Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABA(A) receptors

Recent studies have emphasized that nonequilibrium conditions of postsynapt ic GABA(A) receptor (GABA(A)R) activation is a key factor in shaping the ti me course of IPSCs (Puia et al., 1994; Jones and Westbrook, 1995). Such non equilibrium, resulting from extremely fast agonist time course, may affect the interaction between pharmacological agents and postsynaptic GABA(A)Rs. In the present study we found that chlorpromazine (CPZ), a widely used anti psychotic drug known to interfere with several ligand and voltage-gated cha nnels, reduces the amplitude and accelerates the decay of miniature IPSCs ( mIPSCs). A good qualitative reproduction of the effects of CPZ on mIPSCs wa s obtained when mIPSCs were mimicked by responses to ultrafast GABA applica tions to excised patches. Our experimental data and model simulations indic ate that CPZ affects mIPSCs by decreasing the binding (k(on)) and by increa sing the unbinding (k(off)) rates of GABA(A)Rs. Because of reduction of k(o n) by CPZ, the binding reaction becomes rate-limiting, and agonist exposure of GABA(A)Rs during mIPSC is too short to activate the receptors to the sa me extent as in control conditions. The increase in unbinding rate is impli cated as the mechanism underlying the acceleration of mIPSC decaying phase. The effect of CPZ on GABA(A)R binding rate, resulting in slower onset of G ABA-evoked currents, provides a tool to estimate the speed of synaptic clea rance of GABA. Moreover, the onset kinetics of recorded responses allowed t he estimate the peak synaptic GABA concentration.