GABAA-benzodiazepine agonists

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)...

GABAA benzodiazepine j8-carbolines act as inverse agonists of the GABAA benzodiazepine receptor (Mehta and Ticku 1989). Whereas benzodiazepines such as diazepam stimulate Cl- influx, j8-carbolines inhibit it. Harmine, harmaline, harmane, and harmalol inhibit flunitrazepam binding in the micromolar range (half-maximal inhibition between 28 and 130 pM) (Mousah et al. 1986). Endogenous j8-carbolines, such as harmane, have also been found in the human brain, but their endogenous functions are uncertain (Tse et al. 

For more than 40 years, the most frequently used anxiolytic compounds have been benzodiazepines. Benzodiazepine agonists such as diazepam act via modulation of y-aminobutyric acidergic (GABAergic) transmission at GABAa receptors (see chapter by Duman and Duman, this volume), which consist of about 20 subunits. Several mutant mice with deletions of different subunits have been engineered (Holmes 2001) and most of these mutants perform altered anxiety-related behavior, thus emphasizing the intimate link between benzodiazepine receptors and anxiety. 

Buck KJ, Harris RA Benzodiazepine agonist and inverse agonist actions on GabaA receptor-operated chloride channels, 11 chronic effects of ethanol. J Pharmacol Exp Ther 253 713-719, 1990... 

Wieland HA, Liiddens H, Seeburg PH. A singie histidine in GABAa receptors is essentiai for benzodiazepine agonist binding, J Biol Chem 1992 267 1426-1429. 

Although flumazenil binds with high affinity to the benzodiazepine site of GABAa receptors, it has practically no action when given alone. However, flumazenil competitively blocks the action of benzodiazepine site agonists. Flumazenil can be used to terminate the action of benzodiazepines, e.g., after a benzodiazepine overdose. It may also serve as a diagnostic tool in this regard. 

The binding site for barbiturates on the GABAa receptor is less well defined. Barbiturates act by increasing the conductance level. In contrast to benzodiazepines, they also display direct agonistic action on GABAa receptors. Also in contrast to... 

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