1MeTIQ and olanzapine, despite their neurochemical impact, did not ameliorate performance in fear conditioning and social interaction tests in an MK-801 rat model of schizophrenia.

BACKGROUND: The aim of the present study was to evaluate the effect of 1MeTIQ on fear memory and social interaction in an MK-801-induced model of schizophrenia. The results obtained after administration of 1MeTIQ were compared with those obtained with olanzapine, an antipsychotic drug. METHODS: Sprague-Dawley rats received a single injection of MK-801 to induce behavioral disorders. 1MeTIQ was given either acutely in a single dose or chronically for 7 consecutive days. Olanzapine was administered once. In groups receiving combined treatments, 1MeTIQ or olanzapine was administered 20 min before MK-801 injection. Contextual fear conditioning was used to assess disturbances in fear memory (FM), and the sociability of the rats was measured in the social interaction test (SIT). Biochemical analysis was carried out to evaluate monoamine levels in selected brain structures after treatment. RESULTS: Our results are focused mainly on data obtained from neurochemical studies, demonstrating that 1MeTIQ inhibited the MK-801-induced reduction in dopamine levels in the frontal cortex and increased the 5-HT concentration. The behavioral tests revealed that acute administration of MK-801 caused disturbances in both the FM and SIT tests, while neither 1MeTIQ nor olanzapine reversed these deficits. CONCLUSION: 1MeTIQ, although pharmacologically effective (i.e., it reverses MK-801-induced changes in monoamine activity), did not influence MK-801-induced social and cognitive deficits. Thus, our FM tests and SIT did not support the main pharmacological hypotheses that focus on dopamine system stabilization and dopamine-serotonin system interactions as probable mechanisms for inhibiting the negative symptoms of schizophrenia.

Pro-cognitive effect of 1MeTIQ on recognition memory in the ketamine model of schizophrenia in rats: the behavioural and neurochemical effects.

RATIONALE: Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. OBJECTIVES: In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. METHODS: We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. RESULTS: Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. CONCLUSIONS: 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.

1-Methyl-1,2,3,4-tetrahydroisoquinoline - The toxicological research on an exo/endogenous amine with antidepressant-like activity - In vivo, in vitro and in silico studies.

BACKGROUND: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) demonstrates significant neuroprotective activity. It can interact with agonistic conformation of dopamine (DA) receptors. 1MeTIQ inhibits the formation of 3,4-dihydroxyphenylacetic acid as well as production of free radicals and shifts DA catabolism toward COMT-dependent O-methylation. 1MeTIQ inhibits both MAO-A and B enzymes activity and increases neurotransmitters levels in the brain. It shows significant antidepressant-like effect in forced swim test (FST) in rats. This compound might be effective for depression therapy in a clinical setting but its success is determined not only by good efficacy, but also by an acceptable its ADMET profile. The use of combination in silico prediction with in vivoand in vitro studies greatly simplifies the search for new, safer and effectively acting drugs. METHODS: The aim of this study was to investigate the degree of histopathological changes in different rats tissues after acute and chronic administration of 1MeTIQ. Additionally, prediction of its properties in terms of absorption, distribution, metabolism, elimination and toxicity in the human body was performed. RESULTS: The obtained data did not show extensive and significant toxic effects of tested substance in in vivo and in vitro studies in rats, and in silico ADMET prediction. CONCLUSIONS: These results can help to discover a new effective and safe antidepressant substance and have important significance in the treatment of depression in clinic. Additionally, the use in the treatment of depression substance with neuroprotective, antioxidant and antidepressant-like effects in the CNS and existing endogenously might be also beneficial in controlling the adverse CNS inflammatory processes accompanying depression.

Resilient Phenotype in Chronic Mild Stress Paradigm Is Associated with Altered Expression Levels of miR-18a-5p and Serotonin 5-HT1a Receptor in Dorsal Part of the Hippocampus.

