Vos P E, Steinbusch H W, Ronken E, van Ree J M
Department of Pharmacology, Rudolf Magnus Institute for Neurosciences, Faculty of Medicine, University of Utrecht, Utrecht, Netherlands.
Brain Res. 1999 Jun 12;831(1-2):237-47. doi: 10.1016/s0006-8993(99)01453-5.
To investigate within one study regenerative capacities of dopaminergic axons and cell bodies, short and long term recovery of behavioral and biochemical impairments following a bilateral 6-hydroxydopamine (6-OHDA) lesion of the ventral tegmental area (VTA)-nucleus accumbens (NAc) pathway was investigated in rats. Novelty-induced motility, presynaptic functions and the levels of dopamine (DA) and its metabolites were reduced when cell bodies in the VTA or axons in the NAc were lesioned. Spontaneous recovery of the behavioral deficit was observed 4 weeks after a lesion of the NAc. Subsequently presynaptic functions recovered as shown by the reappearance of low dose apomorphine (50 mg/kg)-induced hypomotility, normalization of [(3)H]dopamine uptake, reinnervation of the NAc and normalization of levels of DA and its metabolites within 24 weeks. In contrast, after a VTA lesion no recovery was observed during 48 weeks, neither from hypomotility and loss of the low dose apomorphine response nor from decreased [(3)H]dopamine uptake and levels of DA in the NAc. Short term postsynaptic supersensitivity (hypermotility upon a higher dose of apomorphine (125 mg/kg)) was present 1 and 4 weeks after the lesion but not thereafter. A near total absence of dopaminergic neurons in the VTA and axons in the NAc were found 24 weeks postlesion. Treatment with the ACTH-(4-9) analog ORG 2766 (10 mg/kg s.c., 6 days once daily) facilitated recurrence of presynaptic functions after a lesion of axons but had no short or long term effect when cell bodies were lesioned. These findings substantiate the postulate that the peptide facilitates recovery processes.
为了在一项研究中探究多巴胺能轴突和细胞体的再生能力，对大鼠腹侧被盖区（VTA）-伏隔核（NAc）通路进行双侧6-羟基多巴胺（6-OHDA）损伤后，研究行为和生化损伤的短期和长期恢复情况。当VTA中的细胞体或NAc中的轴突受损时，新奇诱导的运动能力、突触前功能以及多巴胺（DA）及其代谢产物的水平会降低。NAc损伤后4周观察到行为缺陷的自发恢复。随后，突触前功能恢复，表现为低剂量阿扑吗啡（50 mg/kg）诱导的运动减少再次出现、[³H]多巴胺摄取正常化、NAc重新神经支配以及24周内DA及其代谢产物水平正常化。相比之下，VTA损伤后48周内未观察到恢复，既没有从运动减少和低剂量阿扑吗啡反应丧失中恢复，也没有从NAc中[³H]多巴胺摄取减少和DA水平降低中恢复。损伤后1周和4周出现短期突触后超敏反应（高剂量阿扑吗啡（125 mg/kg）时运动增加），但此后没有。损伤后24周发现VTA中几乎完全没有多巴胺能神经元，NAc中也几乎没有轴突。用促肾上腺皮质激素-（4-9）类似物ORG 2766（10 mg/kg皮下注射，每天一次，共6天）治疗可促进轴突损伤后突触前功能的恢复，但当细胞体受损时没有短期或长期影响。这些发现证实了该肽促进恢复过程的假设。
