Experimental hemiparkinsonism in the rat following chronic unilateral infusion of MPP+ into the nigrostriatal dopamine pathway--I. Behavioural, neurochemical and histological characterization of the lesion.
1-Methyl-4-phenylpyridinium ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, has been chronically infused (10 micrograms/24 h for 7 days) via osmotic minipumps into the left median forebrain bundle of the rat in order to determine whether it can induce permanent damage to the nigrostriatal dopamine system. Its effects were assessed over a period of 6 months post lesion. Four to 5 days following minipump implantation, all MPP+-treated animals displayed spontaneous ipsilateral postural bias indicating a marked imbalance in striatal dopamine and degeneration of the ipsilateral nigrostriatal dopamine pathway. After 3-5 weeks, MPP+-infused animals showed dose-related ipsilateral and contralateral circling in response to methamphetamine (1-5 mg/kg i.p.) and apomorphine (0.05-0.25 mg/kg s.c.) respectively. In vivo, using bilateral monitoring of striatal dopamine in MPP+-infused animals at 2 and 4 months by push-pull perfusion, both basal and methamphetamine- (2.5 mg/kg i.p.) stimulated release of dopamine was undetectable in the ipsilateral striatum, indicating a complete loss of dopamine terminals. In contrast, in the contralateral striatum of these animals and in striata of saline-infused animals, there were 4-5-fold increases in dopamine release in response to methamphetamine. Six months after lesion, animals infused with MPP+ continue to exhibit robust rotational behaviour in response to methamphetamine and apomorphine. In the ipsilateral striatum of the MPP+-infused animals the tissue concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were all undetectable; however, the levels of noradrenaline, serotonin and its metabolite, 5-hydroxyindoleacetic acid, were not significantly different from control values. In contrast to the striatum, MPP+ had no significant effect on the levels of dopamine and its metabolites in the ipsilateral nucleus accumbens; in addition, the levels of noradrenaline and serotonin and its metabolite were comparable to control levels. Histological examination revealed a marked loss of cells and severe gliosis in the substantia nigra pars compacta of MPP+-infused animals. The present results provide evidence that direct infusion of MPP+ into the medial forebrain bundle of the rat can lead to a complete loss of dopamine neurons in the pars compacta of the substantia nigra with ensuing behavioural, neurochemical and biochemical changes characteristic of the lesion.(ABSTRACT TRUNCATED AT 400 WORDS)
Sirinathsinghji
D J
DJ
Department of Neuroendocrinology, AFRC Institute of Animal Physiology and Genetics Research, Babraham, Cambridge, U.K.
Heavens
R P
RP
Richards
S J
SJ
Beresford
I J
IJ
Hall
M D
MD
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007839:Functional Laterality; D008694:Methamphetamine / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D011187:Posture; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
D011726:Pyridinium Compounds; D008694:Methamphetamine; D001058:Apomorphine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine