Unidirectional cross-tolerance from levetiracetam to carbamazepine in amygdala-kindled seizures.

PURPOSE: Tolerance is a potential problem in long-term anticonvulsant therapy of epilepsy, bipolar disorder, and neuropathic pain. The present study was designed to determine whether cross-tolerance occurs between levetiracetam (LEV) and carbamazepine (CBZ) in amygdala-kindled rats. METHODS: Male Sprague-Dawley rats were implanted with an electrode into the left amygdala. While kindling stimulation was started, animals received repeated treatment (i.p.) with saline (n = 7) or LEV (150 mg/kg, n = 8). Saline-injected rats were subsequently challenged with a single dose of 150 mg/kg LEV when full kindling developed (stage > or =4). Both groups of rats were then administered long-term CBZ (5 mg/kg) until rats developed complete tolerance. All CBZ-tolerant rats were subsequently re-exposed to LEV (150 mg/kg) for an additional 10 consecutive days. RESULTS: Repeated LEV treatment significantly suppressed the increase in seizure stage, seizure duration, and afterdischarge duration induced by amygdala stimulation, markedly increasing the number of stimulations to achieve a kindling major motor seizure. The LEV challenge produced a more robust suppression of seizure stage in saline-injected rats compared with LEV-treated animals. CBZ treatment markedly suppressed fully kindled seizures in rats initially injected with saline, and then anticonvulsant tolerance rapidly developed after 3-4 days of repeated treatment. In contrast, rats that had initially received repeated LEV treatment did not show a response to treatment with CBZ (5 mg/kg). When CBZ-tolerant rats were subsequently exposed to LEV (150 mg/kg), noticeable anticonvulsant effects were observed; but these were gradually lost with increasing numbers of LEV exposures. CONCLUSIONS: Whereas LEV shows potent antiepileptogenic and anticonvulsant effects in amygdala-kindled rats, its repeated treatment induces anticonvulsant tolerance and unidirectional cross-tolerance to CBZ. In contrast, anticonvulsant tolerance to CBZ does not transfer to LEV. The mechanistic implications of the present results for clinical therapeutics remain to be evaluated.

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.

The benzodiazepine partial inverse agonist Ro15-4513 alters anticonvulsant and lethal effects of carbamazepine in amygdala-kindled rats.

Ro15-4513 (ethyl-8-azido-5,6-dihydro-5methyl-6-oxo-4H-imidazo-[1,5-a]-1,4-benzodiazepine-3-carboxylate), a benzodiazepine partial inverse agonist of the GABA(A) receptor, is known to protect against alcohol toxicities. The present study was designed to determine the role of Ro15-4513 in preventing anticonvulsant, toxic, and lethal effects of carbamazepine (CBZ) in amygdala-kindled rats. Acute treatment with CBZ (25 mg/kg, i.p.) produced anticonvulsant effects in fully kindled rats characterized by a significant decrease in afterdischarge and seizure duration and stage. Repeated administration of this high dose of CBZ induced sedation and high (56%) lethality. The anticonvulsant and sedative effects of CBZ were strikingly suppressed by pretreatment with Ro15-4513 (2.5 and 5 mg/kg, i.p.), and there was no mortality in animals co-administrated with Ro15-4513 during the entire experimental period. These results indicate that Ro15-4513 protects against CBZ-induced sedation and lethality, while suppressing the anticonvulsant effects of CBZ, suggesting a role for the GABA(A) receptor in CBZ efficacy and side effects. The potential clinical implications for CBZ-induced toxicity and overdose remain to be explored.