title: Effects of clozapine, haloperidol and iloperidone on neurotransmission and synaptic plasticity in prefrontal cortex and their accumulation in brain tissue: an in vitro study.
abstract: The mode of action of the antipsychotic drugs clozapine, haloperidol and iloperidone was investigated in layer V of prefrontal cortex slices using extracellular field potential, intracellular sharp-electrode as well as whole-cell voltage clamp recording techniques. Intracellular investigations on a broad range of concentrations revealed that the typical neuroleptic haloperidol at higher concentrations significantly depressed the excitatory postsynaptic component induced by electrical stimulation of layer II. This was not seen with the atypical neuroleptics clozapine and iloperidone. None of the three compounds had any effect on the resting membrane potential, spike amplitude or input resistance at relevant concentrations. Synaptic plasticity was assessed by means of extracellular field potential recordings. Clozapine significantly facilitated the potentiation of synaptic transmission, whereas haloperidol and iloperidone showed no effects. In line with its facilitating effect on synaptic plasticity, it could be demonstrated by whole-cell voltage clamp recordings that clozapine increased N-methyl-D-aspartic acid receptor-mediated excitatory postsynaptic currents in the majority of prefrontal cortical neurones. These investigations were made with neuroleptic drugs applied to the bath in the micromolar concentration range in order to approach clinical brain concentrations that are reached after administration of therapeutic doses. The drug concentrations reached in the slices after the experiments were assessed by means of high-pressure liquid chromatography coupled with mass-spectrometric detection. Surprisingly, drug accumulation in the in vitro preparation was of similar degree as reported in vivo. In conclusion, the typical neuroleptic haloperidol significantly depressed excitatory synaptic transmission in layer V neurones of the prefrontal cortex. In contrast, the two atypical neuroleptics iloperidone and clozapine revealed no depressing effects. This feature of the atypical neuroleptics might be beneficial since a hypofunctionality of this brain area is thought to be linked with the pathophysiology of schizophrenia. Additionally, clozapine facilitated long-term potentiation, which might be linked with the clinically observed beneficial effects on certain cognitive parameters. The clozapine-induced increase of N-methyl-D-aspartic acid receptor-mediated currents suggests that clozapine facilitates the induction of long-term potentiation. Furthermore, the present study points to the importance of considering the significant accumulation of neuroleptic drugs in in vitro studies.
authors.affiliation: Nervous System Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: A Y
authors.initials: AY
authors.lastname: Gemperle
authors.forename: A
authors.initials: A
authors.lastname: Enz
authors.forename: M F
authors.initials: MF
authors.lastname: Pozza
authors.forename: A
authors.initials: A
authors.lastname: Lüthi
authors.forename: H R
authors.initials: HR
authors.lastname: Olpe
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D007555:Isoxazoles; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D008274:Magnesium; D003024:Clozapine; D006220:Haloperidol; C081732:iloperidone