Short and long term plasticity after lesioning of the cell body or terminal field area of the dopaminergic mesocorticolimbic system in the rat.
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.
Department of Pharmacology, Rudolf Magnus Institute for Neurosciences, Faculty of Medicine, University of Utrecht, Utrecht, Netherlands. p.vos@czzoneu.azn.nl
P E
PE
Vos
H W
HW
Steinbusch
E
E
Ronken
J M
JM
van Ree
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
D018377:Neurotransmitter Agents; D010446:Peptide Fragments; C013765:Org 2766; D016627:Oxidopamine; D000324:Adrenocorticotropic Hormone; D001058:Apomorphine; D004298:Dopamine