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

Abstract

Introduction

Microelectrode arrays (MEAs) with cultured neuronal networks are highly suitable to quantify neuroactive activity and neurotoxicity of applied substances.

Objective

Multiparametric characterization of functional alterations of in vitro-neuronal network activity by different typical and atypical antipsychotics.

Aims

To identify differential effects of antipsychotics on spontaneous neuronal network activity as a functional readout.

Methods

Cultured networks of dissociated cortical cells of postpartal mice coupled to MEAs were exposed to increasing doses of aripiprazole, clozapine, haloperidol, olanzapine, raclopride, and risperidone.

Results

We 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.

Conclusion

In 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 interest

The authors have not supplied their declaration of competing interest.