Guner Ulak

Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats

Abstract Rationale: There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in central physiological mechanisms. NO is synthesized from l-arginine by nitric oxide synthase (NOS), as a response to activation of N-methyl-d-aspartate (NMDA) receptors by excitatory amino acids. NMDA receptor antagonists also produce antidepressant-like actions in preclinical models. Objective: In the present study, the involvement of NO in the mechanism of depression was investigated. 7-Nitroindazole (7-NI) (15, 30, 60, 90 mg/kg IP), a selective inhibitor of neuronal NOS was examined. Methods: The Porsolt forced swimming test (FST) has been used as a test for screening new antidepressant agents. Results: 7-NI dose-dependently decreased the immobility time in FST, but produced no significant change in locomotor activity in naive rats. Neither l-arginine, nor d-arginine (100 mg/kg) affected the immobility time in the FST or revealed any effect on locomotion. l-Arginine but not d-arginine, given 10 min before 7-NI, reversed the 7-NI-induced effect on immobility time. Conclusion: Our findings suggest that NO might be an important modulator of depression in rats.

Anxiolytic-like effects of 7-nitroindazole in the rat plus-maze test.

It is considered that nitric oxide (NO) is one of the most interesting research subjects. Because the actual role of NO in the mechanism of anxiety is still unclear, in this study, the involvement of NO in the mechanism of anxiety was investigated, using the plus-maze test. 7-Nitroindazole (7-NI) (15, 30, 60, 90, and 120 mg/kg), a new nitric oxide synthase (NOS) inhibitor was studied. The time spent on open arms and open-arm visits was evaluated. 7-NI, at 15-120 mg/kg doses potently increased the time spent on open arms and open-arm visits. However, at 120 mg/kg it attenuated the time spent on the open arms, compared to at 90 mg/kg. This effect was attributed to decreased locomotor activity in the higher dose group. Neither L-arginine, nor D-arginine (100 mg/kg) significantly affected any of the behavioral parameters measured in the rat elevated plus-maze test. Neither drugs revealed any effect on locomotion. L-Arginine but not D-arginine given 10 min before 7-NI, reversed the 7-NI induced anxiolytic-like effects. These data support an involvement of NO in the process of anxiety, and further suggest that the anxiolytic-like effect of 7-NI may be attributable to the inhibition of NO synthesis.

Effects of neuronal and inducible NOS inhibitor 1-[2-(trifluoromethyl) phenyl] imidazole (TRIM) in unpredictable chronic mild stress procedure in mice

Nitric oxide is an intracellular messenger which is involved in several functions and pathologies such as depression, anxiety, learning and memory. In many studies nitric oxide synthase inhibitors (NOSI) were shown to possess antidepressant-like effects in animal models of depression. The aim of this study is to investigate the effects of a selective neuronal and inducible nitric oxide synthase inhibitor TRIM (30 mg/kg/day, 35 days) in mice subjected to unpredictable chronic mild stress and then compare its effect with a conventional selective serotonin reuptake inhibitor fluoxetine (15 mg/kg/day, 35 days). Stressed vehicle animals showed a significant disturbed coat state when compared with nonstressed animals and this effect was reversed by TRIM or fluoxetine. Both TRIM and fluoxetine prevented the stress-induced deficit in the grooming behaviour in the splash test. TRIM and fluoxetine also significantly decreased the attack frequency when compared to the stressed control group in the resident-intruder test. These results support the assumption that NOS inhibitors can be a new class of antidepressant drugs possibly acting on neuronal NOS.

Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats.

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10-50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.

7-Nitroindazole, a neuronal nitric oxide synthase inhibitor, impairs passive-avoidance and elevated plus-maze memory performance in rats.

