The effect of a tetracyclic antidepressant compound, Org GB94, on the turnover of biogenic amines in rat brain

The acute administration of Org GB94 resulted in an increased incorporation of [3H]tyrosine into [3H]noradrenaline in the cerebral cortex, brain stem and mid-brain of the rat. The incorporation of labelled tyrosine into dopamine was slightly increased in the cerebellum. Following the chronic administration of Org GB94, the incorporation of tritiated tyrosine into noradrenaline was increased, whereas the incorporation of this amino acid into dopamine was unaffected. The incorporation of [3H]tryptophan into [3H]serotonin was unaffected after either the acute or chornic administration of the compound. It is concluded that Org GB94 increases the turnover of noradrenaline in the rat brain and in this respect differs qualitatively in its action from the tricyclic antidepressants. When rats were injected intraperitoneally with 3 mg Org GB94 daily for 14 days, the plasma levels decreased from approximately 170 ng/ml at 1 hr after the last dose to approximately 2.5 ng/ml after 24 hr. The effect of Org GB94 on the turnover of noradrenaline was most marked 24 hr after the chronic dose. The brain concentration of Org GB94 decreased from 3400 ng total brain at 1hr after the last dosing to 95 ng/total brain at 24 hr after dosing. There does not appear to be a correlation between the increase in brain noradrenaline turnover and the concentration of the drug in the brain. No significant differences were found between the concentration of Org GB94 after a single dose and the last dose of chronic treatment. There is clinical evidence that Org GB 94 (1,2,3,4,10,14b-hexahydro-2-methyl-dibenzo(c,f) pyrazino-(1,2-a) azepine monohydrochloride) has antidepressant properties. It is widely accepted that endogenous depression results from a deficiency of noradrenaline and/or serotonin at post synaptic receptor sites within the brain. It is generally thought that the efficacy of the tricyclic antidepressants of the imipramine type is due to their ability to reduce the re-uptake of these biogenic amines from the synaptic cleft into the pre-synaptic neurone thereby increasing the effective concentration of the amines at the receptors. Neurochemical evidence suggests that Org GB94 has effects on brain monoamine metabolism which differs from those of the tricyclic antidepressants.