Iron administered in the neonatal period changed memory, brain monoamine levels, and BDNF mRNA expression in adult Sprague-Dawley rats.

BACKGROUND: Iron is one of the key microelements in the mammalian body and is the most abundant metal in the brain. Iron, a very important chemical element in the body of mammals, is the most abundant metal in the brain. It participates in many chemical reactions taking place in the central nervous system acting as a cofactor in key enzymatic reactions involved in neurotransmitter synthesis and degradation, dendritic arborization, and myelination. Moreover, iron accumulation in the brain has been implicated in the pathogenesis of neurogenerative disorders. MATERIAL AND METHODS: The aim of our study was to assess the influence of iron administered orally (30 mg/kg) to rats in the neonatal period (p12-p14) by testing the performance of rats in the open field and social interaction tests, and by evaluating the recognition memory, monoamine levels in some brain structures, and BDNF mRNA expression. The behavioral and biochemical tests were performed in adult p88-p92 rats. RESULTS: Iron administered to rats in the neonatal period induced long-term deficits in behavioral tests in adult rats. It reduced the exploratory activity in the open field test. In the social interaction test, it induced deficits in the parameters studied, and decreased memory retention. Moreover, iron changed the brain monoamine levels in some studied brain structures and decreased the expression of BDNF mRNA in the hippocampus. CONCLUSIONS: All earlier and our present results indicated that iron administered to rats in the neonatal period induced an increase in oxidative stress which resulted in a change in the brain monoamine levels and decreased BDNF mRNA expression which may play a role in iron-induced memory impairment in adult rats.

Acute and Chronic Exposure to Linagliptin, a Selective Inhibitor of Dipeptidyl Peptidase-4 (DPP-4), Has an Effect on Dopamine, Serotonin and Noradrenaline Level in the Striatum and Hippocampus of Rats.

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters-dopamine, serotonin and noradrenaline-and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices.

Network analysis of monoamines involved in anxiety-like behavior in a rat model of osteoarthritis.

BACKGROUND: Chronic pain is a major health problem that affects a significant number of patients, resulting in personal suffering and substantial health care costs. One of the most commonly reported causal conditions is osteoarthritis (OA). In addition to sensory symptoms, chronic pain shares an inherent overlap with mood or anxiety disorders. The involvement of the frontal cortex, striatum and nucleus accumbens, in the affective processing of pain is still poorly understood. METHODS: Male Wistar rats were divided into two groups: MIA (monoiodoacetate injected into the knee-model of OA) and sham (NaCl). Behavioral tests assessing pain, anxiety, and depressive behavior were performed at week 1, 3, 4, 6, 8, and 10. Neurochemical assays were conducted at weeks 3, 6, and 10 post-MIA injection, followed by the neurotransmitters and their metabolites correlation matrix and network analysis. RESULTS: OA animals developed rapid pain phenotype, whereas anxiety-like behavior accompanied the development of a pain phenotype from 6 week post-MIA injection. We did not detect any depressive-like behavior. Instead, immobility time measured in the forced swimming test transiently decreased at 3 weeks post-MIA in the OA group. We detected changes in noradrenaline and serotonin levels in analyzed structures at distinct time points. Network analysis revealed noradrenaline and serotonin neurotransmission changes in the nucleus accumbens, confirming it to be the key structure affected by chronic pain. CONCLUSION: Animals with chronic pain exhibit symptoms of anxiety-like behavior and we identified underlying neurochemical changes using network analysis.

Advantages and Limitations of Animal Schizophrenia Models.

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

The Effect of Glutathione Deficit During Early Postnatal Brain Development on the Prepulse Inhibition and Monoamine Levels in Brain Structures of Adult Sprague-Dawley Rats.

Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6 mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5 mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8 mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.

The Impact of the Combined Administration of 1MeTIQ and MK-801 on Cell Viability, Oxidative Stress Markers, and Glutamate Release in the Rat Hippocampus.

MK-801, as an N-methyl-D-aspartate (NMDA) receptor inhibitor, causes elevation in glutamate release, which may lead to an increase in excitotoxicity, oxidative stress and, consequently, cell death. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) shows antioxidant activity. The aim of the present study was to evaluate the effect of combined treatment with 1MeTIQ and MK-801 on cell viability, antioxidant enzyme activity, and glutamate release in the rat hippocampus. Cytotoxicity was measured using lactate dehydrogenase leakage assay (LDH) and the methyl tetrazolium (MTT) assay; antioxidant enzyme activity (glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT)) were measured by ELISA kits. The release of glutamate in the rat hippocampus was measured using in vivo microdialysis methodology. An in vitro study showed that MK-801 induced cell death in a concentration-dependent manner and that 1MeTIQ partially reduced this adverse effect of MK-801. An ex vivo study indicated that MK-801 produced an increase in antioxidant enzyme activity (GPx, GR, and SOD), whereas coadministration of MK-801 and 1MeTIQ restored the activity of these enzymes to the control level. An in vivo microdialysis study demonstrated that combined treatment with both drugs decreased the release of glutamate in the rat hippocampus. The above results revealed that 1MeTIQ shows limited neuroprotective activity under conditions of glutamate-induced neurotoxicity.

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.

Effect of combined treatment with aripiprazole and antidepressants on the MK-801-induced deficits in recognition memory in novel recognition test and on the release of monoamines in the rat frontal cortex.

