Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABAA receptor.

Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET-induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p-FADD and other neuroplastic markers in brain. Low (5-15 mg/kg) and high (150 mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex. During the time course of KET (150 mg/kg)-induced sleep (up to 50 min) p-MEK was increased (up to +79%) and p-ERK decreased (up to -46%) indicating disruption of MEK to ERK signal. Subhypnotic KET (5-15 mg/kg) also revealed uncoupling of p-MEK (+13-81%) to p-ERK (unchanged content). KET did not alter contraregulatory MAPK mechanisms such as inactivated p-MEK1 (ERK dampening) and phosphatases MKP1/2/3 (ERK dephosphorylation). As other relevant findings, KET (5, 15 and 150 mg/kg) upregulated p-FADD in a dose-dependent manner, and for the hypnotic dose the effect paralleled the time course of sleep which resulted in increased p-FADD/FADD ratios. KET (150 mg/kg) also increased NF-κΒ and PSD-95 neuroplastic markers. Flumazenil (a neutral allosteric antagonist at GABAA receptor) prolonged KET sleep and blocked p-MEK upregulation, indicating the involvement of this receptor as a negative modulator. SL-327 (a MEK inhibitor) augmented KET sleep, further indicating the relevance of reduced p-ERK1/2 in KET-induced hypnosis. These findings suggest that hypnotic and subhypnotic doses of KET inducing uncoupling of p-MEK to p-ERK signal and regulation of p-ERK (downregulation) and p-FADD (upregulation) may participate in the expression of some of its adverse effects (e.g. amnesia, dissociative effects).

Evidence for the Involvement of Monoaminergic Pathways in the Antidepressant-Like Activity of Cymbopogon citratus in Mice.

Objectives Depression is a complex neuropsychiatric disorder, which affects the quality of life of the sufferers and treatment approach is associated with serious adverse effects and sometimes therapeutic failures. Cymbopogon citratus leaf (CC) has been reported to exert anti-depressant effect but its mechanism of action is yet to be elucidated hence, the need for this study. Methods The anti-depressant-like effect of Cymbopogon citratus aqueous leaf was evaluated using forced swim test (FST), tail suspension test (TST) and yohimbine-induced lethality test (YLT) in aggregated mice. Interaction studies involving p-chlorophenylalanine (pCPA), an inhibitor of serotonin biosynthesis and yohimbine, α2-adrenergic receptor antagonist were carried out to evaluate the role of monoaminergic system in the anti-depressant-like effect of CC. The effect of CC on spontaneous motor activity (SMA) was also assessed using activity cage. ResultsCymbopogon citratus (25 and 50 mg/kg, p.o.) demonstrated antidepressant-like activity devoid of significant stimulation of the SMA in mice. However, the antidepressant-like property of CC was significantly (p<0.05) attenuated by pretreatment with yohimbine suggesting involvement of noradrenergic pathway in the action of the extract. Also, pCPA reversed the anti-immobility effect of CC, indicating the role of serotonergic system in the mediation of its antidepressant activity. Moreover, CC (25 and 50 mg/kg) potentiated the lethal effect of yohimbine in aggregated mice, which further suggest the involvement of monoaminergic systems in its action. Conclusions The results of the study showed that C. citratus might be interacting with serotonergic and noradrenergic pathways to mediate its anti-depressant-like effect in mice.

Kamishoyosan reduces conditioned fear-induced freezing behavior in socially isolated ovariectomized rats.

In the present study, we investigated the effect of kamishoyosan (KSS) on conditioned fear-induced freezing in ovariectomized (OVX) rats. Socially isolated OVX rats showed the longest freezing time among the following four groups: group-housed sham-operated (Sham), isolated Sham, group-housed OVX, and isolated OVX rats. Repeated oral administration of KSS (30-300 mg/kg) reduced conditioned fear-induced freezing in socially isolated OVX rats. The reduction of freezing by KSS was reversed by flumazenil (3 mg/kg) and bicuculline (3 mg/kg). These findings suggest that the GABAA-benzodiazepine receptor complex is involved in the anxiolytic effect of KSS in socially isolated OVX rats.

