Substance abuse disorders exert large financial and social costs in the U.S.; therefore, better treatments for these disorders need to be developed. Pharmacological replacement therapies (i.e. varenicline and methadone) have become effective tools in reducing some types of addictive drug use. However, effective replacement therapies are still needed for psychostimulant abuse (i.e. cocaine and methamphetamine). Dopamine (DA) receptor partial agonists have been proposed as a strategy to replace the reduced DA tone that underlies the negative reinforcement of psychostimulant addiction, but modulating the DA system is challenging because DA receptors are expressed on a variety of cell types. Adding further complication, the dopamine D2 receptor (D2R) is expressed as two isoforms, short and long, which differ by a 29 amino acid insertion. The long D2R isoform is thought to be responsible for DA's effect on post-synaptic medium spiny neurons (MSNs), whereas the short D2R isoform is thought to function mainly as an autoreceptor on pre-synaptic DA neurons. Recently, our lab has shown that the long D2R isoform in MSNs can signal through a ?-arrestin-mediated pathway and that this pathway is largely responsible for the D2R- dependent locomotor effects of amphetamine. In contrast, all of the known functions of D2R autoreceptors (presumably the short isoform) can be solely ascribed to G protein signaling. This is significant because if pre- and post-synaptic D2R function can be pharmacologically separated due to a fundamental difference between the two D2R isoforms in coupling to ?-arrestin, then it may be possible to selectively increase DA tone acting upon post-synaptic D2Rs on MSNs without causing a simultaneous decrease in DA release. Thus, the objective of this fellowship will be to determine if differences in D2R isoform expression patterns and signaling through ?-arrestin could be exploited to achieve selective targeting of post-synaptic D2R receptor function.
By elucidating the behavioral relevance of the signaling and expression properties of the dopamine D2 receptor isoforms, this project will provide a framework that could be used to develop the first pharmacological replacement therapy for treating psychostimulant abuse. Thereby, the burden of addictive drug abuse on society could be lessened.
