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  • Title: Kindled rats are more sensitive than non-kindled rats to the behavioural effects of combined treatment with MK-801 and valproate.
    Author: Dziki M, Hönack D, Löscher W.
    Journal: Eur J Pharmacol; 1992 Nov 10; 222(2-3):273-8. PubMed ID: 1360405.
    Abstract:
    The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.
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