V1: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 α2δ subunits of voltage-gated calcium channels (VGCCs) and are licensed for neurological disorders including dopamine-dysregulated restless leg syndrome. We explored whether gabapentinoids modulate dopamine signalling with potential in targeting calcium and dopamine in Parkinson’s. We reveal that gabapentinoids ex vivo promote dopamine release in mouse striatum, via sex-specific dependence on α2δ1/2 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 disease expressing human α-synuclein rescued deficits in dopamine release, dysregulation in GABAergic inhibition and dopamine content, and abolished parkinsonian deficits in movement transitions. Gabapentinoids urgently deserve renewed attention for potential repurposing for therapeutic intervention in Parkinson’s disease.