Behavioral evaluation of the anti-excitotoxic properties of MK-801: comparison with neurochemical measurements.
The ability of MK-801 to protect striatal neurons from the excitotoxic action of quinolinic acid was evaluated by means of apomorphine-induced rotational behavior and by measurement of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activity, neurochemical markers for cholinergic and GABAergic neurons, respectively. Animals with a unilateral quinolinic acid lesion of the striatum exhibited a vigorous rotational response when challenged with apomorphine (0.5 mg/kg, s.c.) 6 days later and were found to have an 88 90% depletion of striatal ChAT and GAD activity. Treatment with a high dose of MK-801 (10 mg/kg, i.p.) prior to intrastriatal injection of quinolinic acid eliminated the subsequent rotational response to apomorphine and resulted in complete protection of striatal ChAT and GAD activity. Lower doses of MK-801 (1, 3 and 5 mg/kg, i.p.) failed to significantly reduce the rotational response to apomorphine but provided partial, dose-dependent protection of both ChAT and GAD activity. The rotational response to apomorphine correlated with the percent reduction in both ChAT activity (r = 0.57, P less than 0.0005) and GAD activity (r = 0.49, P less than 0.0005). Rotational behavior may thus provide a means to evaluate the functional integrity of the striatum.
Susel
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Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
Engber
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TM
Chase
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D000818:Animals; D000927:Anticonvulsants; D001058:Apomorphine / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D003986:Dibenzocycloheptenes / Q000494:pharmacology* / Q000627:therapeutic use; D016291:Dizocilpine Maleate; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D011725:Pyridines / Q000037:antagonists & inhibitors*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013239:Stereotyped Behavior / Q000187:drug effects*
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D011725:Pyridines; D011805:Quinolinic Acids; D016291:Dizocilpine Maleate; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid; D001058:Apomorphine