The effects of neuroleptics on the GABA‐induced Cl− current in rat dorsal root ganglion neurons: differences between some neuroleptics

Several neuroleptics inhibited the 3 μM γ‐aminobutyric acid induced‐chloride current (GABA‐current) on dissociated rat dorsal root ganglion neurons in whole‐cell patch‐clamp investigations. The IC50 for clozapine, zotepine, olanzapine, risperidone and chlorpromazine were 6.95, 18.26, 20.30, 106.01 and 114.56 μM, respectively. The values for the inhibitory effects of neuroleptics on the GABA (3 μM)‐current, which were calculated by the fitting Hill's equations where the concentrations represent the mean therapeutic blood concentrations, were ranked clozapine>zotepine>chlorpromazine>olanzapine>risperidone. These inhibitory effects, weighted with the therapeutic concentrations of neuroleptics, were correlated with the clinical incidences of seizure during treatment with neuroleptics. Clozapine reduced the picrotoxin‐inhibiton, and may compete with a ligand of the t‐butylbicyclophosphorothionate (TBPS) binding site. Haloperidol and quetiapine did not affect the peak amplitude of the GABA (3 μM)‐current. However, haloperidol reduced the clozapine‐inhibition, and may antagonize ligand binding to TBPS binding site. Neuroleptics including haloperidol and quetiapine enhanced the desensitization of the GABA (3 μM)‐current. However, haloperidol and quetiapine at 100 μM inhibited the desensitization at the beginning of application. Blonanserin (AD‐5423) at 30 and 50 μM potentiated the GABA (3 μM)‐current to 170.1±6.9 and 192.0±10.6% of the control current, respectively. Blonanserin shifted GABA concentration‐response curve leftward. Blonanserin only partly negatively interacted with diazepam. The blonanserin‐potentiation was not reversed by flumazenil. Blonanserin is not a benzodiazepine receptor agonist. The various effects of neuroleptics on the GABA‐current may be related to the clinical effects including modifying the seizure threshold. British Journal of Pharmacology (2002) 135, 1547–1555; doi:10.1038/sj.bjp.0704608