Ontogenic profile of seizures evoked by the beta-carboline DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in rats

Abstract

The beta-carboline, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), is a potent chemoconvulsant. While it has been utilized in adult rodents, it has not been previously examined for effects across postnatal development. DMCM is a negative allosteric modulator of benzodiazepine-sensitive GABAA receptors, receptor subtypes that are particularly enriched in limbic brain regions. This raises the possibility that DMCM may be particularly effective at evoking forebrain seizures, which is a challenge in neonatal animals due to the relative immaturity of the forebrain seizure network. The ability to selectebrain seizures is desirable when screening for drugs to use in temporal lobe epilepsy, which is characterized by seizures within the forebrain (limbic) network. To determine the profile of DMCM action across development, we examined the dose-dependent ability of DMCM to induce seizures in rats at P7, P10, P13, P14, P21 and in adulthood. We found that the highest sensitivity to DMCM occurred in P10, P13, and P14 rats. The lowest sensitivity occurred in P21 rats. Neonatal (P7) and adult (P60+) rats displayed moderate sensitivity. With moderate (0.2–0.4mg/kg) doses of DMCM, we were able to reliably evoke limbic motor seizures without tonic–clonic components in animals as young as P7. These data support the utility of DMCM in assessing seizure threshold during development and raise the possibility for future exploration of DMCM as an agent to screen anticonvulsant drugs during the postnatal period.