The development of pharmacotherapeutics for cocaine use disorder has lagged behind development of therapies for other psychiatric conditions such as depression, anxiety or schizophrenia due in large part to a lack of novel therapeutic targets. The current project is in response to RFA-RM-18-021 entitled ?Pilot Projects Investigating Understudied G Protein-Coupled Receptors, Ion Channels, and Protein Kinases?. Our target, the G-protein coupled receptor Gpr12, has a PubMed score of 13.55 and a PubTater score of 8.24, qualifying this target as a very understudied yet druggable target. In response to the RFA, this project will use our novel viral vector to validate addiction- and/or depression-related changes in rodent behavioral and electrophysiological models. Gpr12 was identified via regional topographical differences in gene expression in the nucleus accumbens shell (shNAc) as part of an innovative convergent functional genomics approach. The regional expression analysis is combined with our transcriptomic data set of transcripts regulated by cocaine and transcripts regulated by environmental enrichment, a manipulation that produces a protective addiction phenotype. The ultimate long-term goal of this project is to develop a useful novel therapeutic for cocaine addiction or depression, with the near-term objective of this specific grant being to validate this novel target in behavioral and electrophysiological paradigms. The overall hypothesis of this project is that our convergent functional genomics approach of regionally-enhanced gene expression in the shNAc (using the Allen Brain Atlas) combined with quantitative cocaine and environmental enrichment RNA-sequencing data sets will identify novel druggable targets that can be developed for therapeutic use. In support of this hypothesis, the shNAc-enhanced proteins Atf3, Htr2c, Cartpt, Cyp26b1, and Fabp5 have been validated previously.
Aim 1 will test Gpr12 for its ability to regulate cocaine taking/seeking in rats, as well as depression and anxiety models that are also dependent heavily upon the shNAc. A novel shRNA adeno-associated viral vector will knock down long-term expression of Gpr12 in the shNAc prior to behavioral testing. To complement the behavioral experiments, Aim 2 will evaluate corresponding functional changes in neuronal activity/excitability after knockdown of Gpr12. The current barrier to developing novel therapeutics for this understudied target is the transition from discovery-based to hypothesis-driven science. The current project will overcome that barrier by seeding the behavioral and electrophysiological validation of this novel shNAc-enhanced target.
The druggable proteome has been incompletely exploited for therapeutic benefit, with the largest obstacle being initial validation of understudied proteins in disease models. The current pilot/exploratory project grant (R03; RFA-RM-18-021) will validate the easily druggable, yet understudied G-protein coupled receptor Gpr12 in behavioral and electropysiological animal models of cocaine use disorder and major depression. Gpr12 is regulated by cocaine, by environmental enrichment, and is highly enriched in the nucleus accumbens shell, a region vitally important for addiction and depression-related behavior.
