Heroin regulates the voltage-gated sodium channel auxiliary subunit, SCN1b, to modulate nucleus accumbens medium spiny neuron intrinsic excitability and cue-induced heroin seeking.

Abstract

Self-administration of addictive substances like heroin can couple the rewarding/euphoric effects of the drug with drug-associated cues, and opioid cue reactivity contributes to relapse vulnerability in abstinent individuals recovering from an opioid use disorder (OUD). Opioids are reported to alter the intrinsic excitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a key brain reward region linked to drug seeking, but how opioids alter NAc MSN neuronal excitability and the impact of altered MSN excitability on relapse-like opioid seeking remain unclear. Here we discovered that self-administered, but not experimenter-administered, heroin reduced NAc protein levels of the voltage-gated sodium channel auxiliary subunit, SCN1b in male and female rats. Viral-mediated reduction of NAc SCN1b increased the intrinsic excitability of MSNs, but without altering glutamatergic and GABAergic synaptic transmission. While reducing NAc SCN1b levels had no effect on acquisition of heroin self-administration or extinction learning, we observed a significant increase in cue-reinstated heroin seeking, suggesting that NAc SCN1b normally limits cue-reinstated heroin seeking. We also observed that NAc SCN1b protein levels returned to baseline following heroin self-administration, home-cage abstinence, and extinction training, suggesting that the noted reduction of NAc SCN1b during acquisition of heroin self-administration likely enhances MSN excitability and the strength of heroin-cue associations formed during active heroin use. As such, enhancing NAc SCN1b function might mitigate opioid cue reactivity and a return to active drug use in individuals suffering from OUD.

Significance Statement Opioid use disorder (OUD) is a chronic, relapsing disease characterized by excessive craving. Here we found that repeated heroin self-administration reduced the expression of the sodium channel subunit, SCN1b, in the nucleus accumbens, a brain area important for reward signaling and addiction. We show here that reducing SCN1b increased excitability of NAc neurons and increased relapse-like drug seeking in a rodent model of opioid craving. The discovery of this novel mechanism of opioid action in the brain could help lead to future treatments for patients that suffer from OUD.