Pelin Tanyeri

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.

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.

Involvement of serotonin receptor subtypes in the antidepressant-like effect of trim in the rat forced swimming test

Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT(1) and 5-HT(2) receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate l-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3x150mg/kg, i.p.) partially attenuated TRIM (50mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3mg/kg i.p, a 5-HT(2) receptor antagonist) or ketanserin (5mg/kg i.p, a 5HT(2A/2C) receptor antagonist) prevented the effect of TRIM (50mg/kg) in the FST. WAY 100635 (0.1mg/kg i.p, a selective 5-HT(1A) receptor antagonist) and GR 127935 (3mg/kg i.p, a selective 5-HT(1B/1D) receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT(2) receptors while non-significant effects were obtained with 5-HT(1) receptors.

Effects of Olanzapine and Clozapine on Radial Maze Performance in Naive and MK-801-Treated Mice

Attention, working memory and long-term memory dysfunctions are the most commonly seen cognitive impairments in schizophrenic patients. Conflicting results exist regarding the effects of antipsychotics on cognitive abnormalities. The aim of this study was to investigate the effects of atypical antipsychotic drugs olanzapine (0.4, 0.8 and 1.25u2009mg/kg, i.p.) and clozapine (0.5 and 1u2009mg/kg, i.p.) on spatial working memory in naive and MK-801 (0.2u2009mg/kg, i.p.) treated BALB-c mice in an 8-arm radial arm maze (RAM) task. None of the antipsychotic drugs studied altered number of errors in naive mice, whereas MK-801 significantly increased working memory errors in RAM test. Olanzapine and clozapine potently reversed MK-801 induced increasement of working memory errors. Olanzapine and clozapine prolonged latency of the animals in naive mice. The MK-801-induced enhancement in the speed of mice in performing the RAM task was blocked by olanzapine but not clozapine. Our study shows that atypical antipsychotics olanzapine and clozapine might improve cognitive deficits in schizophrenic patients.

Effects of olanzapine and clozapine on memory acquisition, consolidation and retrieval in mice using the elevated plus maze test.

Clozapine and olanzapine are antipsychotic drugs commonly used to treat schizophrenia and psychosis; however, few studies have investigated their effects on cognitive function using animal models. Thus, the effects of olanzapine and clozapine on memory acquisition, consolidation and retrieval were investigated in naive mice using a modified elevated plus maze (mEPM) task. Olanzapine (0.15 and 0.30 mg/kg) and clozapine (0.5 and 1 mg/kg) were injected intraperitoneally (i.p.) into male Balb-c mice before training, immediately after training or before the second day of the trial. Our results showed that both olanzapine and clozapine disrupted the acquisition of spatial memory. In addition, clozapine impaired the consolidation of spatial memory, while olanzapine had no effect. Furthermore, olanzapine and clozapine significantly disrupted memory retrieval in naive mice. Thus, these results at least suggest that olanzapine can be a superior treatment for schizophrenia compared to clozapine.