β-Endorphin via the Delta Opioid Receptor is a Major Factor in the Incubation of Cocaine Craving

Cue-induced cocaine craving intensifies, or 'incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid beta-endorphin. In the present study, we examined the possible involvement of beta-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in beta-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while beta-endorphin levels remained unchanged. Intra-NAc infusion of an anti-beta-endorphin antibody (4 mu g) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic beta-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the delta opioid receptor antagonist naltrindole (1 mu g) on day 1 and naltrindole together with beta-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the m opioid receptor antagonist CTAP (30 ng and 3 mu g) had no behavioral effect. Altogether, these results demonstrate a novel role for beta-endorphin and the delta opioid receptor in the development of the incubation of cocaine craving.