Degeneration of pre-labelled nigral neurons induced by intrastriatal 6-hydroxydopamine in the rat: behavioural and biochemical changes and pretreatment with the calcium-entry blocker nimodipine.
Intrastriatal application of 6-hydroxydopamine (6-OHDA) initiates a delayed and progressive loss of nigral dopaminergic neurons and therefore may better resemble the slowly developing neuropathology of Parkinson's disease. We investigated the anatomical, behavioural and biochemical consequences of intrastriatal 6-OHDA after prior labelling of nigral dopaminergic neurons in rats and whether the dihydropyridine L-type calcium channel blocker nimodipine protected from the induced deficits. Adult rats received bilateral intrastriatal injections of the retrograde fluorescence tracer fluorogold and nimodipine (n=12) or placebo (n=9) pellets implanted subcutaneously. One week later all rats were injected unilaterally with 6-OHDA (20 microg) at the same intrastriatal site. Placebo-treated rats displayed relatively few d-amphetamine-induced ipsilateral net rotations (R) (1.3+/-1.4 R/min; mean+/-SEM) 1 week after the lesion with a slight but non-significant decline thereafter (after 2, 3 and 4 weeks). In nimodipine-treated rats the rotation behaviour after 1 week was more prominent (3.5+/-0.8 R/min; mean+/-SEM) with a similar slight decline until week 4. Fluorescent and immunocytochemical analysis of the midbrain after 4 weeks revealed a 35% and 39% loss of tyrosine hydroxylase positive cells and a 62% and 56% (placebo and nimodipine, respectively) loss of fluorogold-labelled cells in the ipsilateral substantia nigra pars compacta. Striatal dopamine levels were reduced to 47% (placebo) and 43% (nimodipine) of the control side and the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to about 50%. Pretreatment with nimodipine failed to antagonize or to ameliorate any of the lesion-induced deficits. We conclude that pretreatment with 80 mg nimodipine pellets does not prevent nigrostriatal damage induced by intrastriatal 6-OHDA.
Sautter
J
J
Klinikum Grosshadern, University of Munich, Department of Neurology, Germany.
Kupsch
A
A
Earl
C D
CD
Oertel
W H
WH
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007267:Injections; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology*; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013565:Sympatholytics / Q000008:administration & dosage / Q000633:toxicity*
D002121:Calcium Channel Blockers; D013565:Sympatholytics; D009553:Nimodipine; D016627:Oxidopamine; D004298:Dopamine