The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural subtrates are responsible for the reinforcing actions of these two drugs.