Edyta Możdżeń

Antidepressant-like activity of the endogenous amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline in the behavioral despair test in the rat, and its neurochemical correlates: A comparison with the classical antidepressant, imipramine

Disturbances in noradrenergic and serotonergic transmissions have been postulated to form neurochemical background of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which exhibits neuroprotective, antiaddictive and monoamine oxidase (MAO)-inhibiting properties. In the present study, we tested antidepressant-like effects of 1MeTIQ in comparison with the tricyclic antidepressant, imipramine in the forced swimming test in the rat. Additionally, in neurochemical studies, we estimated the rate of monoamine (dopamine, noradrenaline and serotonin) metabolism in the rat brain structures. The findings have shown that 1MeTIQ similarly to imipramine produced a dose-dependent antidepressant-like effect in the forced swimming test. The neurochemical data showed that 1MeTIQ produced a significant elevation of serotonin concentration in the brain structures with simultaneous reduction of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Moreover, 1MeTIQ slightly increased noradrenaline level but induced a significant elevation of its metabolite, 3-metoxy-4-hydroxyphenylglycol (MHPG). Furthermore, 1MeTIQ affected also dopamine metabolism, and decreased the level of 3,4-dihydroxyphenylacetic acid (DOPAC) with a simultaneous significant increase in the concentration of 3-methoxytyramine (3-MT) in all investigated structures. Such mechanism of action leads to a decrease in the production of free radicals during MAO-dependent dopamine oxidation in the brain. In conclusion, we suggest that antidepressant-like activity of 1MeTIQ is based on the unique and complex mechanism of action in which the activation of monoaminergic systems and scavenging of free radicals plays a crucial role. 1MeTIQ as an endogenous compound may be beneficial from the clinical point of view as a new safer and more efficient antidepressant.

1,2,3,4-Tetrahydroisoquinoline produces an antidepressant-like effect in the forced swim test and chronic mild stress model of depression in the rat: Neurochemical correlates.

1,2,3,4-Tetrahydroisoquinoline (TIQ) is an exo- and endogenous amine naturally present in mammalian brain which displays antidepressant-like effect in various animal models: the forced swim test (FST) and chronic mild stress (CMS) paradigm in rats. To elucidate this action we compared the effects of TIQ with imipramine, a classic antidepressant drug and one of the most clinically effective. Applied behavioral tests showed that TIQ produced an antidepressant-like effect with a potency comparable to that of imipramine. TIQ (25-50mg/kg i.p.), similarly to imipramine (10-30mg/kg i.p.), reduced the immobility time in FST and completely reversed the decrease in sucrose intake caused by CMS in the rat. In addition, in order to avoid the possible psychostimulating effect of TIQ we examined the influence of its administration on locomotor activity in rats. TIQ, like imipramine, produced a reduction in horizontal locomotor activity. This suggested that TIQ did not have psychostimulant properties and that prolonged swimming in the FST was a result of an increased motivation to escape from the stressful situation. The biochemical analyses have shown that TIQ activates monoaminergic systems as a reversible monoamine oxidase (MAO) inhibitor and free radical scavenger. Beyond the activation of noradrenaline and serotonin systems, TIQ also moderately affects the dopamine system. On the basis of the presented behavioral and biochemical studies we suggest that TIQ is a potential new antidepressant which may be effective for the depression therapy in a clinical setting.

1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous Neuroprotectant and MAO inhibitor with antidepressant-like properties in the rat.

Oxidative stress is a major contributing factor in a range of brain pathologies and in the etiology of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which is present in the mammalian brain and exhibits neuroprotective, and monoamine oxidase (MAO)-inhibiting properties. In the present study, in order to investigate the potential role of 1MeTIQ as an antidepressant, we tested antidepressant-like effects of 1MeTIQ in comparison with desipramine (a classic antidepressant) in the forced swimming test (FST), and using HPLC methodology, we measured the concentrations of monoamines (dopamine, noradrenaline, serotonin) and the rate of their metabolism. 1MeTIQ given alone as well as in combination with desipramine produced an antidepressant-like effect and decreased the immobility time in the FST. Neurochemical data have shown that 1MeTIQ like desipramine, activated the noradrenergic system. However, the mechanism of action of 1MeTIQ is broader than the actions of desipramine, and 1MeTIQ inhibits the MAO-dependent oxidation of dopamine and serotonin in all investigated structures. We can conclude that 1MeTIQ exhibits antidepressant-like activity in the FST in the rat. The mechanism of its antidepressant action differs from desipramine and seems to be mostly associated with the inhibition of the catabolism of monoamines and their increased concentrations in the brain. 1MeTIQ seems to be very beneficial from the clinical point of view as a reversible MAO inhibitor with a significant antidepressant effects.

