GABAa receptor binding, alterations

Benes EM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J. Neurosci. 1992 12 924-929. Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb. Cortex 2002 12 1063-1070. 

The main effects of BZs occur via positive allosteric modulation. The BZs and GABA bind to separate sites on the GABAa receptor complex. When a BZ occupies the BZ receptor, GABA s ability to open the chloride channels increases. With greater opening of the chloride channel, cellular excitability decreases (Ballenger, 1995). The final result of this decreased cellular excitability is widespread because of the extensive inhibitory role of GABA in the CNS. As a result, BZs may alter the turnover of neurotransmitters such as norepinephrine and serotonin (5-hydroxytryptamine [5-HT]). 

The exact mechanism of action of most volatile substances remains unknown. Altered function of ionotropic receptors and ion channels throughout the central nervous system has been demonstrated for a few. Nitrous oxide, for example, binds to NMDA receptors and fuel additives enhance GABAa receptor function. Most inhalants produce euphoria increased excitability of the VTA has been documented for toluene and may underlie its addiction risk. Other substances, such as amyl nitrite ("poppers"), primarily produce smooth muscle relaxation and enhance erection, but are not addictive. With chronic exposure to the aromatic hydrocarbons (eg, benzene, toluene), toxic effects can be observed in many organs, including white matter lesions in the central nervous system. Management of overdose remains supportive. 

The BZR ligands, regardless of intrinsic activity, do not directly alter transmembrane chloride conduction to produce their observed characteristic physiologic anxiolytic or anxiogenic effects. The BZR is an allosteric modulator of GABA binding to the GABAa receptor complex that, in turn, modulates the transmembrane conductance of chloride. 

I Mice genetically altered to have only 50% of 72 subunits (linked to BDZ binding site) in GABAa-BDZ receptors (receptor knockout ) have behavioural equivalent of anxiety. 

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