Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat

Abstract

Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both compounds may be effective for the therapy of depression in clinic as new antidepressants which, when administered peripherally easily penetrate the blood-brain barrier, and as endogenous compounds may not have adverse side effects.

Fig. 1

Chemical structure of TIQ and its close derivative, 1MeTIQ

Fig. 2

The effect of acute and repeated administration with a low dose of reserpine on FST in rat. Reserpine (0.2 mg/kg i.p.) was administered acute or chronically, once daily for 14 days. Control group received chronically 1 % Tween 80. FST was carried out 120 min after the last dose of reserpine. The data are the mean ± SEM. The results were analyzed by means of one-way ANOVA, followed when appropriate, by post hoc Duncan’s test. Statistical significance: *P < 0.05 versus control group

Fig. 3

The effect of acute and repeated administration with a low dose of reserpine on the horizontal and vertical motor activity in rat. Reserpine (0.2 mg/kg i.p.) was administered acute or chronically, once daily for 14 days. Control group received chronically 1 % Tween 80. Horizontal locomotor activity was defined as the travelled distance (in cm) and the vertical activity as rearing times (in seconds). Locomotor activity was analyzed 120 min after acute and chronic treatment of reserpine (0.2 mg/kg i.p.) during 60 min using Auto-Track Software Program. The data are the mean ± SEM. The number of animals per group, N = 6–8. The results were analyzed by means of one-way ANOVA, followed when appropriate, by post hoc Duncan’s test. Statistical significance: **P < 0.001 versus control group

Fig. 4

The effect of chronic administration TIQ and 1MeTIQ (25 mg/kg i.p.) on reserpine (0.2 mg/kg i.p.) evoked depressive-like effect in FST in rat. Reserpine (0.2 mg/kg i.p.) was administered chronically, once daily for 14 days. TIQ and 1MeTIQ (25 mg/kg i.p.) were administered 30 min before each dose of reserpine (combined groups). Control group received chronically 1 % Tween 80. FST was carried out 120 min after the last dose of reserpine. The data are the mean ± SEM. The results were analyzed by means of one-way ANOVA, followed when appropriate, by post hoc Duncan’s test. Statistical significance: *P < 0.05, **P < 0.01 versus control group. ⁺ P < 0.05, ⁺⁺ P < 0.01 versus reserpine group