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Neurosteroids and GABAA receptor function.

Abstract

In 1984, a potent and selective interaction of the steroidal anaesthetic alphaxalone with the GABAA receptor was demonstrated. Subsequent studies established that certain naturally occurring steroids were potent positive allosteric modulators of the GABAA receptor. Although peripheral endocrine glands are an important endogenous source, the brain can synthesize 'neurosteroids', and these have the potential to influence the activity of the GABAA receptor in the CNS. Systemic administration of steroids have clear behavioural effects. In this article, Jeremy Lambert and colleagues review recent advances in this field and discuss the therapeutic potential of this novel, non-genomic effect of steroids and investigate whether they may influence behaviour under physiological, or pathophysiological, conditions.

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BibTeXRIS

J J Lambert, D Belelli, C Hill-Venning, J A Peters. 1995. Neurosteroids and GABAA receptor function.. https://doi.org/10.1016/s0165-6147(00)89058-6

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Anesthetics↗

Identification of a molecular target mediating the general anesthetic actions of pentobarbital.

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 ligand-gated channels is modulated by barbiturates, the target(s) mediating the anesthetic actions of barbiturates in vivo are unknown. Studying pentobarbital action in beta3(N265M) mice harboring beta3-containing GABAA 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 beta3(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 beta3-containing GABAA receptors. Thus, in contrast to etomidate and propofol, pentobarbital can elicit respiratory depression by a beta3-independent pathway. Pentobarbital reduced heart rate and body temperature to a slightly smaller extent in beta3(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 beta3(N265M) mice and wild-type mice, suggesting that they are not dependent on beta3-containing GABAA receptors. In summary, we show a clear pharmacological dissociation of the immobilizing/hypnotic and respiratory/cardiovascular actions of pentobarbital.

Anesthetics↗