Punishment-Induced Suppression of Methamphetamine Self-Administration Is Accompanied by the Activation of the CPEB4/GLD2 Polyadenylation Complex of the Translational Machinery

Methamphetamine use disorder (MUD) is a significant public health challenge characterized by high rates of relapse and compulsive behavior. Understanding the molecular drivers of compulsive versus non-compulsive drug-taking is critical for developing new treatments. This study investigated whether the dopamine receptor D1 (DRD1) antagonist SCH23390 could influence methamphetamine self-administration and identified distinct striatal gene expression profiles that differentiate between shock-resistant (compulsive) and shock-sensitive (non-compulsive) rats.

The researchers used a model where rats were punished with footshocks while self-administering methamphetamine. The study categorized the rats into compulsive (shock-resistant) and non-compulsive (shock-sensitive) groups. Compulsive rats exhibited higher drug intake despite punishment and displayed increased incubation of methamphetamine craving after 30 days of withdrawal. RNA sequencing of the dorsal striatum revealed that compulsive rats had upregulated expression of CREB1, CBP, and JunD. In contrast, non-compulsive rats showed increased mRNA levels of CPEB4, a protein involved in regulating mRNA stability and translation.

The study further analyzed the CPEB4-interacting proteins in the dorsal striatum of non-compulsive rats. It identified an activation of the CPEB4/GLD2 polyadenylation complex, which included increased levels of GLD2 and its target, the glutamate receptor subunit GLUN2A. This suggests that the translational machinery—specifically the ability to regulate poly(A) tail length and mRNA stability—plays a key role in the brain's capacity to suppress habitual drug-seeking behaviors. This finding provides a potential novel molecular target, the mRNA polyadenylation complex, for future therapeutic interventions.