Dopamine Transporter Knockout Rats Display Epigenetic Alterations in Response to Cocaine Exposure.

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Cocaine use disorder (CUD) lacks effective treatments, necessitating novel therapeutic strategies.
• Epigenetic mechanisms are emerging as promising targets for CUD pharmacotherapy.
• Dopamine Transporter (DAT) transgenic rats serve as a novel model for CUD susceptibility research.

Purpose of the Study:

• To investigate the impact of chronic cocaine exposure on epigenetic modulators KDM6B and BRD4.
• To examine sex- and genotype-dependent alterations in these epigenetic markers within the prefrontal cortex (PFC).
• To explore the potential of targeting KDM6B and BRD4 for CUD treatment.

Main Methods:

• Chronic cocaine administration (10 mg/kg for 8 days) to DAT transgenic rats (wild-type, heterozygous, and knockout).
• Analysis of KDM6B and BRD4 expression in the prefrontal cortex (PFC).
• Comparison of epigenetic marker expression across different genotypes and sexes.

Main Results:

• Cocaine altered KDM6B and BRD4 expression in a sex- and genotype-dependent manner.
• HET male rats showed decreased KDM6B and BRD4 expression post-cocaine, while HET females showed increased expression.
• KO rats exhibited increased BRD4 expression, with KO females also showing significantly increased KDM6B expression, with larger effects observed in females.

Conclusions:

• Epigenetic modulators KDM6B and BRD4 are implicated in the neurobiological response to cocaine.
• Sex-specific alterations in KDM6B and BRD4 expression suggest a role for these targets in sex-dependent addiction mechanisms.
• Targeting KDM6B and/or BRD4 may represent a viable therapeutic avenue for treating CUD-related behaviors in a sex-specific manner.