Effect GABAa receptors

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

The definition of desired therapeutic and side effects in the case of the benzodiazepines very much depends on the clinical problem in question. The sedative and hypnotic actions are desired effects in the treatment of insomnia, but undesired effects in the treatment of anxiety disorders. Effects that are usually undesired include daytime drowsiness, potentiation of the sedative effects of ethanol, and anterograde amnesia. They are mediated via the benzodiazepine site of GABAa receptors, since they can be antagonized with flumazenil. 

Neurosteroids prolong the mean open time of recombinant GABAa receptor channels. Whereas, at least in recombinant systems, the identity of the a and (3 subunits has little or no effect on neurosteroid action, substitution of the y subunit by a 8 subunit suppresses the GABA-modulatory activity of the neurosteroids. 

Figure 11.10 Glycine receptor pharmacology and structure, (a) Amino acids that act as agonists at glycine receptors, and strychnine a competitive antagonist, (b) Subunit composition of foetal and adult glycine receptors in the spinal cord. The receptors are shown with a pentameric assembly but the a. and subunits are distinct from those that form GABAa receptors. Picrotoxin is also an effective glycine antagonist and in recombinant systems is selective for homomeric receptors...

Shingai, R, Sutherland, ML and Barnard, EA (1991) Effects of subunit types of the cloned GABAa receptor on the response to a neurosteroid. Eur. J. Pharmacol. 206 77-80. 

Dysfunction of the GABAa receptor complex such that the effects of all benzodiazepine receptor ligands are shifted in the direction of inverse agonism. In this case, fiumazenil (which normally has zero efficacy) should induce anxiety in anxious patients but have no effects in healthy subjects because they have normal receptors. 

Figure 19.8 A schematic representation of the GABAa receptor shift hypothesis. This proposes that patients with panic disorder have dysfunctional GABAa receptors such that the actions of drugs that behave as antagonists in normal subjects are expressed as inverse agonism in panic patients. It is unlikely that this theory extends to generalised anxiety disorder (GAD), for which benzodiazepine agonists are highly effective treatments, but it could explain why these drugs are relatively ineffective at treating panic disorder. (Based on Nutt et al. 1990)...

Barbiturates are rare these days but these depressants produce their pharmacological effects by increasing the duration of CU channel opening associated with GABAa receptors (see Chapter 11). 

---