GABAA receptor positive allosteric modulation has symptomatic and disease modifying effects in a mouse model of chronic stress

Abstract

Chronic stress is a risk factor for anxiety and depression and all are linked to reduced cognitive performance and neuronal atrophy. In these, there is reduced number of GABAergic neurons, reduced GABA release and altered GABAA receptor (GABAAR) functioning. GABAARs contain α subunits that essentially dictate functional outcome: sedation with α1 subunit potentiation, anxiolytic effects with α2/α3 and cognition with α5. Common GABAergic drugs, like benzodiazepines, act at α1/2/3/5-GABAARs but have side effects (sedation, dependence) mixed with mild anxiolytic effects and no cognitive benefits. Therefore, a therapy designed to increase α2/3/5 activity while also devoid of α1 activity has significant clinical relevance and potential. We investigated two enantiomers separately, GL-I-54 and GL-II-73, as well as their combined use as a racemic mixture (termed GL-RM) because of the desirable positive allosteric modulation profile when combined (α2/3/5 and α5 respectively). Using the unpredictable chronic mild stress (UCMS) model in C57BL6 mice (50% female; N=48 per study), anxiolytic, anti-depressant and pro-cognitive effects of GL-RM were assessed after acute or chronic administration. GL-RM reduced stress induced anxiety-like phenotypes and overcame stress induced cognitive deficits. Golgi staining after chronic GL-RM found GL-RM rescued dendritic spine density after UCMS in the PFC and CA1. Results support the value of a therapy with a α2/3/5 GABAAR selective profile to overcome chronic stress-induced mood symptoms and cognitive deficits, and detriments in neuronal morphology.