Conditioned rewarding effects of morphine and methadone in mice pre-exposed to cocaine

Methadone is widely accepted as the most effective treatment of opioid dependence. However, clinical observations indicate that the medication is less effective in individuals abusing cocaine. Diminished therapeutic efficacy of methadone in cocaine users is intriguing, but its mechanism has not been studied. Here, the conditioned place preference (CPP) procedure was used to examine the effects of the dose, number of conditioning sessions and pre-exposure to cocaine on the rewarding effects of morphine and methadone. Vehicle-pre-exposed and cocainesensitized mice (five injections of 10mg/kg over 16 days) were conditioned using methadone (0, 0.1, 0.5, 3, and 5mg/kg) or morphine (0, 1, and 10mg/kg). Place preference was measured after one and again after two additional conditioning sessions. As expected, morphine at 10mg/kg produced CPP following just one conditioning session. While a single conditioning session with 1mg/kg of morphine produced no CPP, the rewarding effect became apparent following two additional conditioning sessions as well as in mice pre-exposed to cocaine. Methadone produced CPP following one conditioning session at doses of 0.5, 3 and 5mg/kg. However, unlike with morphine, methadone's rewarding effect was not enhanced by two additional conditioning sessions or by pre-exposure with cocaine. Prior exposure to cocaine increases unconditioned motivational effects of morphine but not of methadone.