Melatonin modulates tonic immobility and vigilance behavioural responses of broiler chickens to lighting regimens during the hot-dry season.

Experiments were conducted with the aim of determining the influence of melatonin administration on vigilance and tonic immobility (TI) responses of Marshall broiler chickens. The broiler chickens were reared on different lighting regimens and subjected to heat stress during the hot-dry season. Simple random sampling was used to assign 300 broiler chicks into three groups, comprising 100 broiler chicks each. Group I (12D:12L cycle) was raised under natural photoperiod of 12-h light and 12-h darkness, without melatonin supplementation. Group II (CL) was kept under 24-h continuous lighting, without melatonin administration. Group III (CL+MEL) was raised under 24-h continuous lighting; with melatonin supplementation at 0.5mg/kg per os, via drinking water using a syringe. Beginning from day-old, broiler chickens in group III were individually administered with melatonin once daily for 8weeks at 17:00h. TI was induced by manual restraint, and vigilance elicited at self-righting graded for three days, two weeks apart, in 15 labeled broiler chickens from each of the three groups; at 06:00h, 13:00h and 18:00h, starting from week 4-8. Each broiler chicken was laid on its back in a U-shaped cradle, covered with cloth. Thermal microenvironment parameters of dry bulb temperature (DBT) and relative humidity (RH) were recorded at the experimental site, concurrently during the vigilance and TI tests. Inside the broiler chickens' house, the weekly temperature-humidity index (THI) was lowest at week 4 of the study, with the value of 48.60±0.08°C. At week 4, the relationship between the THI and TI induction attempts was stronger in 12D:12L cycle (r=0.589, P<0.001) than CL (r=0.264, P>0.05) or CL+MEL (r=0.096, P>0.05) broiler chickens. This indicated that the broiler chickens on 12D:12L cycle were more active compared to their melatonin-treated counterparts, apparently due to adverse effects of high DBT and high RH on the broiler chickens during the hot-dry season. The highest numbers of TI induction trial attempts were recorded at 13:00h in 12D:12L cycle and CL groups (2.13±0.34 and 2.15±0.22, respectively), when the broiler chickens were at week 8. The overall mean values of induction trial attempts differed significantly (P<0.0001) between the groups; with the lowest mean values of 1.22±0.4 recorded in CL+MEL broiler chickens. At day 42, the lowest mean TI duration of 101.87±10.24s in the CL group, recorded at 06:00h rose (P<0.001) to 184.07±23.69s at 13:00h. The overall mean duration of TI differed significantly (P<0.0001) again between the groups; with the highest mean duration of 167.82±8.35s, recorded in CL+MEL broiler chickens administered with melatonin. The overall mean vigilance behavioural ranking values of 1.85+0.07 and 1.70+0.08, obtained in 12D:12L cycle and CL broiler chickens, respectively were higher (P<0.0001) than the value of 1.44+0.05 recorded in melatonin-treated broiler chickens. The results indicated that broiler chickens belonging to both 12D:12L cycle and CL groups were more emotional, fearful or anxious, compared to CL+MEL broiler chickens. It was concluded that melatonin administration elicits boldness and confidence by suppressing freezing behaviour in broiler chickens, and it may improve their welfare and productivity.

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice.