The role of nitric oxide (NO) on cognitive performance in a modified elevated plus-maze (mEPM) and passive-avoidance (PA) task was investigated by using the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI) and an NO precursor l-arginine. The interaction between the activation of N-methyl-d-aspartate (NMDA) receptors and NO synthesis on memory retention was also studied. 7-NI, l-arginine or MK-801, a non-competitive NMDA receptor antagonist were injected intraperitoneally (i.p) to male Wistar rats 30 min before the first training session of the PA test or 30 min before on the first day testing (acquisition session) of mEPM task. Transfer latency, the time rat took to move from the open arm to the enclosed arm, was used as an index of learning and memory in a mEPM test. The retention session was performed 24 h after the acquisition one. In the PA task, the retention test was carried out 24 h after training and reduction of retention latency was used to evaluate the acquisition of learning and memory. Blood glucose level and locomotor activity of the rats was also evaluated. 7-NI (10, 20, 25, 50 mg/kg) and MK-801 (0.15 mg/kg) significantly prolonged the transfer latency on retention session in a mEPM test and shortened step-through latency in PA test. 7-NI-induced impairment in memory and learning was partly reversed by l-arginine (200 mg/kg), a competitive substrate for NOS. However subeffective doses of 7-NI (5 mg/kg) and MK-801 (0.075 mg/kg) given in combination significantly impaired plus-maze and PA performances in rats. Thus NMDA receptor mediated NO pathways may be implicated in the PA and mEPM behaviours in rats. Since 7-NI does not affect blood pressure and did not alter blood glucose level and locomotor activity in conscious rats, 7-NI-induced impairment of memory is not due to either hypertension, changes in blood glucose level or effects on locomotor activity.

Dextromethorphan attenuates ethanol withdrawal syndrome in rats.

The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.

Effects of fluoxetine, tianeptine and olanzapine on unpredictable chronic mild stress-induced depression-like behavior in mice

AIMS Tianeptine is an atypical antidepressant drug that has a different mechanism of action than other antidepressants. Olanzapine is an atypical antipsychotic drug used for the treatment of schizophrenia. The present study was undertaken to investigate effects of chronic administration of tianeptine or olanzapine on unpredictable chronic mild stress (UCMS)-induced depression-like behavior in mice compared to a widely used SSRI antidepressant, fluoxetine. MAIN METHODS Male inbred BALB/c mice were subjected to different kinds of stressors several times a day for 7weeks and were treated intraperitoneally with tianeptine (5mg/kg), olanzapine (2.5mg/kg), fluoxetine (15mg/kg) or vehicle for 5weeks (n=7-8 per group). KEY FINDINGS All the drugs tested prevented stress-induced deficit in coat state during UCMS procedure, in grooming behavior in the splash test, decreased the attack frequency in the resident intruder test and decreased the immobility time in the tail suspension test. In the open field test olanzapine had anxiolytic-like effects in both stressed and non-stressed mice. Tianeptine, olanzapine and fluoxetine decreased the enhanced levels of plasma ACTH and IL-6. Chronic treatment with tianeptine resulted in a significant increase in both total number and density of BrdU-labeled cells in stressed animals, while fluoxetine and olanzapine had a partial effect. SIGNIFICANCE The results of this study support the hypothesis that tianeptine can be as effective as fluoxetine for the treatment of depression in spite of the differences in the mechanism of action of these drugs. Moreover, olanzapine could be used effectively in psychotic patients with depression.

Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice

Cognitive dysfunction in schizophrenia is associated with functional disease symptoms. The beneficial effects of second generation antipsychotic drugs on cognitive function in schizophrenic patients are controversial. In this study, we investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on cognitive function in the Morris water maze task in naive or MK-801-treated animals. Male balb-c mice were treated subchronically with olanzapine (1.25, 2.5 and 5mg/kg, i.p.), sertindole (0.63, 1.3, 2.5mg/kg, s.c.) or clozapine (0.5 and 1mg/kg, i.p.), and cognitive deficits were induced by MK-801 (0.2mg/kg, i.p.) administration. Water maze performance was expressed as escape latency to find the hidden platform, the time spent in target quadrant, the mean distance to platform and the swim speed. In naive mice olanzapine impaired water maze performance, whereas sertindole and clozapine had no effect while the MK-801-induced cognitive impairment was reversed by the second generation antipsychotics - olanzapine, sertindole and clozapine at the doses used. These results revealed that while olanzapine had some disturbing effects on cognitive functions in naive animals; olanzapine, sertindole and clozapine might improve cognitive deficits in schizophrenic patients.

Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice

We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test. Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5mg/kg; s.c.) or clozapine (0.5 and 1mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia.