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.

The aim of the present study was to investigate and compare the ability of three novel 5-HT6 and/or 5-HT7 receptor antagonists as follows: PZ-668-a preferential 5-HT6 antagonist; PZ-1433-a preferential 5-HT7 antagonist; and ADN-1184-a monoaminergic ligand with potent 5HT6/7 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-HT6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT7 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.

Changes in Monoaminergic Neurotransmission in an Animal Model of Osteoarthritis: The Role of Endocannabinoid Signaling.

Chronic pain is a main symptom of osteoarthritis (OA). Moreover, a high percentage of OA patients suffer from mental health problems. The endocannabinoid (EC) system has attracted attention as an emerging drug target for pain treatment together with its activity on the mesolimbic reward system. Understanding the circuits that govern the reward of pain relief is crucial for the search for effective analgesics. Therefore, we investigated the role of the EC system on dopamine (DA) and noradrenaline (NA) in an animal model of OA-related chronic pain. OA rats exhibited significant decreases in DA metabolism in the nucleus accumbens (NAc), striatum (STR) and hippocampus (HC). NA metabolism was also significantly decreased by chronic pain in OA rats; however, this disruption was limited to the frontal cortex (FCx) and HC. URB597 (an inhibitor of EC metabolism) treatment completely reversed the decreased DA metabolism, especially in the brain reward system and the HC. Furthermore, administration of URB597 normalized the impairment of NA activity in the HC but potentiated the decreased NA levels in the FCx. Our results demonstrated that chronic pain in OA rats was reflected by the inhibition of mesolimbic and mesocortical dopaminergic transmission, and may indicate the pro-pain role of NA in the FCx. The data provide understanding about changes in neurotransmission in chronic pain states and may explain the clinical improvement in perceived life quality following cannabinoid treatment. Additional mechanistic studies in preclinical models examining the intersection between chronic pain and reward circuits may offer new approaches for improving pain therapy.

Antidepressant-Like Effect of the Endogenous Neuroprotective Amine, 1MeTIQ in Clonidine-Induced Depression: Behavioral and Neurochemical Studies in Rats.

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders especially depression. Animal models are widely used to study antidepressant-like effect in rodents; however, it should be taken into account that pharmacological models do not always answer to the complexity of the disease processes. This study verified the behavioral (forced swim test (FST), locomotor activity test) and neurochemical effects (monoamines metabolism) of a low dose of clonidine (0.1 mg/kg i.p.) which was used as an experimental model of depression. In such pharmacological model, we investigated the antidepressant-like effect of an endogenous neuroprotective amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) administered in a dose of 25 mg/kg (i.p.) before clonidine in the behavioral and neurochemical tests carried out in rats. The behavioral study has shown that clonidine produced depression in the locomotor activity test but did not cause pro-depressive effect in the FST. 1MeTIQ produced antidepressant-like effect in the FST and completely antagonized clonidine-induced sedation in the locomotor activity test. Neurochemical data demonstrated that clonidine produced a significant inhibition of monoamine metabolism in the central nervous system. The release of dopamine, noradrenaline, and serotonin as well as the rate of their metabolism were diminished in the investigated brain structures (frontal cortex, hypothalamus, and striatum). 1MeTIQ completely antagonized the clonidine-induced depression of monoaminergic systems and restored their levels to the control values. 1MeTIQ as an endogenous neuroprotective compound with a distinct antidepressant-like activity in rodents produces hope on the efficiency of antidepressant medicines for future practical clinical use.

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 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.

Repeated Transcranial Direct Current Stimulation Induces Behavioral, Metabolic and Neurochemical Effects in Rats on High-Calorie Diet.

Due to its high prevalence, obesity is considered an epidemic, which stimulated research on non-invasive methods to reduce excess body fat. Transcranial direct current stimulation (tDCS) is a non-invasive technique used to modulate the activity of cerebral cortex, which has already found increasing interest in medicine as a promising methodology. The aim of this study was to analyze the impact of tDCS on feeding behavior, metabolic abnormalities and neurotransmitters in certain brain areas involved in appetite control of obese rats. The male Wistar rats were divided into five subgroups depending on consumed diet effect (lean, obese) and tDCS type (anodal, cathodal, sham, and no stimulation). Two 10-min daily sessions of tDCS for 8 consecutive days of the study were applied. Rats subjected to active tDCS (anodal right or cathodal left of the prefrontal cortex) had reduced appetite and showed lesser body weight gain than the animals subjected to sham procedure or those receiving no stimulation at all. Furthermore, tDCS contributed to reduction of epididymal fat pads and to a decrease in blood concentration of leptin. Neurochemical examination revealed that tDCS modulated serotonin pathways of the reward-related brain areas and contributed to a significant decrease in the density of D2 but not D1 dopamine receptors in the dorsal striatum, recorded 5 h after the last stimulation. No significant effect of tDCS on dopamine and it's metabolites in examined brain regions was observed. It seems that the hypothalamus was not affected by tDCS application as no changes in measured neurotransmitters were detected at any examined time point. However, these results do not exclude the possibility of the delayed response of the monoamines in the examined brain areas to tDCS application. Altogether, these findings imply that repeated tDCS of the prefrontal cortex may change feeding behavior of obese rats. Either right anodal or left cathodal tDCS were sufficient to decrease food intake, to reduce body adiposity and to normalize other metabolic anomalies. These beneficial effects can be at least partially explained by changes in serotoninergic and in lesser extent dopaminergic system activity within some brain areas belonging to reward system.

The impact of 1MeTIQ on the dopaminergic system function in the 6-OHDA model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder which is caused by degeneration of dopaminergic neurons of the nigrostriatal pathway. As a model of PD we used 6-hydroxydopamine (6-OHDA) which exerts toxic effects on catecholaminergic neurons and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) as neuroprotective compound. The aim of the present study, was to investigate the potential neuroprotective properties of 1MeTIQ against 6-OHDA-induced neurotoxic effects in the rat. METHODS: In the behavioral study, we measured locomotor activity and catalepsy. In the biochemical studies using HPLC methodology, we analyzed the concentration of dopamine and its metabolites in rat brain. RESULTS: Behavioral tests showed that 6-OHDA decreased rat locomotor activity and produced an increase of catalepsy. These effects did not blocked by 1MeTIQ injections. Biochemical studies indicated that 6-OHDA lesion significantly reduced the concentration of dopamine and its metabolites in the nigro-striatal pathway in the lesioned (ipsilateral) side. Moreover, 6-OHDA induced an increase in the rate of dopamine oxidation. Both acute and chronic administration of 1MeTIQ did not reverse the effects of 6-OHDA lesion on the ipsilateral side, however, it produced a significant elevation of the dopamine concentration in the contralateral side. It is evident that multiple treatments with 1MeTIQ stimulate undamaged neurons to increased activity. CONCLUSION: 1MeTIQ was shown to possess neuroprotective potential to the dopaminergic neurons damaged by 6-OHDA lesion. This compound has a protective effect but does not have neurorestorative capacity. It does not reverse damage already caused but will maintain the function and activity of undamaged dopamine neurons at physiological level.

Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT6 partial agonist in rats.

It was shown that 5-HT6 receptor agonists can exert pharmacological activity due to various modifications in monoamines' level and metabolism activity in rats' brain structures. This finding was correlated with antidepressant- or anxiolytic-like properties of these compounds. The study was designed to establish a possible mechanism of the antidepressant-like activity of the partial 5-HT6 receptor agonist EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) in rats. The concentrations of monoamines (dopamine (DA), noradrenaline (NA), and serotonin (5-HT)) and the rate of their metabolism were measured ex vivo in the brain structures (hippocampus, nucleus accumbens, striatum) using high-performance liquid chromatography (HPLC). The rats were killed after the forced swim test (FST); the collected tissue samples were used to ex vivo experiments. The potency of EMD386088 to blockade dopamine transporter (DAT) was tested in a functional in vitro study. FST was used to assess the involvement of D1- and D2-like receptor subfamilies in antidepressant-like properties of EMD386088. Neurochemical data from ex vivo experiments showed that antiimmobility activity of EMD386088 may be connected with the activation of dopaminergic system, while neither noradrenergic nor serotonergic ones are involved in its effect. EMD386088 also possesses a significant affinity for DAT which may be a mechanism in the abovementioned effect. Behavioral data seem to confirm the importance of dopaminergic system activation in antidepressant-like activity of EMD386088, since this effect, observed in the FST, was abolished by the preferential D1- and D2-like receptor subfamily antagonists SCH23390 and sulpiride, respectively. Dopaminergic system is involved in antidepressant-like activity of EMD386088.

Acute treatment with doxorubicin induced neurochemical impairment of the function of dopamine system in rat brain structures.

BACKGROUND: The clinical studies have shown that chemotherapy may impair cognitive functions especially in the patients treated for breast cancer. It should be mention that only few studies have made use of animals to investigate the effects of chemotherapy on the brain function. Doxorubicin (Adriamycin) is an anthracycline antibiotic commonly used for chemotherapy of breast cancer. METHODS: This study examined the effect of doxorubicin (1.5 and 3.0mg/kg ip) after acute administration on the levels of dopamine, noradrenaline, serotonin and their metabolites in the rat brain structures connected with cognition and psychiatric disorders. RESULTS: The data indicate that doxorubicin produced a significant and specific for the dopamine system inhibition of its activity in the investigated structures connected with the fall of dopamine concentration (decrease from 25 to 30% in the frontal cortex; from 30 to 60% in the hippocampus and about 20% of the control in the striatum, p<0.05) and its extraneuronal metabolite, 3-MT (from 35% in the frontal cortex to 60% in the hippocampus of the control level, p<0.01). However, doxorubicin did not affect others monoaminergic transmitters in the brain: noradrenaline and serotonin. CONCLUSION: Summing up, these data indicate that a single injection of doxorubicin produced a clear and significant inhibition of dopamine system activity in all investigated structures with the strongest effect in the hippocampus what may lead to the disturbances of the cognitive functions at the patients treated for cancer. Moreover, such treatment did not significantly affect others monoaminergic transmitters such as noradrenaline and serotonin.

Neuroprotective Effect of the Endogenous Amine 1MeTIQ in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that is hallmarked by pathological changes associated with the death of dopaminergic neurons, particularly in the extrapyramidal system (substantia nigra pars compacta, striatum) of the brain. Although the causes of slow neuronal death in PD are unknown, both genetic and environmental factors are likely involved. Endogenous isoquinolines, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), present in the human brain have been previously reported to participate in the pathogenesis of PD. The chronic administration of 1BnTIQ induced parkinsonism in primates, and this effect might be associated with idiopathic PD. However, another endogenous derivative of tetrahydroisoquinoline, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), displays clear neuroprotective properties in the brain. In the present study, we investigated the neuroprotective effects of 1MeTIQ (25 and 50 mg/kg) in an animal model of PD after the chronic administration of 1BnTIQ (25 mg/kg). Behavioral analyses demonstrate that both acute and repeated treatment with 1MeTIQ completely antagonized 1BnTIQ-induced changes in rat locomotor activity. Neurochemical experiments indicate that 1MeTIQ co-administered with 1BnTIQ completely antagonized 1BnTIQ-induced reduction in the dopamine (DA) concentration in rat brain structures. In conclusion, the results demonstrate that 1MeTIQ possesses important neuroprotective properties in the animal model of PD and that the rats did not develop tolerance after its chronic administration.

Chronic salsolinol administration prevents the behavioral and neurochemical effects of L-DOPA in rats.