Disturbed serotonergic signaling in the hippocampus observed in many individuals vulnerable to stress has been suggested as one of the primary factors contributing to the development of depression. However, little is known about the physiology of the brain in the resilient phenotype. Resilient subjects maintain a positive mood and psychological balance despite being under the stress influence. In our study, we generated stress-vulnerable and resilient rats by using a chronic mild stress (CMS) paradigm. Using different molecular approaches, we revealed that resilient animals exhibited a significantly decreased expression level of miR-18a-5p and, in the same time, an elevated level of 5-HT1AR in dorsal, but not ventral, part of the hippocampus. Described biochemical changes were not observed in animals behaviorally vulnerable to stress. Further, in vitro analysis showed that miR-18a-5p may be a negative epigenetic regulator of 5-HT1AR since the treatment of adult hippocampal neurons with miR-18a-5p mimic significantly lowered the expression level of mRNA encoding 5-HT1AR. Moreover, bioinformatic analysis of potential target genes expressed in the hippocampus and being regulated by miR-18a-5p showed that this microRNA may regulate biological processes, such as axonogenesis, which are important in the functioning of the hippocampus in both rats and humans. All these molecular features may contribute to serotonergic homeostatic balance at the level of serotonin turnover observed in hippocampi of resilient but not stress-vulnerable rats. Delineation of further molecular and biochemical markers underlying resilience to stress may contribute to the development of new antidepressant strategies which will restore resilient phenotype in depressed patients.

Comparison of the effects of 1MeTIQ and olanzapine on performance in the elevated plus maze test and monoamine metabolism in the brain after ketamine treatment.

Anxiety is a common symptom of schizophrenia. Ketamine, which acts as a noncompetitive antagonist of glutamatergic NMDA receptors by binding to the phencyclidine site, may induce schizophrenia-like symptoms and promote anxiogenic-like behaviour. The symptoms of anxiety in rodents can be measured by the elevated plus maze (EPM) test. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), as a neuroprotective and antiaddictive substance, produces pharmacological effects by influencing monoaminergic and glutamatergic activity, as previously demonstrated by us. The aim of the present study was to investigate the anxiolytic-like potential of 1MeTIQ after the administration of ketamine. These results were compared to the effects of olanzapine, an antipsychotic drug commonly used in the treatment of schizophrenia. We conducted the EPM test, during which the percentage of time spent in and the number of entries into the open arms were measured. In addition, locomotor activity was measured. Furthermore, we conducted biochemical analyses to verify changes in the levels of neurotransmitters and their metabolites in selected rat brain structures. Behavioural analyses showed that 1MeTIQ, similar to olanzapine, completely inhibited ketamine-induced anxiogenic effects in the EPM test. On the other hand, neurochemical data indicated that 1MeTIQ, as a reversible inhibitor of MAO, significantly blocked the dopamine MAO-dependent oxidation pathway, whereas olanzapine significantly increased the activity of this pathway. The results above suggest that the anxiolytic-like properties of 1MeTIQ are connected to its influence on the catabolism of dopamine, the elevation of serotonin concentrations and the reduction in the levels of noradrenaline.

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.

The Protective Effect of Repeated 1MeTIQ Administration on the Lactacystin-Induced Impairment of Dopamine Release and Decline in TH Level in the Rat Brain.

Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) caused by a progressive loss of nigrostriatal dopaminergic neurons. Dysfunction of the ubiquitin-proteasome system (UPS) plays an important role in the pathogenesis of PD. Intranigral administration of the UPS inhibitor lactacystin is used to obtain a valuable animal model for investigating putative neuroprotective treatments for PD. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous amine that displays neuroprotective properties. This compound acts as a reversible monoamine oxidase (MAO) inhibitor and a natural free radical scavenger. In the present experiment, we investigated the effect of acute and chronic treatment with 1MeTIQ on locomotor activity and the release of dopamine as well as its metabolites in the striatum of unilaterally lactacystin-lesioned and sham-operated rats using in vivo microdialysis. Additionally, changes in the level of tyrosine hydroxylase (TH) in the substantia nigra were measured. Unilateral lactacystin injection into the substantia nigra caused significant impairment of dopamine release (approx. 45%) and a marked decline in the TH level. These effects were completely antagonized by multiple treatments with 1MeTIQ. The results obtained from the in vivo microdialysis study as well as from the ex vivo experiments suggest that multiple administration of 1MeTIQ protects dopaminergic neurons against the lactacystin-induced decline in TH concentration in the substantia nigra and prevents disturbances of dopamine release in the striatum. We have demonstrated that 1MeTIQ is capable of maintaining the physiological functions of the striatal dopamine neurons damaged by unilateral lactacystin lesion.

Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat.

RATIONALE: The role of somatostatin and its receptors for the stress-related neuropsychiatric disorders has been widely raised. Recently, we have also demonstrated the involvement of somatostatin receptor type 2-sst2R and dopamine receptor type 2-D2R in stress. OBJECTIVE: In this context, we decided to find if these receptors are involved in response to antidepressant treatment in animal model of depression-chronic mild stress (CMS). METHODS: Here, we report data obtained following 7-week CMS procedure. The specific binding of [125I]Tyr3-Octreotide to sst2R and [3H]Domperidone to D2R was measured in the rat brain, using autoradiography. Additionally, the level of dopamine and metabolites was measured in the rat brain. RESULTS: In the final baseline test after 7 weeks of stress, the reduced consumption of sucrose solution was observed (controls vs the stressed animals (6.25 0.16 vs. 10.39 0.41; p < 0.05). Imipramine was administered for the next 5 weeks, and it reversed anhedonia in majority of animals (imipramine-reactive); however, in some animals, it did not (imipramine-non-reactive). Two-way repeated measures ANOVA revealed significant effects of stress and treatment and time interaction [F(16, 168) = 3.72; p < 0.0001], n = 10 per groups. We observed decreased binding of [125I]Tyr3-Octreotide in most of rat brain regions in imipramine non-reactive groups of animals. The decrease of D2R after stress in striatum and nucleus accumbens and no effect of imipramine were observed. In the striatum and prefrontal cortex, the significant role of stress and imipramine in dopamine levels was observed. CONCLUSIONS: The results obtained in binding assays, together with dopamine level, indicate the involvement of sst2R receptors for reaction to antidepressant treatment. Besides, the stress context itself changes the effect of antidepressant drug.

Combined brain Fe, Cu, Zn and neurometabolite analysis - a new methodology for unraveling the efficacy of transcranial direct current stimulation (tDCS) in appetite control.

Obesity is a chronic, multifactorial origin disease that has recently become one of the most frequent lifestyle disorders. Unfortunately, current obesity treatments seem to be ineffective. At present, transcranial direct current brain stimulation (tDCS) represents a promising novel treatment methodology that seems to be efficient, well-tolerated and safe for a patient. Unfortunately, the biochemical action of tDCS remains unknown, which prevents its widespread use in the clinical arena, although neurobiochemical changes in brain signaling and metal metabolism are frequently reported. Therefore, our research aimed at exploring the biochemical response to tDCS in situ, in the brain areas triggering feeding behavior in obese animals. The objective was to propose a novel neurochemical (serotoninergic and dopaminergic signaling) and trace metal analysis of Fe, Cu and Zn. In doing so, we used energy-dispersive X-ray fluorescence (EDXRF) and high-performance liquid chromatography (HPLC). Anodal-type stimulation (atDCS) of the right frontal cortex was utilized to down-regulate food intake and body weight gain in obese rats. EDXRF was coupled with the external standard method in order to quantify the chemical elements within appetite-triggering brain areas. Major dopamine metabolites were assessed in the brains, based on the HPLC assay utilizing the external standard assay. Our study confirms that elemental analysis by EDXRF and brain metabolite assay by HPLC can be considered as a useful tool for the in situ investigation of the interplay between neurochemical and Fe/Cu/Zn metabolism in the brain upon atDCS. With this methodology, an increase in both Cu and Zn in the satiety center of the stimulated group could be reported. In turn, the most significant neurochemical changes involved dopaminergic and serotoninergic signaling in the brain reward system.

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.

Multiple Administration of Endogenous Amines TIQ and 1MeTIQ Protects Against a 6-OHDA-Induced Essential Fall of Dopamine Release in the Rat Striatum: In Vivo Microdialysis Study.

