Exenatide treatment exerts anxiolytic- and antidepressant-like effects and reverses neuropathy in a mouse model of type-2 diabetes.

BACKGROUND: Comorbid neurobehavioral disturbances and type-2 diabetes mellitus (T2DM) warrant immediate research attention. Exenatide, which is a potent and selective agonist for the glucagon-like peptide-1 (GLP-1), is used in the treatment of T2DM. Exenatide displays a multitude of effects in the central nervous system. The aim of this study was to investigate the anxiolytic- and antidepressant-like effects and analgesic effects of exenatide in a type-2 diabetic mouse model. MATERIAL/METHODS: Modified elevated plus-maze test for anxiolytic-like, forced swimming test for depression-like behavior and hotplate test for neuropathy were used as behavioral tasks. Behavioral parameters were investigated in a streptozocin--(100 mg/kg, i.p.) and nicotinamide--(240 mg/kg, i.p.) induced type-2 diabetic mouse model. Exenatide (0.1 µg/kg, s.c., twice daily) was administered for 2 weeks. Vehicle (control), diabetic, and exenatide-treated diabetic mice were tested. RESULTS: Our results confirm that exenatide exerts anxiolytic- and antidepressant-like effects and might be effective in diabetic neuropathy in a diabetic mouse model. CONCLUSIONS: Exenatide may be a good candidate as a treatment option for depression, anxiety, and neuropathy in patients with type-2 diabetes.

Involvement of serotonin receptor subtypes in the antidepressant-like effect of beta receptor agonist Amibegron (SR 58611A): an experimental study.

New therapeutic strategies against depression, with less side effects and thus greater efficacy in larger proportion of depressed patients, are needed. Amibegron (SR58611A) is the first selective ß3 adrenergic agent that has been shown to possess a profile of antidepressant activity in rodents. To investigate the involvement of serotonin receptors in the effects of amibegron, we used the serotonin 5HT1A receptor antagonist WAY-100635 (WAY) or serotonin 5HT2A-2C receptor antagonist ketanserin or serotonin 5HT3 receptor antagonist ondansetron in mice forced swimming test (FST). The locomotor activity was evaluated by measuring the total distance moved in the apparatus and the speed of the animals in the open field test. Imipramine (30mg/kg) significantly reduced immobility time compared to vehicle-treated group while amibegron (5 and 10mg/kg) dose dependently reduced immobility time in the FST. WAY(0.1mg/kg), ondansetron (1mg/kg), ketanserin(5mg/kg) had no effect on immobility time in naive mice while all of the drugs partially and significantly reversed amibegron (10mg/kg) induced decreasement in the immobility time in FST. None of the drugs alter locomotor activity in the open field test. The antidepressant-like effect of amibegron in the FST seems to be mediated by an interaction with serotonin 5-HT1A, serotonin 5-HT2A-2C and serotonin 5-HT3 receptors.

Effects of L-arginine on 7-nitroindazole-induced reference and working memory performance of rats.

BACKGROUND/AIMS: This study was performed in order to elucidate the effects of 7-nitroindazole (7-NI) and L-arginine on cognitive functions of rats in a three-panel runway task. METHODS: 7-NI (2.5, 5, 10 mg/kg) and L-arginine (200 mg/kg) were injected intraperitoneally into male Wistar rats 30 min before the test. RESULTS: 7-NI (5, 10 mg/kg) significantly increased the number of errors (pushes made on the 2 incorrect panels of the panel gate at 4 choice points) and prolonged the latency of reference memory in the three-panel runway task. The negative effects of 7-NI on reference memory was counteracted by L-arginine, a substrate for nitric oxide synthase. While having no effect on the number of working memory errors in working memory trials, 7-NI prolonged the latency from the 2nd to the 6th trial at the 5- and 10-mg/kg doses. Concurrent administration with L-arginine counteracted the 7-NI-induced prolongation of latency from the 2nd to the 6th trial. CONCLUSION: 7-NI impaired reference memory but not working memory in the three-panel runway test. Moreover, nitric oxide played an essential role in the development of reference memory and the negative effects of 7-NI on memory were counteracted by L-arginine.

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.