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bioRxiv · 10.1101/2025.09.16.675586

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

Brimblecombe, K. R.·Harris, A. L.·Bengoa-Vergniory, N.·O'Connor, B.·Duquenoy, L. S.·Anand, R.·Lopes, E. F.·Roberts, B. M.·Burgeno, L.·Walton, M. E.·Cragg, S. J.
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Abstract

Neuronal entry and handling of intracellular calcium have long-been hypothesised to burden vulnerable dopamine neurons in Parkinsons disease. However, no treatments for Parkinsons target calcium biology. Gabapentinoid drugs bind to 2{delta} 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 Parkinsons. In mouse striatum, we reveal that gabapentinoids ex vivo promote dopamine release, via sex-specific dependence on 2{delta}1/2 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 Parkinsons 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 Parkinsons disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/675586v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@16cd7e1org.highwire.dtl.DTLVardef@d104e5org.highwire.dtl.DTLVardef@98683eorg.highwire.dtl.DTLVardef@1e3e3ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Brimblecombe, K. R., Harris, A. L., Bengoa-Vergniory, N., O'Connor, B., Duquenoy, L. S., Anand, R., Lopes, E. F., Roberts, B. M., Burgeno, L., Walton, M. E., Cragg, S. J.. 2025-09-17. Gabapentinoids promote striatal dopamine release and rescue multiple deficits of a mouse model of early Parkinson's. https://doi.org/10.1101/2025.09.16.675586

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