The present study was performed in order to establish whether dopamine (DA) release from behaviorally functional intracerebral DA transplants is dependent on changes in neuronal impulse flow, and is under control of the host brain. Rats were subjected to combined intraventricular and ventral tegmental injections of 6-hydroxydopamine (6-OHDA) in order to obtain a severe bilateral lesion of the ascending mesocorticolimbic DA projections. Cell suspension grafts of fetal ventral mesencephalic neurons were thereafter implanted into the medial frontal cortex (MFC) and the nucleus accumbens (NAc). Since the neurotoxin injections removed also the ascending noradrenergic systems, fetal locus coeruleus neurons were added to the graft suspension in one group of animals. Age-matched lesion-only and normal animals served as controls. The lesion-induced alterations in spontaneous, amphetamine- and apomorphine-induced locomotor activity and in a skilled paw reaching task were evaluated before transplantation, and at 3 and 6 months post-grafting. Microdialysis probes were finally implanted in the MFC and NAc in order to monitor extracellular DA and noradrenaline (NA) levels ( i) during administration of pharmacological agents which augment or depress catecholamine release in the intact brain; ( ii) during exposure of the rats to stressful manipulations ( handling and immobilization) or appetitive stimuli ( eating) known to enhance cortical and limbic DA or NA release in intact animals. The lesion-induced reduction in amphetamine-induced locomotor activity was reversed in all grafted animals, which also showed a higher than normal spontaneous overnight activity. Daytime spontaneous locomotor activity (which was reduced in the lesion-only rats) as well as apomorphine-induced hyperactivity was reversed by the grafts of DA neurons only. By contrast, the lesion-induced impairment in skilled forelimb use was not alleviated by the grafts. The grafted DA neurons restored normal steady-state DA overflow in the NAc, whereas they enhanced cortical DA overflow to significantly higher than normal levels. Restoration of both cortical and striatal NA overflow was observed in the group that received mixed DA and NA grafts, whereas animals that received DA grafts only did not differ from the lesioned controls. The changes in extracellular DA and NA levels measured in the grafted MFC and NAc under potassium depolarization (100 mM KCl), inhibition of terminal catecholamine reuptake (10 μM nomifensine), and sodium channel blockade (1 μM TTX) indicated that graft-derived DA or NA release had normal neuronal properties, and was dependent on an intact axonal impulse flow. The grafted DA and NA neurons lacked the ability to respond to immobilization stress with enhanced transmitter release. However, most of the animals that received DA grafts exhibited an enhanced DA overflow in the NAc following handling stimulation. When the animals were engaged in eating, a significant 20% increase in DA overflow was detected in the grafted cortices, and a marginally significant 58% increase in DA overflow was measured in the DA-grafted NAc. By contrast, neither cortical nor accumbens DA overflow was significantly affected during eating behavior in the lesion-only controls. NA overflow from the grafted locus coeruleus neurons was also unaffected by the appetitive stimulus. The present results indicate that DA or NA release from intracortically and intrastriatally grafted DA and NA neurons is dependent on changes in axonal impulse flow. The findings of enhanced DA release from intracortically grafted DA neurons during eating and from intrastriatally grafted DA neurons during rewarded behavior and handling stimulation, suggest that the transplanted DA neurons are reached by physiologically relevant inputs from the host brain. On the other hand, the lack of response to forced immobilization (i.e. a stimulus which is normally a powerful activator of cortical DA release), reveals that the functional integration of the grafted DA neurons with the host brain is incomplete.