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.

Grant Number: 5R21DA059919-02
NIH Institute/Center: NIH
Principal Investigator: Rong Chen