Effects of two convulsant beta-carboline derivatives, DMCM and beta-CCM, on regional neurotransmitter amino acid levels and on in vitro D-[3H]aspartate release in rodents.
Clonic seizures were induced in Swiss or DBA/2 mice by methyl-6-7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), 0.048 mmol/kg i.p., or by methyl-beta-carboline-3-carboxylate (beta-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 gamma-aminobutyric acid (GABA) (in all regions after beta-CCM, and in cortex and hippocampus after DMCM), and an increase in glycine in the striatum after beta-CCM. Aspartate levels fell (in cortex and hippocampus) after DMCM, but were unchanged in all regions after beta-CCM. Glutamate levels fell in cortex after beta-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 beta-carboline, significantly increased the ED50 for DMCM-induced clonic seizures (4.68 mumol/kg vs. 9.39 mumol/kg). Similar pretreatment did not significantly alter the ED50 for beta-CCM (4.22 mumol/kg vs. 6.6 mumol/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 microM). In contrast, stimulated release of D-[3H]aspartate (from cortex or hippocampus) was not altered in the presence of beta-CCM (100 microM). Although DMCM and beta-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.
Chapman
A G
AG
Cheetham
S C
SC
Hart
G P
GP
Meldrum
B S
BS
Westerberg
E
E
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000032:analysis* / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000032:analysis; D001923:Brain Chemistry / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology*; D002531:Cerebellum / Q000032:analysis; D002540:Cerebral Cortex / Q000032:analysis; D003292:Convulsants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005973:Glutamine / Q000032:analysis; D006624:Hippocampus / Q000032:analysis; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018377:Neurotransmitter Agents / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D000596:Amino Acids; D002243:Carbolines; D003292:Convulsants; D007211:Indoles; D018377:Neurotransmitter Agents; D005973:Glutamine; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; D015763:2-Amino-5-phosphonovalerate; C036150:beta-carboline-3-carboxylic acid methyl ester; C031231:2-amino-7-phosphonoheptanoic acid