Non-competitive inhibition of GABA currents by phenothiazines in cultured chick spinal cord and rat hippocampal neurons

The γ-aminobutyric acid (GABA) inhibiting properties of several classes of antipsychotic medications were studied using gigaseal whole-cell voltage-clamp techniques in cultured chick spinal cord and rat hippocampal neurons. At doses above 1 μM trifluoperazine, chlorpromazine and thioridazine blocked GABA currents in a non-competitive fashion decreasing the maximal transmitter response without altering the half-maximal effective concentration. In contrast, haloperidol was ineffective against GABA at concentrations up to 100 μM. Among the agents studied trifluoperazine was the most potent GABA inhibitor with half maximal effect at 12 μM. Trifluoperazine (100 μM) also inhibited glycine-gated chloride currents in spinal cord neurons to an extent comparable to GABA (85 ± 6% inhibition) but reduced glutamate currents by less than 35% in either spinal cord or hippocampal neurons.