Methadone self-administration substitution tests and methadone-triggered reinstatement of drug-seeking behavior. (a) Representative records of heroin (0.05 mg/kg per infusion) self-administration plus methadone (0.1 mg/kg per infusion) self-administration (SA) over a span of seven consecutive daily replacement tests. (b) Mean self-administration rate during heroin, methadone, or vehicle self-administration testing. (c) Methadone (1, 2, 3, or 5 mg/kg, s.c.) failed to reinstate heroin-seeking behavior, whereas heroin (0.25 mg/kg, s.c.) induced reinstatement of heroin-seeking behavior. *p<0.05, **p<0.01, ***p<0.001, compared with the last day of heroin self-administration in b or the vehicle control group in c. ##p<0.01, ###p<0.001, compared with the last day of methadone self-administration testing in b.