Parkinson's disease (PD) represents one of the neurodegenerative disorders which are caused by degeneration of dopaminergic neurons in the nigrostriatal pathway. Different toxins, e.g., 6-hydroxydopamine (6-OHDA), are used to model PD in animals. 6-OHDA is a neurotoxin which damages catecholaminergic neurons via production of oxygen radicals. Tetrahydroisoquinolines (TIQs) are endogenous amines which are present in the mammalian brain. Some of them, like TIQ and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), demonstrate neuroprotective properties. These compounds act as reversible MAO inhibitors and this way block free radical formation. To continue our previous experiments, we evaluated the effect of acute and chronic treatment with TIQ and 1MeTIQ on locomotor/exploratory activity and the release of dopamine as well as its metabolite 3-methoxytyramine (3-MT) in the striatum of unilaterally 6-OHDA-lesioned and sham-operated rats using in vivo microdialysis methodology. Additionally, the changes in the concentration of tyrosine hydroxylase in the substantia nigra were measured. A unilateral 6-OHDA lesion in the substantia nigra produces a strong reduction in the release of dopamine (approx. 70%) and 3-MT (approx. 50%) in the rat striatum. This effect was completely inhibited by multiple administration of TIQ and 1MeTIQ. The results obtained from the in vivo microdialysis study suggest that multiple treatment with both endogenous amines, TIQ and 1MeTIQ, protects dopaminergic neurons against a 6-OHDA-induced deficit of dopamine release. Furthermore, these amines were able to maintain physiological functions of striatal dopamine neurons damaged by a unilateral 6-OHDA lesion.

The mechanism of neuroprotective action of natural compounds.

Disturbance of cerebral redox homeostasis is the primary cause of human neurodegenerative disorders, such as Parkinson's disease or Alzheimer's disease. Well known experimental research demonstrates that oxidative stress is a main cause of cell death. A high concentration of reactive oxygen and nitrogen species leads to damage of a lot of proteins, lipids and also DNA. Synthetic compounds used for the treatment in the neurodegenerative diseases failed to meet the hopes they had raised and often exhibit a number of side effects. Therefore, in recent years interest in natural compounds derived from plants appears to be on the rise. This review describes a few natural compounds (1MeTIQ, resveratrol, curcumin, vitamin C and Gingko biloba) which revealed neuroprotective potential both in experimental studies and clinical trials. 1MeTIQ has a privileged position because, as opposed to the remaining compounds, it is an endogenous amine synthesized in human and animal brain. Based on evidence from research, it seems that a common protective mechanism for all the above-mentioned natural compounds relies on their ability to inhibit or even scavenge the excess of free radicals generated in oxidative and neurotoxin-induced processes in nerve cells of the brain. However, it was demonstrated that further different molecular processes connected with neurotoxicity (e.g. the inhibition of mitochondrial complex I, activation of caspase-3, apoptosis) follow later and are initiated by the reactive oxygen species. What is more, these natural compounds are able to inhibit further stages of apoptosis triggered by neurotoxins in the brain.

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 significance of rotational behavior and sensitivity of striatal dopamine receptors in hemiparkinsonian rats: A comparative study of lactacystin and 6-OHDA.

A growing body of evidence indicates that impairment of the ubiquitin-proteasome (UPS) system in the substantia nigra (SN) plays an important role in the pathogenesis of Parkinson's disease (PD). The aim of our study was to compare two unilateral rat models, one produced by intranigral administration of the UPS inhibitor lactacystin or the other induced by 6-OHDA, in terms of their effect on the amphetamine- and apomorphine-induced rotational behavior, striatal dopamine (DA) D1 and D2 receptor sensitivity and tissue levels of DA and its metabolites. We found that these models did not differ in the intensity of ipsilateral rotations induced by amphetamine. In contrast, apomorphine produced contralateral rotations only in 6-OHDA-lesioned rats, and, depending on the dose, it induced either no or moderate ipsilateral rotations in the lactacystin-lesioned group. In addition, lactacystin induced a strong reduction in the tissue DA level and its metabolites in the lesioned striatum and SN when measured three weeks after the administration which was aggravated six weeks post-lesion, reaching the level comparable to the 6-OHDA group. Binding of [3H]raclopride to D2 receptors was increased in the lesioned striatum in both investigated (PD) models six weeks after lesion. In turn, binding of [3H]SCH23390 to the striatal D1 receptors was not changed in the lactacystin group but was increased bilaterally in the 6-OHDA group. The present results add a new value to the study of DA receptor sensitivity and are discussed in the context of the validity of the lactacystin model as a suitable model of Parkinson's disease.