According to preclinical and clinical studies, the antidepressant-induced increase in the activity of atypical antipsychotics may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we aimed to evaluate the effects of the antidepressants escitalopram and mirtazapine and the atypical antipsychotic drug aripiprazole, administered separately or in combination, on the MK-801-induced deficits in the recognition memory test and on the extracellular levels of monoamines and their metabolites in the rat frontal cortex. Based on the results of the behavioral tests, co-treatment with an ineffective dose of aripiprazole (0.1 mg/kg) and escitalopram (2.5 and 5 mg/kg) or mirtazapine (5 mg/kg) abolished the deficits evoked by MK-801 in the novel object recognition test, and those effects were blocked by the 5-HT1A receptor antagonist (WAY 100,635) or the dopamine D1 receptor antagonist (SCH 23,390). Moreover, co-treatment with aripiprazole (0.3 mg/kg) and escitalopram (5 mg/kg) significantly increased the levels of noradrenaline and serotonin, decreased the level of its metabolite, and did not alter level of dopamine, but decreased the levels of its metabolites. In addition, co-treatment with aripiprazole (0.3 mg/kg) and mirtazapine (10 mg/kg) significantly increased the level of noradrenaline, did not change the levels of dopamine and serotonin, but increased the levels of their metabolites. Based on these results, the increase in the extracellular levels of noradrenaline or serotonin in the cortex induced by co-treatment with an antidepressant and aripiprazole may be very important for the pharmacotherapy of negative and some cognitive symptoms of schizophrenia.

Fluoride Affects Dopamine Metabolism and Causes Changes in the Expression of Dopamine Receptors (D1R and D2R) in Chosen Brain Structures of Morphine-Dependent Rats.

Disturbances caused by excess or shortages of certain elements can affect the cerebral reward system and may therefore modulate the processes associated with the development of dependence as was confirmed by behavioural studies on animals addicted to morphine. Earlier publications demonstrated and proved the neurodegenerative properties of both low and high doses of fluoride ions in animal experiments and in epidemiological and clinical studies. The aim of the experiments conducted in the course of the present study was to analyse the effect of pre- and postnatal exposure to 50 ppm F- on the initiation/development of morphine dependence. For this purpose, the following were conducted: behavioural studies, the analysis of concentrations of dopamine and its metabolites, and the analyses of mRNA expression and dopamine receptor proteins D1 and D2 in the prefrontal cortex, striatum, hippocampus, and cerebellum of rats. In this study, it was observed for the first time that pre- and postnatal exposure to fluoride ions influenced the phenomenon of morphine dependence in a model expressing withdrawal symptoms. Behavioural, molecular, and neurochemical studies demonstrated that the degenerative changes caused by toxic activity of fluoride ions during the developmental period of the nervous system may impair the functioning of the dopaminergic pathway due to changes in dopamine concentration and in dopamine receptors. Moreover, the dopaminergic disturbances within the striatum and the cerebellum played a predominant role as both alterations of dopamine metabolism and profound alterations in striatal D1 and D2 receptors were discovered in these structures. The present study provides a new insight into a global problem showing direct associations between environmental factors and addictive disorders.

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.

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.

Role of endocannabinoid system in dopamine signalling within the reward circuits affected by chronic pain.

The association between chronic pain, depression and anxiety has gained particular attention due to high rates of comorbidity. Recent data demonstrated that the mesolimbic reward circuitry is involved in the pathology of chronic pain. Interestingly, the mesolimbic reward circuit participates both in pain perception and in pain relief. The endocannabinoid system (ECS) has emerged as a highly relevant player involved in both pain perception and reward processing. Targeting ECS could become a novel treatment strategy for chronic pain patients. However, little is known about the underlying mechanisms of action of cannabinoids at the intersection of neurochemical changes in reward circuits and chronic pain. Because understanding the benefits and risks of cannabinoids is paramount, the aim of this review is to evaluate the state-of-art knowledge about the involvement of the ECS in dopamine signalling within the reward circuits affected by chronic pain.

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.

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs.

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25-0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

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.

Combined treatment with aripiprazole and antidepressants reversed some MK-801-induced schizophrenia-like symptoms in mice.

BACKGROUND: Atypical antipsychotic drugs have some efficacy in alleviating the negative and some cognitive symptoms of schizophrenia but those effects are small and mechanisms of this action are still unknown A few clinical reports have suggested that antidepressants (ADs), are able to augment the activity of atypical antipsychotic drugs. Thus, in the present study, we aimed to evaluate the effect of ADs, escitalopram (ESC) or mirtazapine (MIR) and aripiprazole (an atypical antipsychotic drug) given separately or jointly, on the MK-801-induced positive and cognitive symptoms of schizophrenia in mice. METHODS: The experiments were conducted on male Albino Swiss mice. ADs and aripiprazole were given 30min before MK-801 injection. Locomotor hyperactivity induced by MK-801 (0.3mg/kg) was measured for 30min, starting 30min after MK-801 administration. In the novel object recognition test, MK-801 (0.2mg/kg) was given 30min before the first introductory session. Memory retention was evaluated for 5min, starting 90min after the introductory session. RESULTS: Aripiprazole (0.3mg/kg) reduced the locomotor hyperactivity induced by MK-801(0.3mg/kg). Co-treatment with an inactive dose of aripiprazole and ESC or MIR inhibited the effect of MK-801. Moreover, MK-801 (0.2mg/kg) decreased the memory retention. Aripiprazole (0.3mg/kg) reversed that effect. Co-treatment with an inactive dose of aripiprazole and ESC or MIR abolished the deficit of object recognition memory induced by MK-801. CONCLUSIONS: The obtained results suggest that ADs may enhance the antipsychotic-like effect of aripiprazole in the animal tests used for evaluation of some positive and cognitive symptoms of schizophrenia.

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.