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Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored. Impact accelerated TBI by weight drop method causes depression-like behavioral deficits in modified open field exploration, hyper-emotionality and sucrose consumption paradigms. TBI not only causes immediate mechanical damage to the brain, but also induces biochemical changes that lead to delayed neural cell loss leading to a secondary injury. The present study examines the antidepressant effects of ETZ on the TBI-induced depression-like behavior deficits and attempts to explore the underlying mechanism. In order to understand the underlying pathology of TBI and mechanism(s) of ETZ in TBI molecular markers namely, brain cAMP, cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were estimated. Additionally, the level of oxidative (lipid peroxidation) & nitrosative (nitrite) stress markers, along with antioxidant enzymes markers, such as, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured. Furthermore, the involvement of hypothalamic-pituitary adrenal (HPA) axis activity in underlying mechanism was also investigated by measuring serum corticosterone (CORT) level. The results revealed that TBI significantly altered cAMP, pCREB and BDNF levels. Moreover, a significant increase in oxidative–nitrosative stress markers levels, while, significant decreases in antioxidant enzymes markers level were observed. However, no significant change was observed in serum CORT level. Chronic ETZ (0.5 and 1 mg/kg) treatment significantly attenuated TBI-induced behavioral deficits and restored the TBI induced derangements in molecular and biochemical markers. This study indicates that ETZ modulates cAMP signaling and oxidative/antioxidant markers in the TBI model suggesting its prospect as a potential candidate for the pharmacotherapy of depression.

Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARγ) agonist belonging to thiazolidinedione class, is mainly used in diabetes mellitus. Obese subjects are twice likely to become depressed than non-obese individuals. The biological mechanisms linking depression with obesity still remain poorly understood and there is immense need for better therapeutic intervention against such co-morbid disorders. The present study investigates the effect of pioglitazone on the chronic unpredictable mild stress (CUMS) induced depression in obese mice by using behavioral tests and biochemical estimations. Mice were fed with high fat diet (HFD) for 14 weeks and were further subjected to different stress procedures for 28 days to induce depressive behavior. Animals were administered orally with pioglitazone (30 mg/kg p.o.)/escitalopram (10 mg/kg p.o.)/vehicle (10 ml/kg p.o.) daily from day 15–28. Various behavioral paradigms such as sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM) were performed. Biochemical estimations including plasma glucose, total cholesterol, triglycerides, and total proteins were performed. The data obtained from behavioral assays and biochemical assessments indicated that obese animals exhibited severe depressive-like behavior compared to non-obese animals. Furthermore, obese animals subjected to CUMS worsen the depressive behavior compared to obese control animals. Repetitive treatment with pioglitazone reversed the CUMS induced behavioral and biochemical alterations in HFD fed obese mice which atleast in part may be mediated through improving altered plasma glucose. The study suggests that pioglitazone needs further attention with respect to molecular mechanisms that could provide a better therapeutic strategy against depression associated with obesity., Graphical abstract, Highlights • Obese animals subjected to chronic stress worsens depressive symptoms. • Altered plasma glucose involved in depression co-morbid with obesity. • Pioglitazone inhibited behavioral alterations in obese mice subjected to stress. • Pioglitazone attenuated the biochemical changes in obese mice subjected to stress. • Antidepressant-like effect of pioglitazone in depression associated with obesity.

Despite of the enormous research, therapeutic treatment for depression has always been a serious issue. Even though depression and obesity are individual abnormal health conditions, each act as a triggering factor for the other. Obese individuals are twice prone to develop depression than that of non-obese persons. The exact mechanism how obesity increases the risk for depression still remains an area of interest for research in neuropsychopharmacology. Depression and obesity share some common pathological pathways such as hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of oxidant/antioxidant system balance, higher level of inflammatory cytokines, leptin resistance, altered plasma glucose, insulin resistance, reduced neuronal brain derived neurotrophic factor (BDNF) and decreased serotonergic neurotransmission in various regions of brain. The antidepressant-like effect of 5-HT3 receptor antagonists through allosteric modulation of serotonergic pathways is well evident from several research investigations belonging to our and some in other laboratories. Furthermore, serotonin regulates diet intake, leptin, corticosterone, inflammatory mechanisms, altered plasma glucose, insulin resistance and BDNF concentration in brain. The present review deals with various biological mechanisms involved in depression co-morbid with obesity and 5-HT3 receptor antagonists by modulation of serotonergic system as a therapeutic target for such co-morbid disorder.

