Drd3 transcript variants and cocaine self-administration

Project Summary This proposal is prepared in response to PAR-23-041, which supports projects that functionally validate and/or characterize genes or variants implicated in substance use disorder (SUD). We propose to illuminate the roles of several transcript variants of rat Drd3 gene, encoding dopamine D3 receptor (D3R), in the regulation of cocaine-seeking and taking behavior. The D3R has long been implicated in SUD and has recently become an attractive target of pharmacotherapy of SUD. Although a few reported splice variants of Drd3 gene appear to be conserved across species between human and rodents, their functions, especially in the context of SUD, have not been explored previously. We have confirmed the expression of a few Drd3 transcript variants and identified a new variant in rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions critically involved in drug reward. Some variants are expressed in a striking sex- and region-specific manner and importantly, some are sensitive to cocaine self-administration (SA). Built on these novel observations, we will in the R21 phase: a) characterize the function of each Drd3 variant using the heterologous expression system; and b) develop and validate neuron type-specific AAV tools to express Drd3 variants that are sex- specific and cocaine-sensitive. In the R33 phase, we will use the developed AAV tools to determine a) if sex- specific Drd3 variants contribute to sex-dependent cocaine-seeking and taking behavior; b) if cocaine-sensitive Drd3 variants regulate cocaine-seeking and taking behavior; and c) if overexpression of Drd3 variants influences D3R function and dopamine (DA) transmission.