Marked increase in anticonvulsant activity but decrease in wet-dog shake behaviour during short-term treatment of amygdala-kindled rats with valproic acid

https://doi.org/10.1016/0014-2999(88)90002-7Get rights and content

Abstract

The anticonvulsant activity of valproic acid (VPA) was determined in amygdala-kindled rats after single and repeated (total of 7 injections given 3 times per day) administration of 200 mg/kg i.p. After a single injection, VPA significantly reduced the severity and duration of the kindled seizures and increased the duration of after-discharges recorded from the stimulated amygdala, but only 12% of the animals were totally protected from seizures. The percentage of animals totally protected increased to 88% after 7 doses. This pronounced increase in the anticonvulsant activity was not related to alterations in the plasma concentrations of VPA or its major active metabolites. Furthermore, determination of VPA and its metabolites in the substantia nigra after a single and repeated administration yielded the same data, again indicating that the increase in the anticonvulsant activity was not due to drug accumulation. In contrast to the marked increase in the anticonvulsant efficacy of VPA during short-term treatment, wet-dog shake behaviour induced by a single injection of the drug was significantly attenuated after repeated dosing, indicating that the anticonvulsant effect of VPA and the wet-dog shake behaviour induced by the drug were not mediated by the same mechanism. This was substantiated by experiments with one of the major metabolites of VPA in rat plasma, trans-2-en-VPA, which had approximately the same anticonvulsant efficacy as VPA but did not induce wet-dog shakes in rats.

References (41)

  • W. Löscher et al.

    Effect of metabolites of valproic acid on the metabolism of GABA in brain and brain nerve endings

    Neuropharmacology

    (1981)
  • W. Löscher et al.

    Anticonvulsant efficacy of clonazepam and the β-carboline ZK 93423 duringchronic treatment in amygdala-kindled rats

    European J. Pharmacol.

    (1987)
  • W. Löscher et al.

    Is amygdala kindling in rats a model for drug-resistant partial epilepsy?

    Exp. Neurol.

    (1986)
  • W. Löscher et al.

    Pharmacological evaluation of various metabolites and analogues of valproic acid

    Neuropharmacology

    (1985)
  • H. Nau et al.

    Valproic acid and several metabolites: quantitative determination in serum, urine, breast milk and tissues by gas chromatography-mass spectrometry using selected ion monitoring

    J. Chromatogr.

    (1981)
  • R.J. Racine

    Modification of seizure activity by electrical stimulation. II. Motor seizure

    Electroenceph. Clin. Neurophysiol.

    (1972)
  • P.S. Albright et al.

    Development of a new pharmacological seizure model: effects of anticonvulsants on cortical- and amygdala-kindled seizures in the rat

    Epilepsia

    (1980)
  • A. Cowan

    RX 336-M, a new chemical tool in the analysis of the quasi-morphine withdrawal syndrome

  • A. Cowan et al.

    Lysergic acid diethylamide antagonizes shaking induced in rats by five chemically different compounds

    Psychopharmacology

    (1978)
  • Boer T. De et al.

    Di-n-propylacetate-induced abstinence behaviour as a possible correlate of increased GABA-ergic activity in the rat

    Psychopharmacology

    (1980)
  • Cited by (29)

    View all citing articles on Scopus
    View full text