Epigenetic Control of an Auxiliary Subunit of Voltage-Gated Sodium Channels Regulates the Strength of Drug-Cue Associations and Relapse-Like Cocaine Seeking.

BACKGROUND

Repeated use of addictive drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, such as HDAC5 (histone deacetylase 5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear.

METHODS

We used a combination of molecular biology, cultured cells, tandem mass spectrometry, deacetylase activity measurements, co-immunoprecipitation, and molecular dynamics simulations to assess HDAC5 structure-activity relationships. In male and female Long Evans rats, we used viral-mediated expression of HDAC5 mutants in the nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration and cue-reinstated cocaine seeking. We also used in silico analysis of single-nucleus RNA sequencing data, quantitative reverse transcriptase-polymerase chain reaction, viral-mediated expression of Scn4b short hairpin RNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b's effects on NAc intrinsic excitability and cued reward seeking.

RESULTS

We discovered that 2 conserved cysteines located near HDAC5's catalytic domain were required for its intrinsic deacetylase activity and that HDAC5's deacetylase activity was required in NAc medium spiny neurons (MSNs) to limit relapse-like cue-reinstated cocaine seeking. Moreover, we found that HDAC5 limited cocaine-seeking, but not sucrose-seeking, behavior by reducing NAc MSN intrinsic excitability through the deacetylase-dependent repression of Scn4b, which codes for an auxiliary subunit of voltage-gated sodium channels.

CONCLUSIONS

Our findings suggest that HDAC5's control of NAc Scn4b expression governs the formation of cocaine-cue, but not sucrose-cue, associations through modulation of NAc MSN intrinsic excitability and drug-induced NAc plasticity mechanisms.