Benzodiazepine receptors, neurosteroids

Norenberg MD, Itzhak Y, Bender S The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy. Adv Exp Med Biol 1997 420 95-111. 

Mice lacking the 8 subunit, which is mainly expressed in cerebellum and thalamus, display an attenuation of ssatrighting reflex time following the administration of the neurosteroids, alphaxalone and pregnanolone, while the responses to propofol, etomindate, ketamine and the benzodiazepine midazolam were unaffected. This demonstrates the role of GABAa receptors containing the 8 subunit for neurosteroid action. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

Changes have also been reported to occur in the sub-unit composition of the GABA-A receptor following chronic exposure to barbiturates, neurosteroids, ethanol and benzodiazepine agonists. These changes may underlie the development of tolerance, physical dependence and the problems which are associated with the abrupt withdrawal of such drugs. 

Among ai-, a2- and as-point-mutated mice, only the ai(HlOlR) mutants were resistant to the depression of motor activity by diazepam and zolpidem (Rudolph et al. 1999 Low et al. 2000 Crestani et al. 2000). This effect was specific for ligands of the benzodiazepine site, since pentobarbital or a neurosteroid remained as effective in ai(HlOlR) mice as in wild-type mice in inducing sedation. An ai(HlOlR) mouse line was also generated by McKernan et al. (2000), confirming that sedation is finked to ai GABAa receptors and differs mechanistically from the anxiolytic action of benzodiazepines. 

GABA for their action, but their maximal modulatory efficacy never surpasses the maximal response elicited by GABA in the same receptor channel [Puia et al. 1990]. This explains why neurosteroids do and benzodiazepines do not possess anesthetic properties surpassing their anxiolytic effect. 

The GABAj receptor is a protein complex that mediates neuronal inhibition throughout the central nervous system. The inhibitory neurotransmitter GABA and various substances, including benzodiazepines, neurosteroids, barbiturates, and alcohol, all have binding sites on it (Figure 29-1). 

Our knowledge of the binding sites of the other ligands at the GABA receptor is more limited. The barbiturates and neurosteroids act through distinct binding sites, but the specific subunits involved have not been clearly determined. Unlike the benzodiazepines, they do not seem to require the y subunit to function and may just require a and (5 subunits. 

Recently, a further type of chloride-channel receptor has been proposed - termed GABAc - and this form is not sensitive to bicuculline, nor is it not sensitive to modulation by benzodiazepines, barbiturates or neurosteroids. It is expressed strongly in certain sites, including the retina, and contains novel a subunits. Whether this proposed subtype simply represents a further characteristic aggregation of oligomeric subunits is not yet clear. In any event, it may represent a target for novel non-benzodiazepine drug action. 

I The rrtajor psychopharmacological irrterest in GABA is the role of the GABAa receptor complex in ie action of benzodiazepines, barbiturates, alcohol and neurosteroids (Fig. 

Adams RD, Foley JM. The neurological disorder associated with liver disease. In Metabolic and Toxic Diseases of the Nervous System. (H.H. Merritt, and C.C. Hare, eds.)Vol. 32. WiUiams and Wilkins, Baltimore, USA, pp. 198-237, 1953 Ahboucha S, Butterworth RF. The neurosteroid system Implication in the pathophysiology of hepatic encephalopathy. Neurochem. Int., 52, 575-587, 2008 Ahboucha S, Pomier-Layrargues G, Mamer O, Butterworth RF. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Arm. Neurol, 58, 169-170, 2005 Ahboucha S, Coyne L, Hirakawa R, Butterworth RF, Halliwell RF. An interaction between benzodiazepines and neuroactive steroids at GABA receptors in cultured hippocampal neurons. Neurochem. Int., 48, 703-707, 2006... 

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