The effect of amitriptyline, desipramine and imipramine on the vivo brain synthesis of 3H-noradrenaline from 3H-L-dopa in the rat.

3H-L-Dopa was given to rats after a peripheral decarboxylase inhibitor Ro 4-4602 (50 mg/kg) and the effect of 30 min pretreatment with antiptyline (10 mg/kg), desipramine (10 mg/kg) and imipramine (10 mg/kg) on the brain formation of 3H-dopamine, 3H-noradrenaline and their major metabolites was investigated. Desipramine produced a decrease in the level of labelled noradrenaline and its major metabolites free and conjugated 3-methoxy-4-hydroxyphenyleneglycol and 3,4-dihydroxyphenyleneglycol. Imipramine decreased labelled noradrenaline and 3-methoxy-4-hydroxyphenyleneglycol, whereas amitriptyline produced no significant effect on noradrenaline metabolism. The thymoleptic drugs produced no significant effect on endogenous brain noradrenaline and dopamine. These findings provide a strong indication that desipramine and imipramine inhibit the 3H-noradrenaline biosynthesis from 3H-L-Dopamthe effect seems closely related to the well-known membrane inhibitory effect of these drugs, since desipramine produced a more marked effect than imipramine and amitriptyline showed no effect. No conclusive evidence for the precise mechanism of action was obtained but it is possible that the decreased 3H-noradrenaline synthesis is related to interference of desipramine and imipramine with the precursor (s) 3H-L-Dopa or 3H-dopamine at sites of 3H-noradrenaline biosynthesis.