Epigenetic control of an auxiliary subunit of voltage-gated sodium channels regulates the strength of drug-cue associations and relapse-like cocaine seeking

Repeated use of illicit drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, like histone deacetylase 5 (HDAC5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear. 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 nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration (SA) and cue-reinstated cocaine seeking. We also used in silico analysis of single-nucleus RNA sequencing data, quantitative RT-PCR, viral-mediated expression of Scn4b shRNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b's effects on NAc intrinsic excitability and cued reward seeking. We discovered that two 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 to limit relapse-like cue-reinstated cocaine seeking. Moreover, we found that HDAC5 limited cocaine, 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. 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.