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The Journal of Neuroscience, April 1, 1999, 19(7):2474-2488

Chlorpromazine Inhibits Miniature GABAergic Currents by Reducing the Binding and by Increasing the Unbinding Rate of GABA_A Receptors

Jerzy W. Mozrzymas^{1, 2}, Andrea Barberis¹, Krystyna Michalak², and Enrico Cherubini¹

¹ Neuroscience Program and Istituto Nazionale Fisica della Materia Unit, International School for Advanced Studies, 34 014 Trieste, Italy, and ² Department of Biophysics, Wroclaw University of Medicine, 50 368 Wroclaw, Poland

Recent studies have emphasized that nonequilibrium conditions of postsynaptic GABA_A receptor (GABA_AR) activation is a key factor in shaping the time course of IPSCs (Puia et al., 1994; Jones and Westbrook, 1995). Such nonequilibrium, resulting from extremely fast agonist time course, may affect the interaction between pharmacological agents and postsynaptic GABA_ARs. In the present study we found that chlorpromazine (CPZ), a widely used antipsychotic drug known to interfere with several ligand and voltage-gated channels, reduces the amplitude and accelerates the decay of miniature IPSCs (mIPSCs). A good qualitative reproduction of the effects of CPZ on mIPSCs was obtained when mIPSCs were mimicked by responses to ultrafast GABA applications to excised patches. Our experimental data and model simulations indicate that CPZ affects mIPSCs by decreasing the binding (k_on) and by increasing the unbinding (k_off) rates of GABA_ARs. Because of reduction of k_on by CPZ, the binding reaction becomes rate-limiting, and agonist exposure of GABA_ARs during mIPSC is too short to activate the receptors to the same extent as in control conditions. The increase in unbinding rate is implicated as the mechanism underlying the acceleration of mIPSC decaying phase. The effect of CPZ on GABA_AR binding rate, resulting in slower onset of GABA-evoked currents, provides a tool to estimate the speed of synaptic clearance of GABA. Moreover, the onset kinetics of recorded responses allowed the estimate the peak synaptic GABA concentration.

Key words: chlorpromazine; GABA_A receptors; miniature IPSCs; patch-clamp; binding and unbinding rate constants; hippocampus

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1972474-15$05.00/0

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