The “incubation” of drug craving is a phenomenon whereby cue-induced drug-seeking progressively increases over time during withdrawal. After rats undergo repeated self-administration sessions (for instance, 6 h of cocaine self-administration daily for 10 days), during which cocaine is associated with discrete cues, subsequent cue-induced drug-seeking (nonreinforced responding on the previously active lever) increases over time. Responses are significantly higher after 30 days of cocaine withdrawal than after short-term withdrawal (1–7 days).47,50 This time-dependent increase in responding is associated with increased p-ERK in the central amygdala47 and increased levels of BDNF in the VTA, NAc, and amygdala.50 These increases in BDNF and p-ERK appear to facilitate drug seeking. Thus, BDNF infusions into the VTA increase cue-induced drug seeking for up to 30 days after cocaine withdrawal.51 This effect of BDNF is ERK dependent since it is reversed by intra-VTA infusions of the MEK inhibitor U0126.51 Even in the absence of BDNF infusion, U0126 injections into the central amygdala decrease drug seeking during cocaine withdrawal,47 indicating that ERK activity in the central amygdala is required for drug-seeking during cocaine withdrawal.47 This requirement
