic actions of barbiturates in vivo are unknown. Studying pentobarbital action in 3(N265M) mice harboring 3-containing GABA_A receptors insensitive to a variety of general anesthetic agents, we found that the immobilizing action of pentobarbital is mediated fully, and the hypnotic action is mediated in part by this receptor subtype. It was surprising that the respiratory depressant action of pentobarbital is indistinguishable between 3(N265M) and wild-type mice and thus is mediated by other as-yet-unidentified targets. Whereas the target for the immobilizing and hypnotic actions of pentobarbital seems to be the same as for etomidate and propofol, these latter agents' respiratory depressant actions are mediated by 3-containing GABA_A receptors. Thus, in contrast to etomidate and propofol, pentobarbital can elicit respiratory depression by a 3-independent pathway. Pentobarbital reduced heart rate and body temperature to a slightly smaller extent in 3(N265M) mice compared with wild-type mice, indicating that these actions are largely mediated by other targets. Pentobarbital-induced increase of heart rate variability and prolongation of ECG intervals are seen in both 3(N265M) mice and wild-type mice, suggesting that they are not dependent on 3-containing GABA_A receptors. In summary, we show a clear pharmacological dissociation of the immobilizing/hypnotic and respiratory/cardiovascular actions of pentobarbital.

Address correspondence to: Dr. Uwe Rudolph, Laboratory of Genetic Neuropharmacology, McLean Hospital, Harvard Medical School, Belmont, MA 02478. E-mail: urudolph{at}mclean.harvard.edu

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