Revisiting the Role of Histone Deacetylase 5 in Cocaine Relapse: A New Twist in the Prelimbic Cortex

According to the 2023 National Survey on Drug Use and Health, cocaine is the most abused psychostimulant, with 1.3 million people diagnosed with cocaine use disorder within the previous year. Cocaine addiction, despite its devastating impact on public health, is challenging to treat. This is because people with cocaine use disorder often experience relapse during abstinence, which can be triggered by stimuli previously associated with cocaine use ( 1 ). A promising group of therapeutic targets for reducing cocaine relapse is the family of epigenetic enzymes, which regulate gene expression by catalyzing epigenetic modifications without changing DNA sequences. For example, histone deacetylases (HDACs), which remove acetyl groups from histones and thereby condense chromatin, generally suppress gene expression ( 2 ). Literature from the past 15 years has shown that manipulation of epigenetic enzymes such as HDACs, by either pharmacological or viral approaches, can impact cocaine seeking across animal models of relapse ( 3 ), supporting epigenetic enzymes as promising therapeutic targets for reducing drug relapse.