Anti-anxiety effect of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide (6k) using battery tests for anxiety in mice

Objective:

To investigate the anti-anxiety activity of “6k”, a novel 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist in in mice.

Materials and Methods:

Anti-anxiety activity of “6k” (1, 2, and 4 mg/kg, intraperitoneally (i.p.)) was evaluated in mice by behavioral tests such as elevated plus maze (EPM), open field test (OFT), light-dark box (L&D), and hole board test (HBT). Diazepam (2 mg/kg, i.p.) served as reference standard.

Results:

“6k” significantly (P < 0.05) increased the time and entries in open arm in EPM as compared to vehicle control group. Further, “6k” significantly (P < 0.05) increased the central and peripheral ambulation along with rearings and time in central area; whereas, reduced the fecal pellets in OFT as compared to vehicle control group. There was significant (P < 0.05) reduction in the latency to enter dark chamber; whereas, increased number of crossings and time in light chamber in L&D aversion test by treatment with “6k” as compared to vehicle control group. In HBT, “6k” significantly (P < 0.05) increased the number of head dipping and squares crossed; whereas, reduced the latency for first head dip and number of fecal pellets as compared to vehicle control group.

Conclusion:

A novel 5-HT₃ receptor antagonist has anti-anxiety action.KEY WORDS: 5-HT₃ antagonist, anxiety, elevated plus maze, open field test, hole board test     

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g) on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice

Aim:

The aim of the study was to evaluate a novel 5 HT₃ receptor antagonist (6g) on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body''s reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants.

Materials and Methods:

In the present study, a novel and potential 5-HT₃ receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) with good Log P (3.08) value and pA₂(7.5) values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS)-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour.

Results:

The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05) decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05) increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. ‘6g’ (1 and 2 mg/kg, p.o., 21 days) and fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly (P < 0.05) reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities). However fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly decreased the nitrite level in the brain while ‘6g’ (1 and 2 mg/kg, p.o., 21 days) did not show significant (P < 0.05) effect on the nitrite levels in brain.

Conclusion:

Compound ‘6g’ exerted antidepressant-like effects in behavioural despair paradigm in chronically stressed mice by restoring antioxidant mechanisms.KEY WORDS: 5-HT₃ receptor antagonist, chronic unpredictable mild stress, depression, oxidative stress     

Estimating Endogenous Dopamine Levels at D2 and D3 Receptors in Humans using the Agonist Radiotracer [11C]-(+)-PHNO

Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D_2/3 receptors (D_2/3R) in humans in vivo. Our group has developed [¹¹C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D₃R. Thus, the use of [¹¹C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D_2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D₃R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [¹¹C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [¹¹C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D₂R-rich regions (caudate and putamen), mixed D_2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D₃R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [¹¹C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D₂R and D₃R in neuropsychiatric populations.     

Influence of Temperature on Void Collapse in Single Crystal Nickel under Hydrostatic Compression

Employing atomistic simulations, we investigated the void collapse mechanisms in single crystal Ni during hydrostatic compression and explored how the atomistic mechanisms of void collapse are influenced by temperature. Our results suggest that the emission and associated mutual interactions of dislocation loops around the void is the primary mechanism of void collapse, irrespective of the temperature. The rate of void collapse is almost insensitive to the temperature, and the process is not thermally activated until a high temperature (∼1200–1500 K) is reached. Our simulations reveal that, at elevated temperatures, dislocation motion is assisted by vacancy diffusion and consequently the void is observed to collapse continuously without showing appreciable strain hardening around it. In contrast, at low and ambient temperatures (1 and 300 K), void collapse is delayed after an initial stage of closure due to significant strain hardening around the void. Furthermore, we observe that the dislocation network produced during void collapse remains the sample even after complete void collapse, as was observed in a recent experiment of nickel-base superalloy after hot isostatic pressing.     

Mass screening for colorectal cancer

A voluntary community colorectal cancer screening project to detect occult blood in the stool of asymptomatic individuals was undertaken; 49,353 Hemoccult^® II kits were distributed. A total of 23,674 completed kits were returned to a central repository and processed (compliance rate, 48 percent); 851 participants had positive results (3.6 percent). Of the 640 who underwent further medical evaluation, 299 participants (46.7 percent) who had adequate follow-up had no evidence of disease. Diverse disease entities were detected in 341 participants, which was 1.4 percent of those enrolled. Forty-one patients (0.17 percent) showed significant findings that included 29 cancers (0.12 percent) and 12 (0.05 percent) noninvasive malignant polyps. Of the cancers, there were 27 colorectal, one nonHodgkin's lymphoma, and one carcinoma of the vocal cord. In addition, 107 patients (0.45 percent) had benign polyps and 193 patients (0.82 percent) had various diseases of the gastrointestinal tract and other medical conditions. The cost of the program was modest and the results conformed to those found in previous screening surveys. The heightened public awareness of testing for colorectal disease and the detection of early lesions justifies the guaiac test screening program for mass survey.