Effects of typical and atypical antipsychotics on spontaneous neuronal network activity in vitro

Abstract

IntroductionMicroelectrode arrays (MEAs) with cultured neuronal networks are highly suitable to quantify neuroactive activity and neurotoxicity of applied substances.ObjectiveMultiparametric characterization of functional alterations of in vitro-neuronal network activity by different typical and atypical antipsychotics.AimsTo identify differential effects of antipsychotics on spontaneous neuronal network activity as a functional readout.MethodsCultured networks of dissociated cortical cells of postpartal mice coupled to MEAs were exposed to increasing doses of aripiprazole, clozapine, haloperidol, olanzapine, raclopride, and risperidone.ResultsWe found a concentration-dependent inhibition of firing patterns for all substances except olanzapine. All other substances mediated a concomitant irreversible suppression of burst and spike rates, a decrease of the burst duration and the number of spikes in bursts as well as dose-dependent network desynchronization (decrease of Cohen's kappa). The comparison of the different antipsychotics with regard to their half-maximal effective dose values (EC-50) for inhibiting the spike rate yielded an increasing order of EC50 values, i.e. a declining order of toxic potency, of aripiprazole (8.77 μM) < clozapine (9.36 μM) < haloperidol (9.77 μM) < risperidone (15.9 μM) < raclopride (22.7 μM). No significant correlations were identified between EC50 values of the distinct antipsychotics and their binding affinity to the dopamine D(2), the serotonin 5-HT(1A), 5-HT(2A), 5-HT(2C), and the M(1) and M(2) muscarinic acetylcholine receptors.ConclusionIn MEAs, a dose-dependent neurotoxic effect of typical and atypical antipsychotics alike occurred at supratherapeutic doses via a yet unknown mechanism that did not involve actions on major receptor targets of these compounds.Disclosure of interestThe authors have not supplied their declaration of competing interest.