1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is a well-known endogenous compound that has been proposed as a factor involved in the pathogenesis of Parkinson's disease. In the present study, we investigated the impact of acute and chronic salsolinol (100 mg.kg i.p.) administration on L-DOPA-induced locomotor hyperactivity and neurochemical changes (the dopamine level and its metabolism in rat brain structures). Moreover, using the in vivo microdialysis technique, we measured the effect of acute and chronic salsolinol injection on L-DOPA-induced dopamine release in the rat striatum. The behavioral data demonstrated that both acute and chronic salsolinol administration antagonized L-DOPA-mediated hyperactivity. An ex vivo neurochemical experiment indicated that chronic but not acute salsolinol administration partially inhibited the L-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. Additionally, the in vivo dopamine release data obtained from the microdialysis experiments clearly indicated that the differences in the effect of salsolinol on the activities of L-DOPA depended on the mode of salsolinol treatment. Acute injection of salsolinol enhanced the L-DOPA-induced elevation of dopamine release (by ~1200 %; P < 0.01), whereas chronic administration of salsolinol completely blocked the L-DOPA-induced elevation of dopamine release in the rat striatum. These data demonstrated that chronic administration of salsolinol significantly impaired the response of dopaminergic neurons to L-DOPA administration. In conclusion, we propose that an elevated salsolinol level in parkinsonian patients may represent a serious risk factor of the clinical efficacy of L-DOPA therapy.

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.

1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous neurotoxic compound, disturbs the behavioral and biochemical effects of L-DOPA: in vivo and ex vivo studies in the rat.

Environmental factors and endogenously produced toxins, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), are considered to be involved in the pathogenesis of Parkinson's disease (PD). In this study, we investigated the impact of single and multiple 1BnTIQ (25 and 50 mg/kg i.p.) administration on L-DOPA-induced changes in the rate of dopamine and serotonin metabolism in the rat brain. Additionally, using in vivo microdialysis, we measured the impact of acute and multiple 1BnTIQ administrations on L-DOPA-induced dopamine release in the striatum. These data were compared with results from behavioral tests in which we measured the effect of 1BnTIQ and L-DOPA on locomotor activity. Finally, we determined the effect of the repeated administration of 1BnTIQ on the L-DOPA-induced elevation of caspase-3 activity in the hippocampus. An ex vivo neurochemical study indicated that both acute and chronic 1BnTIQ injections strongly inhibited L-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. In contrast, in vivo microdialysis studies suggested that the differences in 1BnTIQ's effects are dependent on the type of treatment. A single dose of 1BnTIQ intensified the elevation of dopamine release induced by L-DOPA administration (~1,300 %; P < 0.01), while multiple administrations of 1BnTIQ significantly enhanced the basal dopamine levels while partially diminishing the effects of L-DOPA injection (~200 %; P < 0.01). Additionally, we found that chronic administration of 1BnTIQ completely blocked the L-DOPA-induced increase in caspase-3 activity in the hippocampus. These findings indicate that both acute and chronic administrations of 1BnTIQ disturbs the behavioral and biochemical effects of L-DOPA in the rat. The data presented from ex vivo and in vivo studies clearly suggest that 1BnTIQ's effects may be connected with the inhibition of DAT and/or COMT activity in the brain. Furthermore, elevated endogenous levels of 1BnTIQ may pose a serious risk in PD patients undergoing L-DOPA therapy.

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.

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.

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.

1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application.

This review outlines the effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), endogenous substances imbued with high pharmacological potential and broad spectrum of action in brain. 1MeTIQ has gained special interest as a neuroprotectant, and its ability to antagonize the behavioral syndrome produced by well-known neurotoxins (e.g., MPTP; rotenone). This review is thus focused on mechanisms of action of 1MeTIQ in behavioral, neurochemical, and molecular studies in rodents; also, effects of TIQ and 1MeTIQ on dopamine metabolism; and neuroprotective properties of TIQ and 1MeTIQ in vitro and in vivo. Finally, antiaddictive properties of 1MeTIQ will be described in cocaine self-administered rats. Findings implicate TIQ and especially its methyl derivative 1MeTIQ in unique and complex mechanisms of neuroprotection in various neurodegenerative illnesses of the central nervous system. We believe that MAO inhibition, free radicals scavenging properties, and antagonism to the glutamatergic system may play an essential role in neuroprotection. In addition, the results strongly support the view that 1MeTIQ has a considerable potential as a drug for combating substance abuse, through the attenuation of craving.

