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Both GABA<jats:sub>A<\/jats:sub> and GABA<jats:sub>B<\/jats:sub> receptors cause hyperpolarization of neuronal membranes and inhibition of neuronal excitability, but their mechanisms differ. GABA<jats:sub>B<\/jats:sub> receptors involve an efflux of K<jats:sup>+<\/jats:sup> rather than an influx of Cl<jats:sup>\u2212<\/jats:sup>, as in the case of GABA<jats:sub>A<\/jats:sub> and GABA<jats:sub>C<\/jats:sub> receptors. The stimulation of GABA<jats:sub>A<\/jats:sub> receptors can sometimes cause depolarization by Cl<jats:sup>\u2212<\/jats:sup> efflux; this efflux is not the result of a transduction mechanism modification, but of Cl<jats:sup>\u2212<\/jats:sup>-concentration gradient modification. Presumably, GABA<jats:sub>A<\/jats:sub> receptor diversity is directly linked to the inhibitory activity of basket cells and other interneuron axons, each innervating several postsynaptic neurons (cortical and hippocampal pyramidal cells for instance). Since the role of this inhibition is to entrain hippocampal and cortical pyramidal neurons into columnary activity, the GABA<jats:sub>A<\/jats:sub> receptor diversification may be a mechanism expressed by these postsynaptic neuron populations that uses different GABA potencies to synchronize pyramidal neurons into columnary activity. Thus, GABA potency variability, which emerges from GABA<jats:sub>A<\/jats:sub> receptor diversity, plays a unifying role in the intrinsic functional mechanism of laminated structures. GABA<jats:sub>A<\/jats:sub> receptor structural differences also play a role in diazepam tolerance, which is a mechanism operative in neuronal circuit adaptation to the extreme amplification of GABA-gated Cl<jats:sup>\u2212<\/jats:sup> current intensities. Partial agonists (such as imidazenil), which modestly amplify GABA action at many GABA<jats:sub>A<\/jats:sub> receptor subtypes, fail to cause tolerance, dependence, ataxia, or ethanol and barbiturate potentiation. Partial agonists might become a new class of anxiolytic and anticonvulsant drugs that are virtually devoid of the side effects that cause serious concerns in the clinical use of full allosteric positive modulators of GABA action, such as diazepam, alprazolam, triazolam, and others. None of the above can be used as anticonvulsants because of an extremely high tolerance liability. <\/jats:p><jats:p> When there is tolerance to diazepam, signs of sensitization to proconvulsive action are exhibited simultaneously. After tolerance, associated changes in GABA<jats:sub>A<\/jats:sub> recepter subtype expression are virtually reversed in 72 h. Also, 96 h after termination of long-term diazepam treatment, rats exhibit anxiety and are more sensitive to kainic acid\u2013elicited convulsions. At the same time, these rats have an increase in brain expression of GLuR1, R2, and R3. It is believed that the supersensitivity to kainic acid, convulsions and anxiety, and the increased expression of GLuR1, R2, and R3 may be parts of the mechanism of diazepam dependence. <\/jats:p>","DOI":"10.1146\/annurev.pharmtox.38.1.321","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T11:45:50Z","timestamp":1027770350000},"page":"321-350","source":"Crossref","is-referenced-by-count":126,"title":["FROM GABA<sub>A<\/sub> RECEPTOR DIVERSITY EMERGES A UNIFIED VISION OF GABAergic INHIBITION"],"prefix":"10.1146","volume":"38","author":[{"given":"E.","family":"Costa","sequence":"first","affiliation":[{"name":"The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"22","reference":[{"key":"b1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ne.17.030194.003033"},{"key":"b2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.62020815.x"},{"key":"b3","first-page":"181","volume":"47","author":"Sieghart W","year":"1995","journal-title":"Pharmacol. 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