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The ghrelin system is a key component of the mood and metabolic responses to chronic psychosocial stress. For example, circulating acyl-ghrelin rises in several rodent and human stress models, administered acyl-ghrelin induces antidepressant-like behavioral responses in mice, and mice with deleted ghrelin receptors (GHSRs) exhibit exaggerated depressive-like behaviors, changed eating behaviors, and altered metabolism in response to chronic stress. However, the mechanisms mediating stress-induced rises in ghrelin are unknown and ghrelin's antidepressant-like efficacy in the setting of chronic stress is incompletely characterized. Here, we used a pharmacological approach in combination with a 10-day chronic social defeat stress (CSDS) model in male mice to investigate whether the sympathoadrenal system is involved in the ghrelin response to stress. We also examined the antidepressant-like efficacy of administered ghrelin and the synthetic GHSR agonist GHRP-2 during and/or after CSDS. We found that administration of the β1-adrenergic receptor (β1AR) blocker atenolol during CSDS blunts the elevation of plasma acyl-ghrelin and exaggerates depressive-like behavior. Neither acute injection of acyl-ghrelin directly following CSDS nor its chronic administration during or after CSDS nor chronic delivery of GHRP-2 during and after CSDS improved stress-induced depressive-like behavior. Thus, β1ARs drive the acyl-ghrelin response to CSDS, but supplementing the natural increases in acyl-ghrelin with exogenous acyl-ghrelin or GHSR agonist does not further enhance the antidepressant-like actions of the endogenous ghrelin system in the setting of CSDS.

Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of the existing conventional drugs with poor outcome may be, in part, due to uncertainty of the mechanism involved that clearly explains the existing comorbidity. The main purpose of this review was to address the sophisticated mechanisms of this comorbidity with a view of developing potential novel targets with higher efficacy and specificity. Data were collected from database searches including PubMed, references from relevant English language research/review articles and other official publications. Articles from 1990 to 2013 were included, and a broad search term criteria were followed for data mining so that relevant information was not missed out. Some of the search terms used included; diabetes-induced depression, diabetes and serotonin, hypothalamic-pituitary-adrenal (HPA) axis and diabetes and glucocorticoids in diabetes. Neuropathologically, depletion of brain monoaminergic activity specifically the serotonin (5-hydroxytryptamine [5-HT]) system, due to chronically persisting diabetic state may lead to the mood and behavioral complications that further add on worsening the quality life years. The 5-HT system through multifunctional tasks regulates neurogenesis and plasticity and by complex receptor mechanism controls the emotional and behavioral activity. Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity. The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits. HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression.

Aim: To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression., Methods: 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments., Results: The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group., Conclusion: 6z is a novel 5-HT3 receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.

N-Cyclohexyl-3-methoxyquinoxalin-2-carboxamide (QCM-13), a novel 5-HT3 antagonist identified from a series of compounds with higher pA2 (7.6) and good log P (2.91) value was screened in rodent models of depression such as forced swim test (FST), tail suspension test (TST), interaction studies with standard anti-depressants and confirmatory studies such as reversal of parthenolide induced depression and reserpine induced hypothermia. In FST (2 and 4 mg/kg) and TST (2 and 4 mg/kg), QCM-13 significantly reduced the duration of immobility in mice without affecting the base line locomotion. QCM-13 (2 and 4 mg/kg) was also found to have significant interaction with standard anti-depressants (fluoxetine and bupropion in FST and TST respectively). Further, reversal of parthenolide induced depression in mice and reserpine induced hypothermia in rat models indicate the serotonergic influence of QCM-13 for anti-depressant potential.

Objective: To investigate the antidepressant-like effect of N-(benzo[d] thiazol-2-yl)-3- ethoxyquinoxalin-2-carboxamide 6k, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist using rodents behavioral battery tests. Materials and Methods: 6k screening was performed with behavioral assays for depression-like forced swim test (FST) at several single doses (0.25-4 mg/kg, intraperitoneal injection (i.p.)) to test the potency of 6k, in which 2 and 4 mg/kg doses were found to be most effective and hence, in further behavioral assays including mechanistic model like 5-hydroxytryptophan (5-HTP)-induced head twitches was performed in mice at acute doses of 6k (2 and 4 mg/kg, i.p.). Furthermore, olfactory bulbectomy (OBX), a surgical model-induced behavioral alterations was performed in rats, and the effect of 6k administered orally (2 and 4 mg/kg, p.o.) after subchronic treatment for 14 days starting from day 15 of postsurgery was examined by percent sucrose preference test and modified open field test (OFT). Results: 6k (1, 2, and 4 mg/kg, i.p.) reduced the immobility time and increased the swimming behavior in FST without affecting the baseline locomotor score showing antidepressant-like effect. 5-HTP-induced head twitch response was potentiated by 6k (2 and 4 mg/kg, i.p.), which indicated rise in the serotonergic neurotransmission in the brain. 6k (2 and 4 mg/kg, p.o.) showed anti-anhedonia effect by increasing the sucrose consumption and reversed the behavioral alterations when exposed to modified open field in OBX rats after subchronic treatment for 14 days, thus exhibiting antidepressant-like effect. Conclusion: 6k attenuated the behavioral derangement in rodents-based behavioral battery tests for depression, indicating antidepressant-like potential. [ABSTRACT FROM AUTHOR]

Background: Depression is a neurological disorder characterized by sad mood, loss of pleasure, agitation and retardation. Though most relevant neuronal pathophysiology is characterized by decrease in monoamine namely; serotonin (5-HT), dopamine, noradrenaline level in central areas regulating mood and behavior, it inadequately explains the exact mechanism involved. Buspirone (BUS), a partial 5-HT1A receptor agonist has shown promising anti-depressant and anxiolytic properties in various pre-clinical and clinical studies, but the molecular and cellular mechanisms are still unclear. Objective: The aim of this study was to investigate, in vivo, the role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation in pathophysiology of depression-related disorders and the anti-depressant like activity of BUS. To simulate HPA axis dysregulation, rats were subjected to bilateral adrenalectomy (ADX). Materials and Methods: We have analyzed effect of BUS (10 mg/kg, i.p.) in ADX and sham rats using open field, sucrose consumption, elevated plus maze and hyper-emotionality tests. Results: In all animal models tested, ADX rats exhibited significant depressive and anxiogenic states while BUS was effective in reversing the psychological diseased condition developed. Conclusion: Taken together, these data showed a prominent role of HPA axis in depression and neuronal mechanism of BUS as anti-depressant and anxiolytic agent. Moreover, our findings suggest that BUS can be a better candidate for stress related depression and anxiety. [ABSTRACT FROM AUTHOR]