Withdrawal from repeated administration of a low dose of reserpine induced opposing adaptive changes in the noradrenaline and serotonin system function: A behavioral and neurochemical ex vivo and in vivo studies in the rat

Reserpine is an inhibitor of the vesicular monoamine transporter 2 (VMAT2) and monoamine releaser, so it can be used as a pharmacological model of depression. In the present paper, we investigated the behavioral and neurochemical effects of withdrawal from acute and repeated administration of a low dose of reserpine (0.2 mg/kg) in Wistar Han rats. We demonstrated the behavioral and receptor oversensitivity (postsynaptic dopamine D1) during withdrawal from chronic reserpine. It was accompanied by a significant increase in motility in the locomotor activity test and climbing behavior in the forced swim test (FST). Neurochemical studies revealed that repeated but not acute administration the a low dose of reserpine triggered opposing adaptive changes in the noradrenergic and serotonin system function analyzed during reserpine withdrawal, i.e. 48 h after the last injection. The tissue concentration of noradrenaline was significantly decreased in the hypothalamus and nucleus accumbens only after repeated drug administration (by about 20% and 35% vs. control; p<0.05, respectively). On the other hand, the concentration of its extraneuronal metabolite, normetanephrine (NM) increased significantly in the VTA during withdrawal both from acute and chronic reserpine. The serotonin concentration was significantly reduced in the VTA after chronic reserpine (by about 40% vs. the control group, p<0.05) as well as its main metabolite, 5-HIAA (by about 30% vs. control; p<0.05) in the VTA and hypothalamus. Dopamine and its metabolites were not changed after acute or chronic reserpine administration. In vivo microdialysis studies clearly evidenced the lack of the effect of a single dose of reserpine, and its distinct effects after chronic treatment on the release of noradrenaline and serotonin in the rat striatum. In fact, the withdrawal from repeated administration of reserpine significantly increased an extraneuronal concentration of noradrenaline in the rat striatum but at the same time produced a distinct fall in the extraneuronal serotonin in this brain structure. On the basis of the presented behavioral and neurochemical experiments, we suggest that chronic administration of reserpine even in such low dose which not yet acted on the release of monoamines but produced an inhibition of VMAT2 caused a long-lasting disadvantageous effect of plasticity in the brain resembling depressive disorders.

Antidepressant-like effect of 1,2,3,4-tetrahydroisoquinoline and its methyl derivative in animal models of depression

BACKGROUND Most of the currently used antidepressant drugs are monoamine-based compounds, acting by the inhibition of re-uptake or metabolism of noradrenaline (NA) and/or serotonin (5-HT), because these neurotransmitters play a key role in the pathophysiology of depression. The aim of this study was to investigate the potential antidepressant-like activity of an endogenous amine, 1,2,3,4-tetrahydroisoquinoline (TIQ) and its close derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ). METHODS The experiments were carried out on male C57BL6J mice. The antidepressant-like activity of TIQs was evaluated in the behavioral tests: the forced swim test (FST) and tail suspension test (TST) and neurochemical analysis. TIQ and 1MeTIQ were administrated in three differences doses of 10, 25 or 50 mg/kg. Imipramine (IMI; 15 or 30 mg/kg) was used as a reference drug. In the neurochemical ex vivo study, the levels of NA, 5-HT and their metabolites, the rate of monoamine metabolism and their neuronal activity in different mouse brain structures were determined by HPLC with electrochemical detection. RESULTS The results of this study have demonstrated that TIQ and 1MeTIQ produced antidepressant-like effect in the FST and TST because they significantly decreased the immobility time comparably to IMI. Biochemical data have demonstrated that administration of TIQs led to the activation of NA and 5-HT systems. CONCLUSIONS The results reported in this paper indicate that TIQ and 1MeTIQ possess a distinct antidepressant activity. In the light of these findings, we suggest that both tested compounds may be effective for the depression therapy in a clinical setting with better tolerance of side effects.BACKGROUND Most of the currently used antidepressant drugs are monoamine-based compounds, acting by the inhibition of re-uptake or metabolism of noradrenaline (NA) and/or serotonin (5-HT), because these neurotransmitters play a key role in the pathophysiology of depression. The aim of this study was to investigate the potential antidepressant-like activity of an endogenous amine, 1,2,3,4-tetrahydroisoquinoline (TIQ) and its close derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ). METHODS The experiments were carried out on male C57BL6J mice. The antidepressant-like activity of TIQs was evaluated in the behavioral tests: the forced swim test (FST) and tail suspension test (TST) and neurochemical analysis. TIQ and 1MeTIQ were administrated in three differences doses of 10, 25 or 50mg/kg. Imipramine (IMI; 15 or 30mg/kg) was used as a reference drug. In the neurochemical ex vivo study, the levels of NA, 5-HT and their metabolites, the rate of monoamine metabolism and their neuronal activity in different mouse brain structures were determined by HPLC with electrochemical detection. RESULTS The results of this study have demonstrated that TIQ and 1MeTIQ produced antidepressant-like effect in the FST and TST because they significantly decreased the immobility time comparably to IMI. Biochemical data have demonstrated that administration of TIQs led to the activation of NA and 5-HT systems. CONCLUSIONS The results reported in this paper indicate that TIQ and 1MeTIQ possess a distinct antidepressant activity. In the light of these findings, we suggest that both tested compounds may be effective for the depression therapy in a clinical setting with better tolerance of side effects.