Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09-1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.