Rats were trained to bar-press for intravenous infusions of morphine sulfate during 1-h daily test sessions. Rates of morphine self-administration were enhanced by lesions of the frontal cortex and hippocampus and transiently reduced by lesions of the medial forebrain bundle and medial thalamus. Dose-response studies indicated that sensitivity to morphine's rewarding property was decreased by frontal cortical and hippocampal lesions. Lesions of the posterior cortex, the tuberculum olfactorium, and the nucleus accumbens had no effect on self-administration behavior. The results are discussed in relation to previous findings with caudate and brainstem lesions. A neuroanatomical substrate for morphine reinforcement is suggested.