FROM GABA(A), RECEPTOR DIVERSITY EMERGES A UNIFIED VISION OF GABAERGIC INHIBITION

Transmitter receptor diversity often indicates differences in transmit ter receptor transduction mechanisms. This is not the case for gamma-a minobutyric acid subtype A (GABA(A)) receptor subtypes despite the pre sence of 16 genes to encode the 5 families of native GABA(A) receptor subtypes. Similar considerations apply to GABA(C) receptors and GABA(B ) receptors. Both GABA(A) and GABA(B) receptors cause hyperpolarizatio n of neuronal membranes and inhibition of neuronal excitability, but t heir mechanisms differ. GABA(B) receptors involve an efflux of K+ rath er than an influx of Cl-, as in the case of GABA(A) and GABA(C) recept ors. The stimulation of GABA(A) receptors can sometimes cause depolari zation by Cl- efflux, this efflux is not the result of a transduction mechanism modification, but of Cl--concentration gradient modification . Presumably, GABA(A) receptor diversity is directly linked to the inh ibitory activity of basket cells and other interneuron axons, each inn ervating several postsynaptic neurons (cortical and hippocampal pyrami dal cells for instance). Since the role of this inhibition is to entra in hippocampal and cortical pyramidal neurons into columnary activity, the GABA(A) receptor diversification may be a mechanism expressed by these postsynaptic neuron populations that uses different GABA potenci es to synchronize pyramidal neurons into columnary activity. Thus, GAB A potency variability, which emerges from GABA(A) receptor diversity, plays a unifying role in the intrinsic functional mechanism of laminat ed structures. GABA(A) receptor structural differences also play a rol e in diazepam tolerance, which is a mechanism operative in neuronal ci rcuit adaptation to the extreme amplification of GABA-gated Cl- curren t intensities. Partial agonists (such as imidazenil), which modestly a mplify GABA action at many GABA(A) receptor subtypes, fail to cause to lerance, dependence, ataxia, or ethanol and barbiturate potentiation. Partial agonists might become a new class of anxiolytic and anticonvul sant drugs that are virtually devoid of the side effects that cause se rious concerns in the clinical use of full allosteric positive modulat ors of GABA action, such as diazepam, alprazolam, triazolam, and other s. None of the above can be used as anticonvulsants because of an extr emely high tolerance liability. When there is tolerance to diazepam, s igns of sensitization to proconvulsive action are exhibited simultaneo usly. After tolerance, associated changes in GABA(A) recepter subtype expression are virtually reversed in 72 h. Also, 96 h after terminatio n of long-term diazepam treatment, rats exhibit anxiety and are more s ensitive to kainic acid-elicited 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 anx iety, and the increased expression of GLuR1, R2, and R3 may be parts o f the mechanism of diazepam dependence.