Ketamine, a dissociative anesthetic, produces rapid and sustained antidepressant effects at subanesthtic doses. However, it still inevitably induces psychotomimetic side effects. N,N-dimethylglycine (DMG) is a derivative of the amino acid glycine and is used as a dietary supplement. Recently, DMG has been found acting at glycine binding site of the N-methyl-d-aspartate receptor (NMDAR). As blockade of NMDARs is one of the main mechanisms responsible for the action of ketamine on central nervous system, DMG might modulate the behavioral responses to ketamine. The present study determined the effects of DMG on the ketamine-induced psychotomimetic, anesthetic and antidepressant-like effects in mice. DMG pretreatment reversed the ketamine-induced locomotor hyperactivity and impairment in the rotarod performance, novel location and novel object recognition tests, and prepulse inhibition. In addition, DMG alone exhibited antidepressant-like effects in the forced swim test and produced additive effects when combined with ketamine. However, DMG did not affect ketamine-induced anesthesia. These results reveal that DMG could antagonize ketamine's psychotomimetic effects, yet produce additive antidepressant-like effects with ketamine, suggesting that DMG might have antipsychotic potential and be suitable as an add-on therapy to ketamine for patients with treatment-resistant depression.

Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats.

Over 180 million people consume cannabis globally. Cannabis use peaks during adolescence with a trend for continued consumption by adults. Notably, several studies have shown that long-term and heavy cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders, although the neurobiological mechanisms underlying this association remain largely unknown. In this study, we evaluated whether, in female rats, chronic administration of increasing doses of the psychotropic plant-derived cannabis constituent, delta-9-tetrahydrocannabinol (THC), during adolescence (PND 35-45) could affect microglia function in the long-term. Furthermore, we explored a possible contribution of microglia to the development of THC-induced alterations in mood and cognition in adult female rats. Present data indicate that adolescent THC administration induces a persistent neuroinflammatory state specifically localized within the adult prefrontal cortex (PFC), characterized by increased expression of the pro-inflammatory markers, TNF-α, iNOS and COX-2, and reduction of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with down-regulation of CB1 receptor on neuronal cells and up-regulation of CB2 on microglia cells, conversely. Interestingly, blocking microglia activation with ibudilast during THC treatment significantly attenuates short-term memory impairments in adulthood, simultaneously preventing the increases in TNF-α, iNOS, COX-2 levels as well as the up-regulation of CB2 receptors on microglia cells. In contrast, THC-induced depressive-like behaviors were unaffected by ibudilast treatment. Our findings demonstrate that adolescent THC administration is associated with persistent neuroinflammation within the PFC and provide evidence for a causal association between microglial activation and the development long-term cognitive deficits induced by adolescent THC treatment.

Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance.

Ketamine, N-methyl-d-aspartate (NMDA) receptor antagonist and anti-inflammatory agent, has rapid therapeutic effects in a subset of patients with more intractable forms of depression. Irregular proinflammatory cytokine and acute-reactive protein levels have been reported in clinical and preclinical depression research. We explored the association between the rapid antidepressant-like effects of ketamine and peripheral proinflammatory profile in a model of antidepressant-resistance. Male Wistar rats were pre-treated with ACTH-(1-24) 100µg/d or saline (0.9%) for 14d. Antidepressant-like effects were assessed with the forced swim test (FST). Ketamine (10mg/kg) significantly reduced immobility duration in saline-pretreated control animals. In contrast, a divergent response was observed in ACTH-pretreated antidepressant resistant animals, with 50% responders and 50% non-responders. Plasma samples were analyzed via enzyme-linked immunosorbent assay (ELISA) for interleukin 6 (IL-6), tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP). Levels of CRP and TNFα differentiated ketamine responders and non-responders.

Antioxidants safeguard telomeres in bold chicks.

Telomeres are sensitive to damage induced by oxidative stress, and thus it is expected that dietary antioxidants may support the maintenance of telomere length in animals, particularly those with a fast rate of life (e.g. fast metabolism, activity and growth). We tested experimentally the effect of antioxidant supplements on telomere length during early development in wild gull chicks with natural individual variations in behaviour pattern and growth rate. Proactive chicks had shorter telomeres than reactive chicks, but the penalty for the bold behaviour pattern was reduced by antioxidant supplementation. Chicks growing faster had longer telomeres during early growth, suggesting that inherited quality supports a fast life history.