In our earlier study we reported the antidepressant activity of ondansetron in obese mice. The present study investigates the effect of ondansetron on depression and anxiety associated with obesity in experimental mice with biochemical evidences. Male Swiss albino mice were fed with high fat diet (HFD) for 14 weeks to induce obesity. Then the subsequent treatment with ondansetron (0.5 and 1 mg/kg, p.o.), classical antidepressant escitalopram (ESC) (10 mg/kg, p.o.) and vehicle (distilled water 10 ml/kg, p.o.) was given once daily for 28 days. Behavioral assay for depression including sucrose preference test, forced swim test (FST) and anxiety such as light dark test (LDT) and hole board test (HBT) were performed in obese mice. Furthermore, in biochemical estimations oral glucose tolerance test (OGTT), plasma leptin, insulin, corticosterone, brain oxidative stress marker malonaldehyde (MDA), antioxidant reduced glutathione (GSH) and serotonin assays were performed. Results indicated that HFD fed obese mice showed severe depressive and anxiety-like behaviors. Chronic treatment with ondansetron inhibited the co-morbid depression and anxiety in obese mice by increasing sucrose consumption in sucrose preference test and reducing the immobility time in FST, increasing time and transitions of light chamber in LDT, improving head dip and crossing scores in HBT compared to HFD control mice. Ondansetron in obese mice inhibited glucose sensitivity in OGTT, improved plasma leptin and insulin sensitivity, reversed hypothalamic pituitary adrenal (HPA) axis hyperactivity by reducing the corticosterone concentration, restored brain pro-oxidant/anti-oxidant balance by inhibiting MDA and elevating GSH concentrations and facilitated serotonergic neurotransmission. In conclusion, ondansetron reversed the co-morbid depression and anxiety associated with obesity in experimental mice by attenuating the behavioral and biochemical abnormalities.

Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity. Mice were fed with high fat diet (HFD) for 14 weeks, further subjected for treatment with QCM-4 (1 and 2 mg/kg p.o.) and standard antidepressant escitalopram (ESC) (10 mg/kg p.o.) for 28 days. Behavioral assays for depression such as sucrose preference test (SPT), forced swim test (FST) and for anxiety such as light and dark test (LDT) and hole board test (HBT) were performed in obese mice. Biochemical assessments including plasma leptin and corticosterone concentration followed by brain oxidative stress parameters malonaldehyde (MDA) and reduced glutathione (GSH) were performed. Results confirmed that QCM-4 exhibits antidepressive effect by increasing the sucrose consumption in SPT, reducing immobility time in FST and anxiolytic effect by increasing transitions and time in light chamber in LDT, increasing head dip and crossing score in HBT. Furthermore, QCM-4 attenuated the hypothalamic–pituitary–adrenal (HPA) axis hyperactivity by reducing the plasma corticosterone, reversing altered plasma leptin, restoring the imbalance of brain MDA and GSH concentration. In conclusion, QCM-4 showed antidepressive and anxiolytic effect by reversing the behavioral alterations that were supported by biochemical estimations in obese mice.

Stimulation of high oxidative stress in the brain is considered as an important factor for neurotoxicity towards the pathophysiology of chronic stress-induced depression disorder. In the present research, a potential 5-HT 3 receptor antagonist N -n-butyl-3-methoxy quinoxaline-2-carboxamide ( 6o ) having good Log P (2.60) and p A 2 (7.7) values was examined for its effect on the behavioral and biochemical changes induced by the chronic unpredictable mild stress (CUMS) model. In the current investigation mice were introduced to different stress procedures daily for a period of 28 days to induce a depressive-like behavior. The results show that CUMS caused a depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and locomotor activity and increase in immobility in the forced swim test (FST). Moreover, it was found that oxidative stress markers such as lipid peroxide and nitrite levels were significantly increased, whereas, antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in the brain tissue of CUMS-subjected mice. “Compound 6o ” (1 and 2 mg/kg, p.o.) and fluoxetine treatment (20 mg/kg, p.o.) for a period of 21 days altered the CUMS-induced behavioral (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxide, increased brain nitrite; decreased GSH, SOD and CAT levels) alterations. Moreover normal mice treated with “compound 6o ” (2 mg/kg, p.o.) showed a significant decrease in the duration of immobility in FST as compared to normal vehicle treated mice. In conclusion, “compound 6o ” produced antidepressant-like effects in behavioral despair paradigm in chronically stressed mice by restoring antioxidant enzyme activity.

Preliminary study in our laboratory showed that etazolate produced antidepressant- and anxiolytic-like effects in rodent models, however, the ability of etazolate to produce antidepressant- and anxiolytic-like effects and underlying mechanism(s) in chronic unpredictable mild stress (CUMS) model have not been adequately addressed. This study was aimed to investigate the beneficial effects of etazolate on CUMS-induced behavioral deficits (depression- and anxiety-like behaviors). In addition, the possible underlying mechanism(s) of etazolate in CUMS model was also investigated by measuring serum corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels. Mice were subjected to a battery of stressors for 28 days. Etazolate (0.5 and 1 mg/kg, p.o.) and fluoxetine (20mg/kg, p.o.) were administered during the last 21 days (8-28th) of the CUMS paradigm. The results showed that 4-weeks CUMS produces significant depression-like behavior in tail suspension test (TST) and partial anxiety-like behavior in elevated plus maze (EPM) and open field test (OFT). Stressed mice have also shown a significant high serum CORT and low BDNF level. Chronic treatment with etazolate (0.5 and 1mg/kg., p.o.) and fluoxetine (20mg/kg., p.o.) produced significant antidepressant-like behavior in TST (decreased duration of immobility), whereas, partial anxiolytic-like behavior in EPM (increased percentage of open arm entries) and OFT (increased % central ambulation score, total ambulation score and time spent in center zone). In addition, etazolate and fluoxetine treatment significantly (p

The present study was designed to investigate the putative antidepressant-like activity of 7a, a 5-HT3 receptor antagonist, (although indirect evidence of 5-HT3 antagonism) with an optimal log P (3.35) and pA2 value (7.6) greater than ondansetron (pA2 — 6.6) using behavioural tests battery of depression. Acute treatment of 7a (0.5-2 mg/kg, i.p.) in mice produced antidepressant-like effects in forced swim test (FST) and tail suspension test (TST) without affecting the baseline locomotion in actophotometer test in mice. Moreover, the combination of a sub-effective dose of 7a (0.25 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) produced an anti-immobility effect in mouse FST. Pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days) and 1-(m-Chlorophenyl)-biguanide (mCPBG, 10 mg/kg, i.p., a 5-HT3 receptor agonist) prevented the anti-immobility effects of 7a (2 mg/kg, i.p.) in the mouse FST. In addition, 7a (0.5–2 mg/kg, i.p.) treatment also potentiated the 5-hydroxytryptophan (5-HTP) and pargyline induced head twitch response in mice. Furthermore, sub-chronic treatment (14 days) with 7a (0.5–2 mg/kg, i.p.) and paroxetine (10 mg/kg, i.p.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in a modified open field paradigm. These results suggest that the antidepressant-like action of 7a may be mediated by an interaction with the serotonergic system and this molecule should be further investigated as an alternative therapeutic approach for the treatment of depression.

