Effects of Two Convulsant β‐Carboline Derivatives, DMCM and β‐CCM, on Regional Neurotransmitter Amino Acid Levels and on In Vitro D‐[3H]Aspartate Release in Rodents

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Abstract
Clonic seizures were induced in Swiss or DBA/2 mice by methyl‐6‐7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), 0.048 mmol/kg i.p., or by methyl‐β‐carboline‐3‐carboxylate (β‐CCM), 0.044 mmol/kg i.p. Measurement of regional brain (cortex, hippocampus, striatum, and cerebellum) amino acid levels after 15 min of seizure activity showed increases in γ‐aminobutyric acid (GABA) (in all regions after β‐CCM, and in cortex and hippocampus after DMCM), and an increase in glycine in the striatum after β‐CCM. Aspartate levels fell (in cortex and hippocampus) after DMCM, but were unchanged in all regions after β‐CCM. Glutamate levels fell in cortex after β‐CCM and in striatum after DMCM. Pretreatment with the excitatory amino acid receptor antagonist, 2‐amino‐7‐phosphonoheptanoic acid, 0.5 mmol/kg i.p., 45 min prior to the β‐carboline, significantly increased the ED50 for DMCM‐induced clonic seizures (4.68 μmol/kg vs. 9.39 μmol/kg). Similar pretreatment did not significantly alter the ED50 for β‐CCM (4.22 μmol/kg vs. 6.6 μmol/kg). Pretreatment with 2‐amino‐7‐phosphonoheptanoic acid, 1.0 mmol/kg, blocked the increase in GABA content produced by DMCM but not the fall in cortical aspartate content. Potassium‐induced release of preloaded D‐[3H]aspartate from rat cortical or hippocampal minislices was enhanced in the presence of DMCM (100 μM). In contrast, stimulated release of D‐[3H]aspartate (from cortex or hippocampus) was not altered in the presence of β‐CCM (100 μM). Although DMCM and β‐CCM are both considered to induce convulsion by acting at the GABA‐benzodiazepine receptor complex, the convulsions differ in several pharmacological and biochemical respects. It is suggested that enhanced release of excitatory amino acid neurotransmitters plays a more important role in seizures induced by DMCM.