The effects of neuroleptics on the GABA-induced Cl- current in rat dorsal root ganglion neurons: differences between some neuroleptics.
1. Several neuroleptics inhibited the 3 microM gamma-aminobutyric acid induced-chloride current (GABA-current) on dissociated rat dorsal root ganglion neurons in whole-cell patch-clamp investigations. 2. The IC(50) for clozapine, zotepine, olanzapine, risperidone and chlorpromazine were 6.95, 18.26, 20.30, 106.01 and 114.56 microM, respectively. The values for the inhibitory effects of neuroleptics on the GABA (3 microM)-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. 3. Clozapine reduced the picrotoxin-inhibiton, and may compete with a ligand of the t-butylbicyclophosphorothionate (TBPS) binding site. 4. Haloperidol and quetiapine did not affect the peak amplitude of the GABA (3 microM)-current. However, haloperidol reduced the clozapine-inhibition, and may antagonize ligand binding to TBPS binding site. 5. Neuroleptics including haloperidol and quetiapine enhanced the desensitization of the GABA (3 microM)-current. However, haloperidol and quetiapine at 100 microM inhibited the desensitization at the beginning of application. 6. Blonanserin (AD-5423) at 30 and 50 microM potentiated the GABA (3 microM)-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. 7. The various effects of neuroleptics on the GABA-current may be related to the clinical effects including modifying the seizure threshold.
Yokota
Kenjiro
K
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan. hateruma@npsych.med.kyushu-u.ac.jp
Tatebayashi
Hideharu
H
Matsuo
Tadashi
T
Shoge
Takashi
T
Motomura
Haruhiko
H
Matsuno
Toshiyuki
T
Fukuda
Akira
A
Tashiro
Nobutada
N
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D003024:Clozapine / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D015994:Incidence; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D000069348:Quetiapine Fumarate; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000453:epidemiology / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*
D014150:Antipsychotic Agents; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D003987:Dibenzothiazepines; D010879:Piperazines; D010880:Piperidines; D000069348:Quetiapine Fumarate; D005680:gamma-Aminobutyric Acid; C079310:blonanserin; D003024:Clozapine; D006220:Haloperidol