Behavioural and convulsant actions of two methyl esters of beta-carboline-3-carboxylic acid in photosensitive baboons and in DBA/2 mice.
The proconvulsant and convulsant actions of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and of methyl-beta-carboline-3-carboxylate (beta-CCM) have been evaluated in two animal models of reflex epilepsy, the photosensitive baboon, Papio papio, and the audiogenic seizure prone DBA/2 mouse. In baboons, myoclonic responses to photic stimulation are markedly enhanced 1 min after DMCM, 0.25 mg/kg i.v. In the absence of photic stimulation DMCM, 0.5 mg/kg i.v. induces a single brief tonic clonic seizure within 10-90 s. beta-CCM, 0.025-0.05 mg/kg i.v. similarly enhances myoclonic responses to photic stimulation. Generalised seizures occur without photic stimulation 0.5-3 min after beta-CCM, 0.1-0.2 mg/kg. Pretreatment with the excitatory amino acid antagonist, 2-amino-7-phosphonoheptanoic acid (2-APH), 110 mg/kg i.v., prevents the generalised seizures induced by DMCM, 0.5 mg/kg, but not those induced by beta-CCM, 0.1-0.2 mg/kg. In DBA/2 mice beta-CCM and DMCM are indistinguishable in potency as convulsants (ED50 values for clonic seizures: 4.4 and 4.6 mg/kg i.p. respectively) and as proconvulsants (ED50 values for facilitation of clonic seizure responses to an 83 dB sound stimulus: 0.25 and 0.23 mg/kg). Pretreatment with 2-APH gives equipotent protection against audiogenic seizures induced by beta-CCM, 1 mg/kg or DMCM, 1 mg/kg. The differences in relative potency of beta-CCM and DMCM in the two species are probably accountable for in terms of differing metabolism. A differential action of the two beta-carbolines on receptor subtypes, with enhancement of excitatory amino acid release playing a more important role in epileptogenesis after DMCM, is proposed.