Histone deacetylase 5 in prelimbic prefrontal cortex limits context-associated cocaine seeking

Area of Science:

• Neuroscience
• Molecular Biology
• Addiction Research

Background:

• Repeated cocaine use leads to neuroadaptations supporting craving and relapse in substance use disorders (SUDs).
• Environmental cues associated with drug use can trigger relapse in SUD patients.
• The molecular mechanisms underlying drug-context associations remain unclear.

Purpose of the Study:

• To investigate the role of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated cocaine seeking.
• To elucidate the molecular mechanisms by which HDAC5 regulates these associations.

Main Methods:

• Utilized a rat intravenous cocaine self-administration (SA) model.
• Employed viral molecular tools, chemogenetics, RNA-sequencing, electrophysiology, and immunohistochemistry.
• Manipulated HDAC5 levels in the PrL and IL cortices.

Main Results:

• Reducing HDAC5 in the PrL augmented context-associated cocaine seeking.
• Overexpressing HDAC5 in the PrL reduced context-associated cocaine seeking but not sucrose seeking.
• HDAC5 and cocaine SA altered gene expression in the PrL, affecting synaptic plasticity and inhibitory transmission.

Conclusions:

• PrL HDAC5 plays a crucial role in limiting associations formed in cocaine-associated environments.
• HDAC5 influences the excitatory/inhibitory balance in the PrL, potentially via epigenetic regulation of synaptic genes.
• HDAC5 is a key regulator of reward circuit neuroadaptations relevant to SUD relapse triggers.