Time course of recovery of extracellular dopamine following partial damage to the nigrostriatal dopamine system

Abstract

Partial damage to the nigrostriatal dopamine (DA) system can produce severe behavioral deficits, from which animals gradually recover. Although the compensatory neuroadaptations that contribute to recovery of function have received considerable attention, the exact role of presynaptic versus postsynaptic contributions remains unclear. For example, it has been suggested that presynaptic adaptations may not be sufficient to account for recovery of function, because compensatory increases in DA biosynthesis, metabolism, and release are maximal within 3 d following a unilateral 6-hydroxydopamine (6-OHDA) lesion, before behavioral recovery is complete. The purpose of this study was to examine another presynaptic adaptation, the normalization of extracellular DA. If this is also complete within 3 d postlesion, it, too, would be insufficient to account for the protracted time course of behavioral recovery. But if the normalization of extracellular DA proceeds more gradually, it could potentially account for the time course behavioral recovery. To address this issue, the extracellular concentration of striatal DA ipsilateral and contralateral to a unilateral 6-OHDA lesion was estimated with microdialysis, either 4 d or 3-4 weeks following the lesion. After estimating the basal extracellular concentration of DA, the ability to increase DA release further was assessed by administering an amphetamine challenge. It was found that in animals with a 6-OHDA lesion, the concentration of DA in dialysate was higher than would be predicted by the extent of DA denervation. Furthermore, in groups matched for lesion size, extracellular DA was significantly higher 3-4 weeks following a 6-OHDA lesion than 4 d following the lesion. These findings suggest that the normalization of extracellular DA may be a relatively gradual process, and therefore may be sufficient to account for the protracted time course of behavioral recovery.