Since the demonstration of dopamine-containing nerve terminals within cortical regions^1,2, studies have confirmed the existence of a dopaminergic projection to the medial prefrontal cortex^3,4. Cortical dopamine (DA) may be a functional neurotransmitter, as there are selective high-affinity receptor binding^5,6 and uptake sites^7,8 within this area, a DA-selective adenylate cyclase system^8,9, cells responsive to iontophoretically applied DA¹⁰, and a pool of DA amenable to release in vivo¹¹ or in vitro^12,13. Lesions of either midbrain cell bodies in the ventral tegmental area^14,15 or of frontal cortical areas directly¹⁶, with subsequent loss of DA terminals from the medial prefrontal cortex, induce hyperactivity in rats¹⁶, and enhanced behavioural responses to amphetamine^16,17. Lesion of subcortical DA pathways results in the opposite effects, suggesting that frontal cortical DA systems may have an inhibitory role in motor behaviour^15,16. Dopamine-dependent hyperactivity and stereotypy is believed to be mediated from extrapyramidal and mesolimbic DA-innervated sites¹⁸. We previously noted that loss of catecholamine terminals within the frontal cortex of the rat results in increased DA turnover and utilization in subcortical striatal and limbic regions after one week¹⁹. We now show evidence of both enhanced pre-synaptic and post-synaptic mechanisms in the terminal regions of the ascending nigrostriatal and mesolimbic DA pathways one month after destruction of DA terminals within the medial prefrontal cortex of the rat. The increased ³H-ADTN and ³H-spiperone binding, enhanced DA-induced stimulation of adenylate cyclase and potentiated uptake capacity for DA within striatum and nucleus accumbens may demonstrate a functional basis for the observed potentiated behavioural responses.