Role of Long Noncoding RNA Gas5 in Cocaine Action

Background: Long noncoding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides in length. Although lncRNAs do not encode proteins, they play numerous functional roles in gene expression regulation. lncRNAs are notably abundant in brain; however, their neural functions remain largely unknown. Methods: We examined the expression of the lncRNA Gas5 in nucleus accumbens (NAc), a key brain reward region, of adult male mice after cocaine administration. We then performed viral-mediated overexpression of Gas5 in NAc neurons to determine its role in addiction-related behaviors. We also carried out RNA sequencing to investigate Gas5-mediated transcriptomic changes. Results: We demonstrated that repeated short-term or long-term cocaine administration decreased expression of Gas5 in NAc. Viral-mediated overexpression of Gas5 in NAc neurons decreased cocaine-induced conditioned place preference. Likewise, Gas5 overexpression led to decreased cocaine intake, decreased motivation, and compulsive-like behavior to acquire cocaine, and it facilitated extinction of cocaine-seeking behavior. Transcriptome profiling identified numerous Gas5-mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5-regulated gene expression changes significantly overlap with chronic cocaine-induced transcriptome alterations, suggesting that Gas5 may serve as an important regulator of transcriptional responses to cocaine. Conclusions: Altogether, our study demonstrates a novel lncRNA-based molecular mechanism of cocaine action.