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.

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.

Comparative behavioral and neurochemical studies of R- and S-1-methyl-1,2,3,4-tetrahydroisoquinoline stereoisomers in the rat.

BACKGROUND: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) is present in human and mammalian brain as a racemate (R,S) of two stereoisomers: R- and S-1MeTIQ. The racemate is a mixture of the endogenous, synthesized in the brain dextrorotary R-1MeTIQ, and the exogenous, levorotary form, S-1MeTIQ. METHODS: In this study, we compared the effect of these two stereoisomers of 1MeTIQ with the racemate in the context of their influence on dopamine metabolism and in vivo dopamine release in the rat striatum. Additionally, a behavioral study was used to examine the influence of both enantiomers R- and S-1MeTIQ on locomotor activity of rats. RESULTS: The behavioral studies showed that both R- and S-1MeTIQ enantiomers, like the racemate, produced biphasic effects: a slight decrease in the exploratory locomotor activity, and then an increase in the basal locomotor activity. Biochemical ex vivo experiments showed that S-1MeTIQ produced a much stronger inhibition of MAO-dependent dopamine oxidation than the racemate. R-1MeTIQ, in opposite to S-isoform and racemate, did not block dopamine oxidation in the structures which contain dopamine nerve endings (striatum, nucleus accumbens), and in fact did not suppress the level of its intraneuronal metabolite, DOPAC in these brain regions. However , an in vivo microdialysis study demonstrated that the racemate and both stereoisomers (R-1MeTIQ to a lesser extent) significantly elevated the concentration of dopamine in the extraneuronal space in the rat striatum. What is more, the concentration of an extraneuronal dopamine metabolite 3-methoxytyramine (3-MT), which is an indicator of its release, was considerably increased by all the compounds. CONCLUSIONS: In summary of the results, it can be stated that S-1MeTIQ, like the racemate and in contrast to R-stereoisomer, inhibits MAO-dependent dopamine oxidation in all investigated brain structures. In addition, both these substances potentiated COMT-dependent O-methylation in the brain, however, also R-1MeTIQ produced such effect but to a lesser extent. In conclusion, we suggest that R- and S-1MeTIQ enantiomers like the racemate may demonstrate neuroprotective properties in the brain via the activation of dopamine O-methylation catabolic pathway and elevation of its methylated product - 3-MT.

Chronic impairment of the vagus nerve function leads to inhibition of dopamine but not serotonin neurons in rat brain structures.

BACKGROUND: Recent clinical studies have shown that the dorsal motor nucleus of the vagus nerve is one of the brain areas that are the earliest affected by α-synuclein and Lewy body pathology in Parkinson's disease. This observation raises the question: how the vagus nerve dysfunction affects the dopamine system in the brain? METHODS: The rats underwent surgical implantation of the microchip (MC) in the abdominal region of the vagus. In this study, we examined the effect of chronic, unilateral electrical stimulation of the left nerve vagus, of two different types: low-frequency (MCL) and physiological stimulation (MCPh) on the dopamine and serotonin metabolism determined by high-pressure chromatography with electrochemical detection in rat brain structures. RESULTS: MCL electrical stimulation of the left nerve vagus in contrast to MCPh stimulation, produced a significant inhibition of dopamine system in rat brain structures. Ex vivo biochemical experiments clearly suggest that MCL opposite to MCPh impaired the function of dopamine system similarly to vagotomy. CONCLUSION: We suggest a close relationship between the peripheral vagus nerve impairment and the inhibition of dopamine system in the brain structures. This is the first report of such relationship which may suggest that mental changes (pro-depressive) could occur in the first stage of Parkinson's disease far ahead of motor impairment.