Linezolid, an oxazolidinone class antibiotic is a reversible and nonselective inhibitor of monoamine oxidase (MAO) enzyme, mainly for MAO-A subtype. Its antidepressant-like effect has been previously demonstrated in the rodent models of depression. MAO-A enzyme has been shown to play a role in the pathophysiology of anxiety disorders and inhibition of MAO-A in the brain could be used to treat anxiety disorders. Thus, the objective of this study was to investigate the putative anxiolytic effects of linezolid in rodent models of anxiety. Mice were acutely injected with linezolid (5-40 mg/kg, i.p.), diazepam (2 mg/kg, i.p.) and moclobemide (10 mg/kg., i.p.). Linezolid (20 and 40 mg/kg), diazepam and moclobemide significantly (p

A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT(3) receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methyl-5-HT, which was expressed in the form of pA(2) value. All the synthesized compounds showed antagonism towards 5-HT(3) receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT(3) receptor antagonists may have hydrophobic interaction with 5-HT(3) receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA(2) values exhibited good anti-depressant-like activity as compared to the vehicle-treated group.

Depression and anxiety tend to be the most prevalent conditions among the multitude of neurobehavioural disorders which cause distress in the survivors of traumatic brain injury (TBI). The objective of the present investigation was to examine depression-like and anxiety-like behaviour of rats following diffuse TBI. Impact accelerated TBI was induced in anaesthetised rats by a modified weight drop method. TBI and sham-operated rats received either a chronic (14 days) regimen of escitalopram (5-20 mg/kg) or vehicle, following which they were subjected to a behavioural test battery. The results evince the depression-like behaviour of TBI rats in modified open field exploration, hyperemotionality, socio-sexual interaction and elevated plus-maze exploration paradigms. In addition, an anxiety-like behaviour was evident in social interaction and marble-burying tests. Chronic escitalopram (10 and 20 mg/kg) treatment significantly attenuated the TBI associated behavioural deficits. In conclusion, the aforesaid behavioural anomalies observed in TBI rats are analogous to comorbid anxiety and depression in humans. These findings substantiate the TBI rats as a candidate model of comorbid anxiety and depression.

1-( m -Chlorophenyl)piperazine ( m CPP) has a fairly complex neuropsychopharmacological profile owing to its affinity to multiple serotonergic receptors. This investigation was designed to establish the effect of m CPP on rodent depression-like behaviour. m CPP was screened in a rodent behavioural test battery comprising of validated antidepressant assays and interaction studies with conventional antidepressants and ligands were carried out in forced swim and tail suspension test (in mice). m CPP (1 mg/kg, i.p.) exhibited depressant-like effects in forced swim and tail suspension test (in mice), without influencing the locomotor status. Potentiation of 5-hydroxytryptophan/pargyline induced head twitches (in mice) and hyperthermic effects (in rats) were observed at the same dose level. Further, the behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic m CPP (1–2 mg/kg) treatment as observed from the modified open field, elevated plus maze and social interaction paradigms. Interaction studies revealed that the m CPP induced depressant-like effects were reversed by ketanserin, escitalopram, amitriptyline, ziprasidone, venlafaxine pretreatments but not by bupropion, harmane, ondansetron, 8-hydroxy-2-(di- n -propylamino) tetralin (8-OH-DPAT) and MK-801. In conclusion, this study provided ample evidence that the stimulation of 5-HT 2A receptors underlies the depressogenic-like effect of m CPP. Finally, the m CPP induced depression-like behaviour in rodents is envisaged as a modified antidepressant assay to identify novel serotonergic antidepressants.

A series of novel 3-substituted quinoxalin-2-carboxamides were designed as per the pharmacophoric requirement for 5-HT(3) receptor antagonists and prepared by microwave irradiation and also by conventional method. The compounds were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. The synthesized compounds were evaluated for 5-HT(3) antagonisms in longitudinal muscle-myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methyl-5-HT. Among the test compounds, N-{3-[(4-methylpiperazin-1-yl)methyl]-4-hydroxyphenyl}-3-methoxyquinoxalin-2-carboxamide 4e showed most favorable 5-HT(3) receptor antagonism.