The effect of multiple imipramine administration on monoaminergic systems of the rat brain.

Abstract

Wistar rats received imipramine (IMI) in daily single doses of 1 or 10 mg/kg ip for up to 4 weeks. They were killed after 1,2 or 4 weeks, 24 hr after the last dose of IMI. Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) were assayed in the whole brain. Whole brain dopa and 5-hydroxytryptophan (5-HTP) were assayed 30 min after administration of a central decarboxylase inhibitor, 3-hydroxybenzylhydrazine (100mg/kg). Specific binding of 3H-clonidine and 3H-WB4101 to cortical membranes was tested in rats after 1 week (only 3H-clonidine binding) and 4 weeks of IMI treatment. The levels of biogenic amines did not change during the treatment; the accumulation of dopa was transiently depressed, and that of 5-HTP - transiently elevated (only after the high dose of IMI), but after 4 weeks of treatment the accumulation of both amino acids did not differ from that in control rats. After 4 weeks of treatment with the high dose of IMI the binding of both 3H-clonidine and 3H-WB4101 to specific receptors was significantly depressed. The results suggest that under the influence of chronically administered IMI transient disturbances of the synthesis of biogenic amines occur, but they disappear after a more prolonged treatment. In the course of prolonged treatment, however, the capability of binding of radioligands by kappa-adrenergic receptors diminishes, and this suggests the development of hyposensitivity of the kappa-adrenergic system.