Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures

Pharmacol Biochem Behav. 2003 Feb;74(3):565-71. doi: 10.1016/s0091-3057(02)01035-3.

Abstract

The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / administration & dosage*
  • Amines*
  • Animals
  • Anticonvulsants / administration & dosage
  • Cyclohexanecarboxylic Acids*
  • Dizocilpine Maleate / administration & dosage*
  • Drug Therapy, Combination
  • Drug Tolerance / physiology
  • Gabapentin
  • Kindling, Neurologic / drug effects*
  • Kindling, Neurologic / physiology
  • Lamotrigine
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy*
  • Seizures / physiopathology
  • Triazines / administration & dosage*
  • gamma-Aminobutyric Acid*

Substances

  • Acetates
  • Amines
  • Anticonvulsants
  • Cyclohexanecarboxylic Acids
  • Triazines
  • gamma-Aminobutyric Acid
  • Gabapentin
  • Dizocilpine Maleate
  • Lamotrigine