Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures.
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.
Zhang
Zhang-Jin
ZJ
Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. zzhang1@usuhs.mil
Russell
Shani
S
Obeng
Kris
K
Postma
Terri
T
Obrocea
Gabriela
G
Weiss
Susan R B
SR
Post
Robert M
RM
D000085:Acetates / Q000008:administration & dosage*; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage; D003509:Cyclohexanecarboxylic Acids; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D004361:Drug Tolerance / Q000502:physiology; D000077206:Gabapentin; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D000077213:Lamotrigine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D014227:Triazines / Q000008:administration & dosage*; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D016291:Dizocilpine Maleate; D000077213:Lamotrigine