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. In the present study we trained male rats to self-administer METH for 20 days, followed by 9 days of foot shock exposure. All rats escalated their METH intake during the first 20 days. The rats that continued to self-administer METH in the presence of aversive stimuli were termed shock-resistant (SR), while those that reduced their intake were shock-sensitive (SS). RNA sequencing showed numerous differentially expressed genes (DEGs) in the prefrontal cortex, nucleus accumbens, dorsal striatum, and midbrain. Ingenuity pathway analysis linked DEGs to addiction-related mechanisms. We identified shared genes with similar expression patterns across four brain regions (SR: <i>Fos</i> and <i>Ahsp</i>; SS: <i>Tet1</i>, <i>Cym</i>, and <i>Tmem30c</i>). The identified genes play key roles in addiction-related brain functions, such as neuronal activity, stress response, and epigenetic regulation, and their importance in METH addiction is highlighted. These genes represent promising targets for developing new treatments aimed at reversing neuroadaptations caused by METH use.