Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis

Abstract

The autoregulation of dopamine release and metabolism by intrastriatal grafts of mesencephalic dopamine neurons was examined in vivo using an intracerebral dialysis technique. Dopamine-rich cell suspension grafts were implanted into the head of the caudate putamen in rats with complete unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. Six months later behavioural tests indicated that the grafts had reversed the lesion-induced rotational behaviour. Extracellular levels of striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were monitored bilaterally in the halothane-anaesthetized grafted rat, both under basal conditions, and also following low (0.05mg/kg) and high (0.5mg/kg) doses of the dopamine receptor agonist apomorphine. The perfusate from the grafted striatum showed levels of dopamine which were not statistically different from those of the intact contralateral striatum, indicating that the baseline release of dopamine from the graft was close to normal. Similarly, 3-4-dihydroxyphenylacetic acid and homovanillic acid levels were well recovered on the grafted side (67% and 52%, respectively, of control values). Consistent with previous observations, levels of the serotonin metabolite 5-hydroxyindoleacetic acid measured in perfusate collected from the grafted side was elevated significantly above normal. Subsequent histological analysis revealed large grafts, rich in dopamine-containing neurons (mean ± SEM number equalled 3138 ± 630), giving rise to an approximately normal density of dopamine-containing fibres in the area of the host caudate putamen surrounding the probe. Treatment with 0.05 mg/kg (subcutaneous) apomorphine did not affect extracellular dopamine recovered from the grafted striatum, while extracellular DA decreased by a maximum of 30% on the intact side. However, a subsequent injection of 0.5 mg/kg apomorphine produced a large decrease of the dopamine recovered from both the grafted (maximum 40% decrease) and intact striata (maximum 80% decrease). Both the low and the high dose of apomorphine reduced extracellular dopamine metabolite levels, a response which was essentially similar for both the intact and grafted sides. Finally, the dopamine reuptake blocker nomifensine (10 −5M) added to the perfusion medium produced similar large increases in dopamine in perfusates collected from both grafted and intact striata, while 3,4-dihydroxyphenylacetic acid and homovanillic acid did not change. The results indicate that the dopamine-receptor-mediated autoregulatory control and dopamine reuptake, which normally operate in the nigrostriatal dopamine pathway, are also functioning in the intrastriatal nigral grafts although dopamine release from grafted neurons is less sensitive to apomorphine treatment. It is proposed that dopamine autoregulation and negative feedback is an important physiological mechanism for tonic regulation of dopamine graft function, and that this may be sufficient for the reinstatement of motoric and sensorimotoric behaviour by intrastriatal nigral grafts.