Antidepressant and anxiolytic effects of the methanol root extract of Capparis thonningii: involvement of monoaminergic, cholinergic and GABAergic systems.

BACKGROUND: Capparis thonningii Schum. (Capparaceae) is used in traditional African Medicine for the treatment of mood disorders. OBJECTIVE: The study investigates antidepressant and anxiolytic activities of methanol root extract of C. thonningii (CT). METHODS: CT (25-100 mg/kg, p. o.) was administered 1 h before behavioral studies were carried out in mice. Antidepressant effect was investigated using the forced swimming test (FST) and tail suspension test (TST). The anxiolytic effect was evaluated using the elevated-plus maze test (EPM), hole-board test (HBT), and light-dark test. RESULTS: CT (25 and 50 mg/kg) increased swimming activity (P<0.05) by 92.73% and attenuated immobility time by 35.72%, similar to anti-immobility effect of imipramine (33.87%) in FST. In addition, CT (50 mg/kg) significantly (P<0.01) reduced immobility time by 30.24% in TST. -However, the antidepressant-like effect elicited by CT was reversed by metergoline, cyproheptadine, and sulpiride (40.81, 45.93, and 48.52%, respectively) pretreatment but prazosin, and yohimbine failed to reverse this antidepressant-like effect. Similar to diazepam, CT (25 mg/kg) increased duration of open arms exploration (P<0.05) by 43.73% in EPM, number of head-dips (HBT) (90.32%), and time spent in the light compartment by 45.77% in light/dark test indicating anxiolytic-like effect. The anxiolytic-like effect of CT was reversed by flumazenil pretreatment. CONCLUSION: The findings from this study suggest antidepressant-like effect of C. thonningii involving interaction with serotonergic (5-HT2), dopaminergic (D2), noradrenergic (α1 and α2), and muscarinic cholinergic systems; and anxiolytic effect through an interaction with GABAA benzodiazepine receptor.

Effects of supplemental vitamin C and chromium on metabolic and hormonal responses, antioxidant status, and tonic immobility reactions of transported broiler chickens.

Three hundred female broilers were assigned to five groups with six replicates and were fed with either a basal diet (two control groups) or the basal diet supplemented with 800-mg vitamin C/kg (Vit C group), 1,200-µg Cr(+3) from chromium (Cr) chloride/kg (Cr group) or 800-mg Vit C and 1,200-µg Cr(+3) from Cr chloride/kg (Vit C + Cr group) from 42 to 49 days of age. Treatments did not affect performance. Transport decreased insulin level in the control and Cr groups and increased glucose/insulin (G/I) ratio in the groups. The level of insulin was higher in the Vit C + Cr group than those in the control and Cr groups after the transport. The G/I ratio was lowest in the Vit C + Cr group after the transport. The transport significantly decreased triiodothyronine (T3) concentration in the groups except the Vit C + Cr group and only increased thyroxin (T4) concentration in the Vit C + Cr group. The T3/T4 ratio was significantly decreased in the groups except the Cr group by transport. The T3/T4 ratio was greatest in the Vit C + Cr group before the transport. Alkaline phosphatase activity was decreased in the Vit C + Cr group due to transport. Transport decreased triglyceride levels in the groups and also decreased low-density lipoprotein cholesterol levels in the Vit-C-supplemented groups. Transport increased malondialdehyde concentration in the control and Vit C groups and also increased glutathione peroxidase (GPx) activity in the Cr-fed groups. The GPx activity was higher in the Vit C + Cr group than those in the control and Cr groups after the transport. Ferric reducing/antioxidant power (FRAP) value was decreased in the Vit C and Cr groups by transport. Either alone or in combination, Cr increased the FRAP value before the transport. Neither transport nor treatments had significant effects on the duration of tonic immobility (TI) and number of inductions to induce TI.

