RNA sequencing identified differentially expressed genes in the mesocorticolimbic and nigrostriatal systems of compulsive METH taking rats.

Methamphetamine (METH) is an extremely addictive drug which continues to cause significant harm to individuals and communities. Differences in patterns of abuse, amounts of METH taken, and in relapse rates exist among METH users who meet DSM-V criteria for METH use disorder (MUD). We are actively investigating the behavioral and molecular differences between compulsive and non-compulsive METH self-administering (SA) rats in the presence of a foot-shock which serves as an aversive stimulus. In the present study, we used male rats that were trained to self-administer METH (0.1 mg/kg/infusion, IV) on an FR-1 schedule for 20 days using a pattern of three 3-h sessions per day and followed by foot-shocks (0.18mA to 0.36mA) for the next 9 days. All the METH taking rats escalated their drug intake during the 20 days of training phase. During the foot-shock phase, a group of rats continued to self-administer METH in the presence of aversive stimuli and were called shock-resistant (SR, compulsive), whereas others who decreased their intake were termed shock-sensitive (SS, non-compulsive). Animals were euthanized 2 hours after the last SA session and the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (DStr) and midbrain (MBr) were isolated for RNA sequencing. RNA sequencing showed a large number of differentially expressed genes (DEGs) in all the brain regions. Our study supports the notion that studying multiple brain regions is critical for a comprehensive understanding of the interconnected neuroadaptive changes which are associated with substance use disorders (SUDs). The present study is of significant translational importance by further supporting the idea that targeting common DEGs identified across multiple brain regions might lead to the development of effective therapeutic approaches against MUD. We trained rats to self-administer METH for 20 days. Then, under the same conditions, the rats continued to self-administer METH in the presence of a foot shock for 9 days.