Gabapentinoids promote striatal dopamine release and rescue multiple deficits of a mouse model of early Parkinson’s

Neuronal entry and handling of intracellular calcium have long-been hypothesised to burden vulnerable dopamine neurons in Parkinson’s disease. However, no treatments for Parkinson’s target calcium biology. Gabapentinoid drugs bind to α 2 δ subunits of voltage-gated calcium channels (VGCCs) and are licensed for neurological disorders including dopamine-dysregulated restless leg syndrome, suggesting their potential utility to modify both calcium biology and dopamine signalling. We therefore tested whether gabapentinoids modulate dopamine signalling, underlying VGCC-dependence, and potential for treating Parkinson’s. In mouse striatum, we reveal that gabapentinoids ex vivo promote dopamine release, via sex-specific dependence on α 2 δ1/2 subunits and alterations to the calcium- and VGCC-subtype-dependence of dopamine release or its tonic inhibition by striatal GABA. In vivo administration of gabapentinoids to a mouse model of early Parkinson’s rescued deficits in dopamine release, dysregulation of GABAergic inhibition and dopamine content, and abolished parkinsonian deficits in movement transitions. Thus, gabapentinoids urgently deserve attention for repurposing for Parkinson’s disease. Abstract Figure