GABA/benzodiazepine receptor complex

Pharmacology Flumazenil antagonizes the actions of benzodiazepines on the CNS and competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. 

Chronic alcohol intake changes the functioning of the GABA benzodiazepine receptor complex. For example, chronic alcohol intake increases the binding [Mhatre et al. 1988] and function of benzodiazepine inverse agonists [Lister and Karanian 1987] and attenuates the effect of benzodiazepine... 

Just as does the GABA-benzodiazepine receptor complex discussed in Chapter 8 (see Figs. 8-18 to 8—20), the NMDA glutamate—calcium channel complex also has multiple receptors surrounding the ion channel, which act in concert as allosteric modulators (Fig. 10—24). One modulatory site is for the neurotransmitter glycine another is for polyamines, and yet another is for zinc (Fig. 10—24). The magnesium ion can block the calcium channel at yet another modulatory site, which is presumably inside the ion channel or closely related to it. Another inhibitory modulatory site,... 

Rothblat DS, Schneider JS (1997) Regionally specific effects of haloperidol and clozapine on dopamine reuptake in the striatum. Neurosci Lett 228 119-22 Roy-Byrne PP (2005) The GABA-benzodiazepine receptor complex structure, function, and role in anxiety. J Clin Psychiatry 66 Suppl 2 14-20... 

Electrophysiological studies show that benzodiazepines, barbiturates and sodium valproate facilitate GABAergic transmission in the animal brain. Further evidence comes from studies on the GABA-benzodiazepine receptor complex, the order of potency of a series of benzodiazepines to displace [3H] diazepam from its receptor site being clearly correlated with the antagonism of pentylenetetrazol seizures, but not with electroconvulsive seizures. However, most classes of anticonvulsants appear to facilitate... 

Nociceptive Novel anxiolytics Impulses that give rise to pain. Drugs chemically unrelated to diazepam that produce their anxiolytic effects by facilitating inhibitory transmission through mechanisms other than the GABA-benzodiazepine receptor complex (e.g. buspir-one). 

Carbamazepine is licenced as an alternative to lithium for prophylaxis of bipolar affective disorder, although clinical trial evidence is actually stronger to support its use in the treatment of acute mania. Carbamazepine appears to be more effective than lithium for rapidly cycling bipolar disorders, i.e. with recurrent swift transitions from mania to depression. It is also effective in combination with lithium. Its mode of action is thought to involve agonism of inhibitory GABA transmission at the GABA-benzodiazepine receptor complex (see also Epilepsy, p. 417). 

Figure 8.7 Correlation (r = 0.993, p < 0.001) between benzodiazepine-free drug concentrations EC50 units producing 50% of the maximal EEG effect (change in amplitudes in the a frequency band, as determined by aperiodic EEG analysis) and affinity to the GABA-benzodiazepine receptor complex (K ). Binding to the benzodiazepine receptor was determined on basis of displacement of [3H]flumazenil in washed brain homogenate at 37 °C for six drugs B, IA, M, F, 0, and C. (Reproduced with permission from Danhof and Mandema, 1995)...

Although benzopiperazinones (l,2,3,4-tetrahydroquinoxalin-2-ones) are structurally related to benzodiazepines, their use in drug discovery is less well established. Examples of biological activity of benzopiperazinones include their action as inhibitors of aldose reductase [208], as partial agonists of the y-aminobutyric acid (GABA)/benzodiazepine receptor complex [209, 210], and as angiotensin II receptor antagonists [211]. In addition, derivatives with antiviral acti vity associated vfith HIV have been reported [212, 213]. 

Binding to GABAA receptors on the GABA-benzodiazepine receptor complex at the somatic level of hippocampal pyramidal neurons increases the chloride conductance of the membrane. This causes hyperpolarization and shunting of excitatory synaptic currents. 

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