Novel antagonists of 5-HT6 and/or 5-HT7 receptors affect the brain monoamines metabolism and enhance the anti-immobility activity of different antidepressants in rats

Abstract The aim of the present study was to investigate and compare the ability of three novel 5-HT 6 and/or 5-HT 7 receptor antagonists as follows: PZ-668—a preferential 5-HT 6 antagonist; PZ-1433—a preferential 5-HT 7 antagonist; and ADN-1184—a monoaminergic ligand with potent 5HT 6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments. The results of our investigations revealed the differences in action of the tested compounds. PZ-668 strongly affected dopaminergic and faintly noradrenergic system, PZ-1433 induced a significant elevation in dopamine, noradrenaline, serotonin, and their metabolite levels, while ADN-1184 appeared to act mostly through dopaminergic transmission. The agent with 5-HT 6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT 7 preferential antagonist facilitated antidepressant effects of escitalopram and, to a lesser extent, bupropion, while ADN-1184, a multireceptor ligand, potentiated the effectiveness of escitalopram, reboxetine, and bupropion. The presented findings may contribute to further investigations of more effective and safer antidepressant drugs, and may help selecting optimal augmentation therapy in treatment-resistant depression.