Abstract:
:The glutamatergic cortico-striatal and subthalamo-entopeduncular pathways are both overactive in parkinsonism. Previous behavioural investigations have shown that intra-entopeduncular injection of either NMDA-site or glycine-site antagonists results in alleviation of parkinsonian symptoms, although injection of the former is associated with the appearance of anaesthetic-like side effects. These behavioural differences may be mediated by action on different NMDA receptor subtypes. Recent neurochemical and molecular pharmacological studies have indicated the existence of NMDA receptor subtypes which display differential modulation by glycine. In the present study, three potential modes of NMDA antagonism were differentiated in vitro by effects on [3H]-glycine binding to striatal sections. Specific [3H]-glycine binding was totally displaced by the glycine partial agonist (R)-HA-966; the NMDA-site antagonist D-CPP had no effect; and the NMDA-site antagonist D-AP5 displaced [3H]-glycine binding in a subpopulation of glycine sites. The anti-parkinsonian effects of (R)-HA-966, D-CPP and D-AP5 were assessed by intra-striatal injection in reserpine-treated rats and 6-OHDA-lesioned rats. Injection of (R)-HA-966 and D-CPP resulted in alleviation of parkinsonian akinesia, although the latter elicited anaesthetic-like side effects; D-AP5 was ineffective as an anti-parkinsonian agent. (R)-HA-966 was also effective as an anti-parkinsonian agent when administered systemically in the reserpine-treated rat. These data suggest that different classes of NMDA antagonist mediate different behavioural responses within the parkinsonian striatum. The behavioural response produced may depend on the exact nature of the conformational change induced by the antagonist and the location of the subtype most sensitive to that class of compound. Selection of a specific mode of NMDA receptor antagonism or targeting of striatal NMDA receptor subtypes may form the basis of a novel therapeutic approach to Parkinson's disease.
journal_name
Psychopharmacology (Berl)journal_title
Psychopharmacologyauthors
Carroll CB,Holloway V,Brotchie JM,Mitchell IJdoi
10.1007/BF02246054subject
Has Abstractpub_date
1995-05-01 00:00:00pages
55-65issue
1eissn
0033-3158issn
1432-2072journal_volume
119pub_type
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更新日期:1976-05-05 00:00:00
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更新日期:2014-05-01 00:00:00
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更新日期:2016-05-01 00:00:00
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更新日期:1984-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:1991-01-01 00:00:00
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journal_title:Psychopharmacology
pub_type: 杂志文章
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更新日期:2020-06-01 00:00:00