Role of SK3 channels in the nucleus accumbens core in modulating opioid-induced addiction behaviors.

Opioid addiction remains a critical public health challenge, yet the underlying neurobiological mechanisms remain incompletely understood. This study investigated the role of small-conductance calcium-activated potassium (SK) channels in the nucleus accumbens core (NAcC) in opioid-related behaviors. Using conditioned place preference (CPP) and intravenous self-administration (IVSA) models in mice, we observed a reduction in the excitability of NAcC medium spiny neurons (MSNs) concomitant with an increase in SK3 channel expression and SK-mediated currents during morphine-induced CPP. Pharmacological activation of SK channels with 1-EBIO enhanced morphine CPP, whereas blockade with apamin attenuated it. Viral-mediated SK3 overexpression in NAcC potentiated both morphine CPP and heroin IVSA, while SK3 knockdown suppressed these behaviors. Electrophysiological recordings confirmed that SK3 modulation bidirectionally regulated MSN excitability and medium afterhyperpolarization (mAHP). These findings demonstrate that SK3 channels in NAcC critically regulate opioid reward and reinforcement by modulating neuronal excitability, suggesting SK3 channel as a potential therapeutic target for opioid addiction.