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Clozapine-induced paroxysmal discharges

The atypical antipsychotic clozapine is a widely prescribed and effective treatment for the positive and negative symptoms of schizophrenia, but reports of side effects are common. In one study EEG abnormalities were observed in 53% of patients treated with clozapine, and the absence or presence of EEG abnormalities correlated with the plasma clozapine concentration. Here, epileptiform activity was present in conventional EEG recordings from a 32 year old male patient with psychiatric illness taking clozapine for 3 weeks. Brief (ca.100ms), transient epileptiform spikes occurred at a frequency of approximately 2 per h and originated primarily in parietal cortex. One month after withdrawal of clozapine, epileptiform spikes were no longer present. An in vitro model was developed using the equivalent region of association cortex, namely 2⁰ somatosensory cortex, in normal rat brain slices to probe such activity with increased spatial and temporal resolution, and to investigate mechanisms underlying its generation. Wide band in vitro recordings revealed that clozapine (10-20µM) induced regular, frequent very fast oscillations (VFO, > 70Hz) in this region. These VFO comprised short transient high frequency discharges and were maximal in patches along layer V. The atypical antipsychotic olanzapine, but not the classical antipsychotic haloperidol, also induced prominent VFO in this region. Sharp electrode intracellular recordings revealed that there was almost no correlation between the somatic activity of layer V regular spiking (RS) pyramidal cells and field VFO, but layer V intrinsically bursting (IB) cells did correlate to some extent with the local field. Interestingly, IB cell spikelets were also weakly correlated with field VFO suggesting a role for axonal hyperexcitability in this cell type in the mechanism. Clozapine-induced VFO persisted following blockade of AMPA, NMDA, and GABAA chemical synaptic receptors, and the gap junction blockers carbenoxolone and quinine also failed to significantly attenuate the power of this activity. Although octanol abolished clozapine-induced VFO, it was not clear that this effect resulted from blockade of gap junctions as this drug also blocks spikes. In addition to VFO events, clozapine (10-20µM) also induced occasional, spontaneous transient paroxysmal discharges, similar to the EEG phenomena, in 33% (11/33 slices) of slices in vitro. Sharp electrode intracellular recordings revealed that clozapine- induced full paroxysmal discharges were associated with spikes, EPSPs and IPSPs in layer V RS and IB cells, suggesting that these events were mediated via chemical synaptic transmission in both of these cell types. Multi-electrode array recordings of local field potentials and units suggested that clozapine-induced paroxysmal events started superficially in association cortex, moved deeper and then propagated horizontally along these deep layers. The onset of clozapine-induced VFO was accompanied by a significant elevation in parvalbumin immunoreactivity, particularly in layer II-IV, where there was a greater than twofold increase in the signal, and this may be relevant to the therapeutic action of the drug.
Date January 2013
CreatorsFisher, Michael
PublisherUniversity of Newcastle upon Tyne
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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