Transmitter synthesis and convulsant drugs: Effects of pyridoxal phosphate antagonists and allylglycine

Abstract

Glutamic acid decarboxylase (GAD) activity in mouse brain homogenates was inhibited after intraperitoneal administration of convulsant doses of three pyridoxal phosphate antagonists, methyldithiocarbazinate (MDTC, 45 mg/kg) thiosemicarbazide (TSC, 100 mg/kg) or 4-deoxypyridoxine (4-DP, 250 mg/kg). Dopa-decarboxylase (DCA) activity in the same homogenates was inhibited to a similar or lesser extent than GAD activity. Addition of pyridoxal phosphate to the homogenates relieved or abolished the inhibition of both GAD and DCA. GAD activity in mouse brain homogenates was inhibited (21 per cent) after intraperitoneal administration of a convulsant dose of allylglycine (AG, 200 mg/kg) which is not a pyridoxal phosphate antagonist. Addition of AG to mouse brain homogenates caused an inhibition of GAD activity. The inhibition was increased by preincubation of the homogenate with AG. In contrast, cerebral DCA activity was unchanged after a convulsant dose of AG, or after addition of AG to brain homogenates with or without preincubation. Brain GABA concentration was decreased after 4DP (250 mg/kg) but dopamine and serotonin concentrations were unchanged. Homovanillic acid and 5-hydroxyindoleacetic acid were significantly increased (26 and 96 per cent respectively). Brain GABA concentration was decreased after AG, while brain monoamine and monoamine metabolites were unchanged (except for a 28 per cent decrease in 5HT at 60 min). The experiments demonstrate that inhibition of DCA activity is not the primary or critical mechanism in the convulsant action of hydrazides and allylglycine.