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.

Comparison of the Effects of Acute and Chronic Administration of Tetrahydroisoquinoline Amines on the In Vivo Dopamine Release: A Microdialysis Study in the Rat Striatum.

The etiology of Parkinson's disease (PD) may involve endogenous and exogenous factors. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), which was shown to be neurotoxic for dopaminergic neurons, is one of such factors, thus it can be used to construct an animal model of PD. In contrast, 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) produce neuroprotective effects acting as monoamino oxidase (MAO) inhibitors and free radical scavengers that reduce oxidative stress in the mammalian brain. In this study, we aimed to investigate the effects of neuroprotective compounds, TIQ and 1MeTIQ, on the dopamine release in vivo in an animal model of PD induced by chronic administration of 1BnTIQ (25 mg/kg i.p.). Using an in vivo microdialysis methodology, we measured the impact of both acute and chronic treatment with TIQ and 1MeTIQ (50 mg/kg i.p.) on 1BnTIQ-induced changes in dopamine release in the rat striatum. Additionally, the behavioral test was carried out to check the influence of repeated administrations of the investigated compounds on the locomotor activity of rats. The behavioral studies showed that the chronic administration of 1BnTIQ produced a significant elevation of exploratory locomotor activity, and both the investigated amines, TIQ and 1MeTIQ, administered together with 1BnTIQ completely prevented 1BnTIQ-produced hyperactivity. The in vivo microdialysis studies demonstrated that the chronic treatment with 1BnTIQ caused a significant and long-lasting increase in the dopamine release (approximately 300 %) to the extracellular space in the rat striatum, which was demonstrated in the basal samples 24 h after 1BnTIQ injection. The combined chronic administration of 1BnTIQ and the investigated compounds, TIQ or 1MeTIQ, completely antagonized the 1BnTIQ-induced essential disturbances of the dopamine releasing to the extracellular space in the striatum. In conclusion, we suggest that higher concentrations of 1BnTIQ in the brain produced distinct impairment in the dopamine release, whereas TIQ and 1MeTIQ (compounds with previously revealed neuroprotective properties) completely prevented 1BnTIQ-induced abnormalities in the function of dopamine neurons and restored the dopamine release to the control values.

The adenosinergic system is involved in sensitization to morphine withdrawal signs in rats-neurochemical and molecular basis in dopaminergic system.

RATIONALE: Experimental data informs that not only do the dose and time duration of dependent drugs affect the severity of withdrawal episodes. Previous withdrawal experiences may intensify this process, which is referred as sensitization to withdrawal signs. Adenosine and dopamine (DA) receptors may be involved in this sensitization. OBJECTIVES: Rats were continuously and sporadically treated with increasing doses of morphine for 8 days. In rats, sporadically treated with morphine, morphine administration was modified by adding three morphine-free periods. Adenosine agonists were given during each of the morphine-free periods (six injections in total). On the 9th day, morphine was injected. One hour later, naloxone was administered to induce morphine withdrawal signs. Then, the animals were placed into cylinders and the number of jumpings was recorded. Next, the rats were decapitated and brain and brain structures (striatum, hippocampus, and prefrontal cortex) were dissected for neurochemical, molecular, and immunohistochemical experiments within DAergic pathways. RESULTS: We demonstrated that previous experiences of opioid withdrawal intensified subsequent withdrawal signs. Adenosine ligands attenuated the sensitization to withdrawal signs. In a neurochemical study, the release of DA and its metabolites was impaired in all structures. Significant alterations were also observed in mRNA and protein expression of DA receptors. CONCLUSIONS: Results demonstrate that intermittent treatment with morphine induces alterations in the DAergic system which may be responsible for sensitization to morphine withdrawal signs. Although adenosine ligands attenuate this type of sensitization, they are not able to fully restore the physiological brain status.

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.