Membrane excitability of nucleus accumbens neurons gates the incubation of cocaine craving.

After drug withdrawal, a key factor triggering relapse is progressively intensified cue-associated drug craving, termed incubation of drug craving. After withdrawal from cocaine self-administration, incubation of cocaine craving develops more reliably in rats compared to mice. This species difference provides an opportunity to determine rat-specific cellular adaptations, which may constitute the critical mechanisms that contribute to incubated cocaine craving in humans. Expression of incubated cocaine seeking is mediated, in part, by cocaine-induced cellular adaptations in medium spiny neurons (MSNs) within the nucleus accumbens (NAc). In rats, decreased membrane excitability in NAc MSNs is a prominent cellular adaptation, which is induced after cocaine self-administration and lasts throughout prolonged drug withdrawal. Here, we show that, similar to rats, mice exhibit decreased membrane excitability of dopamine D receptor (D1)-, but not D (D2)-, expressing MSNs within the NAc shell (NAcSh) after 1 d withdrawal from cocaine self-administration. However, in contrast to rats, this membrane adaptation does not persist in mice, diminishing after 45-d withdrawal. We also find that restoring the membrane excitability of NAcSh MSNs after cocaine withdrawal decreases cocaine seeking in rats. This suggests that drug-induced membrane adaptations are essential for behavioral expression of incubated cocaine craving. In mice, however, experimentally inducing hypoactivity of D1 NAcSh MSNs after cocaine withdrawal does not alter cocaine seeking, suggesting that MSN hypo-excitability alone is insufficient to increase cocaine seeking. Together, our results demonstrate an overall permissive role of cocaine-induced hypoactivity of NAcSh MSNs in gating increased cocaine seeking after prolonged cocaine withdrawal.