GABA neurosteroids

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. 

Neurosteroids are neuroactive steroids, which are synthesized in the brain. Neurosteroids can bind to and modulate the activity of y-aminobuty tie acidA(GABA A) receptors. 

Reddy, DS and Kulkarni, SK (1998) The role of GABA-A and mitochondrial diazepam-binding inhibitor receptors on the effects of neurosteroids on food intake in mice. Psychopharmacology 137 391-100. 

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. 

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. 

Another receptor system with which neurosteroids interact is the N-methyl-D-aspartate [NMDA] receptor. Pregnenolone sulfate acts as a positive allosteric modulator of the NMDA receptor, in analogy to GABA-ergic effects, by increasing the frequency and duration of NMDA-activated channel opening [Bowlby 1993 Irwin et al. 1992 Wu et al. 1991]. 

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. 

In the next section, we describe the other known main ligands of the GABA receptor, that is, neurosteroids, alcohol, and the barbiturates. (The neurosteroid section is only a summary for completeness for a more comprehensive overview, the reader is referred to Siegfried, Chapter 33, in this volume.)... 

Deutsch SI, Mastropaolo J Discriminative stimulus properties of midazolam are shared by a GABA-receptor positive neurosteroid. Pharmacol Biochem Behav 46 963-965, 1993... 

Majewska MD Neurosteroids endogenous bimodal modulators of the GABA receptor mechanisms of action and physiological significance. Prog Neurobiol... 

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