Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia.

Rachel-Karson Thériault,Myles St-Denis,Tristen Hewitt,Jibran Y Khokhar,Melissa L Perreault,Jasmin Lalonde

doi:10.3390/ijms22115511

Rachel-Karson Thériault, Myles St-Denis + Show 4 more

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https://doi.org/10.3390/ijms22115511

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Abstract

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

Highlights

Schizophrenia (SZ) is a chronic psychiatric disorder characterized by positive and negative symptoms, as well as debilitating cognitive dysfunction [1,2]
We sought to elucidate the impact of CBD administration alone, or with ILO, on neuronal systems activity in vitro in cortical neurons derived from the methylazoxymethanol acetate (MAM) model system of SZ, and to evaluate sex differences
Using cortical neuron-glial co-cultures, we showed that neurons developed normally over the course of 4 weeks (Figure 1A,B), with a transient increase in the expression of both synapsin 1 (Syn1) and postsynaptic density 95 (PSD-95) proteins

Summary

Introduction

Schizophrenia (SZ) is a chronic psychiatric disorder characterized by positive (e.g., hallucinations) and negative (e.g., anhedonia) symptoms, as well as debilitating cognitive dysfunction [1,2]. Normalization of impaired circuit function has been proposed as a biomarker of therapeutic efficacy of antipsychotics [18,19] This idea is supported by studies demonstrating that antipsychotic treatments normalize deficits in cortical activity in individuals with SZ [18] and in animal models of SZ [17,19,20,21]. The degree of normalization may positively correlate with improved cognitive functioning [18,19], an effect that is more prominent with atypical antipsychotics than typical antipsychotics [23] This difference in efficacy between these two drug classes is postulated to be due to the increased affinity of atypical antipsychotics for serotonin over dopamine receptors [23]

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