ISOFORM-SELECTIVE MODULATION OF DOPAMINE D2L RECEPTOR EXPRESSION USING ANTISENSE OLIGONUCLEOTIDES

Dopamine D2 receptor signaling plays a central role in the pathophysiology of several neuropsychiatric disorders. However, currently available antipsychotic drugs target dopamine D2 receptor isoforms non-selectively, often resulting in limited therapeutic efficacy and significant adverse effects. The dopamine D2 receptor exists as two main splice isoforms, the long (D2L) and short (D2S) variants, which play distinct biological roles and synaptic functions. This highlights the need for isoform-selective therapeutic strategies that can more precisely modulate dopaminergic signaling. In this study, we performed an in vitro evaluation of antisense oligonucleotides (ASOs) designed to selectively target the D2L isoform. To quantitatively assess D2L synthesis, we employed a plasmid-based reporter system in which the D2L coding sequence was fused to a NanoLuc luciferase reporter. HEK cells transfected with this construct were treated with a panel of D2L-selective ASO candidates, and luciferase activity was measured as a functional readout of D2L expression. Several ASO candidates produced a significant and reproducible reduction in luciferase activity, demonstrating effective and isoform-selective suppression of D2L synthesis in vitro. These results provide a clear proof-of-concept for the selective modulation of D2 receptor isoforms using RNA-based approaches. Ongoing and future studies will extend this work to in vivo mouse models to assess the pharmacodynamic effects, safety profile, and therapeutic potential of D2L-selective ASOs as a novel antipsychotic approach.