Diphenyl diselenide supplemented diet reduces depressive-like behavior in hypothyroid female rats.

Hypothyroidism has been associated to psychiatric disorder development and tissue oxidative damage. In this study, we evaluated the effect of diphenyl diselenide supplementation on depressive-like behavior triggered by methimazole exposure in female rats. Additionally, thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS) and non-protein thiol (NP-SH) levels were analyzed in cerebral cortex, hippocampus and striatum structures of rats. Monoamine oxidase (MAO) activity was evaluated in total brain. Firstly, female rats received methimazole (MTZ) 20mg/100ml in the drinking water for 30days and were evaluated in open-field and forced swimming tests (FST). In this set of experiments, the rats exposed to MTZ presented a depressive-like behavior, which was evidenced by a significant increase in the immobility time when compared to control group. Thereafter, MTZ-induced hypothyroid rats received either a standard or a diet containing 5ppm of diphenyl diselenide, and then they were evaluated monthly in open-field and FST tests during 3months. No alteration on the locomotor performance was observed among the groups. The depressive-like behavior of hypothyroid rats was blunted by diphenyl diselenide supplementation during all experimental periods. The levels of thyroid hormones remained low in MTZ exposed groups until the end of experimental period. The MTZ group had an increase in TBARS and ROS levels that were restored by diphenyl diselenide supplementation. NP-SH content of cerebral structures was not modified by MTZ exposure and/or diphenyl diselenide supplementation. Diphenyl diselenide supplementation restored the MAO B activity that was decreased in MTZ group. In summary, our results show that hypothyroidism induced by MTZ methimazole triggers a depressive-like behavior in female rats and that dietary diphenyl diselenide was able to reduce this effect.

Altered expression of 5-HT1A receptors in adult rats induced by neonatal treatment with clomipramine.

Chronic administration of clomipramine (CMI) to neonatal rats produces behaviors that resemble a depressive state in adulthood. Dysfunctions in the activity of the central nervous system's serotonergic function are important in understanding the pathophysiology of depression. The serotonin system is implicated in major depression and suicide and is negatively regulated by somatodendritic 5-HT1A autoreceptors. Desensitization of 5-HT1A autoreceptors is implicated in the long latency of some antidepressant treatments. Alterations in 5-HT1A receptor levels are reported in depression and suicide. In this study, we analyzed the effect of neonatal administration of CMI on the activity of 5-HT1A receptors, both pre- and post-synaptically, by administering an agonist of 5-HT1A receptors, 8-OH-DPAT, and then subjecting the rats to the forced swimming test (FST) a common procedure used to detect signs of depression in rats. Also measured were levels of the mRNA expression of 5-HT1A receptors in the dorsal raphe (DR), the hypothalamus and the hippocampus. Wistar rats were injected twice daily with CMI at doses of 15mgkg(-1) or saline as vehicle (CON) via s.c. from postnatal day 8 for 14days. At 3-4months of age, one set of rats from each group (CON, CMI) was evaluated for the effect of a selective agonist to the 5-HT1A receptor subtype, 8-OH-DPAT, by testing in the FST. Also determined was the participation of the pre- or post-synaptic 5-HT1A receptor in the antidepressant-like action of 8-OH-DPAT. This involved administering an inhibitor of tryptophan hydroxylase, parachlorophenylalanine (PCPA), and pretreatment with 8-OH-DPAT before the FST test and to evaluate the rectal temperature and locomotor activity. The expression of the mRNA of the 5-HT1A receptors was examined in the dorsal raphe nucleus, the hypothalamus and the hippocampus using the semi-quantitative RT-PCR method. The results from this study corroborate that neonatal treatment with clomipramine induces a pronounced immobility in the FST when animals reach adulthood, manifested by a significant decrease in swimming behavior, though counts of climbing behavior were not modified. This effect was similar in magnitude when 8-OH-DPAT was administered to CON group. Furthermore, the administration of 8-OH-DPAT induces a significant and similar increase in rectal temperature and locomotor activity in both the CON as in the CMI group. Neonatal treatment with CMI resulted in a significant decrease in the expression of the mRNA of the 5-HT1A receptors in the DR (% more than vehicle) in adulthood. In the case of the postsynaptic receptors located in the hypothalamus and hippocampus, neonatal treatment with CMI induced a significant increase in the mRNA expression of the 5-HT1A receptors. These data suggest that neonatal treatment with CMI induces a downregulation of the mRNA of the 5-HT1A autoreceptors in the DR, and an increment in the expression of the postsynaptic 5-HT1A receptors. The results after the administration of PCPA and 8-OH-DPAT on FST, rectal temperature and locomotor activity for both groups suggest that the function of postsynaptic receptors remains unchanged. All together these data show that the depressive behavior observed in adulthood in this animal model may be associated with long-term alterations in the expression of the mRNA of the 5-HT1A receptors.

Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice.

Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT(1D) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.

Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a severely disabling anxiety disorder that may occur following exposure to a serious traumatic event. It is a psychiatric condition that can afflict anyone who has experienced a life-threatening or violent event. Previous studies have shown that changes in 18 kDa translocator protein (TSPO) expression (or function), a promising target for treating neurological disorders without benzodiazepine-like side effects, may correlate with PTSD. However, few studies have investigated the anti-PTSD effects of TSPO ligands. AC-5216, a ligand for TSPO, induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether AC-5216 ameliorates PTSD behavior in mice. Following the training session consisting of exposure to inescapable electric foot shocks, animals were administered AC-5216 daily during the behavioral assessments, i.e., situational reminders (SRs), the open field (OF) test, the elevated plus-maze (EPM) test, and the staircase test (ST). The results indicated that exposure to foot shocks induced long-term behavioral deficiencies in the mice, including freezing and anxiety-like behavior, which were significantly ameliorated by repeated treatment with AC-5216 but without any effect on spontaneous locomotor activity or body weight. In summary, this study demonstrated the anti-PTSD effects of AC-5216 treatment, suggesting that TSPO may represent a therapeutic target for anti-PTSD drug discovery and that TSPO ligands may be a promising new class of drugs for the future treatment of PTSD.

[Study on antidepressant effect of kuanxinjieyutang combined aerobic exercise].

OBJECTIVE: To observe antidepressant effects of Kuanxinjieyutang (KXJYT), short-term aerobic exercise and their joint intervention and its possible mechanism. METHODS: Ninty-six SPF male KM mice were randomly divided into control group, imipramine, low dose (KXJYT 1.8 g crude drugs/kg bw/time/day), high dose (3.6 g crude drugs/kg bw/time/day), exercise group (swimming 30 min/times/day), joint group (low dose and swimming ), with 8 days intervention. The antidepressant effect was evaluated by forced swimming, tail suspension test and overhead cross maze test. After mice were killed, brain monoamine neurotransmitter levels of mice were detected by ELISA, and BDNF expression in brain was analyzed by Western blotting. RESULTS: High dose group showed antidepressant effect like imipramine while low dose didn't. Exercise group showed similar or better antidepressant effect than imipramine. Joint group showed better interaction antidepressant effect. Brain NE, DA of high dose group and brain NE, DA and 5-HT content of exercise group increased significantly, similar to imipramine. Brain NE,DA and 5-HT content of Joint group were significantly higher than those of imipramine. The protein expression of BDNF in brain was more in imipramine, high dose,exercise and joint groups than that of control group, sports group was higher than that of low dose and high dose group, joint group was obviously higher than other groups. CONCLUSION: Moderate KXJYT, short-term aerobic exercise and their joint intervention have obvious antidepressant effect on mild depression. Its mechanism may be related to increasing brain NE and 5-HT content, and inducing brain BDNF expression, which may affect the nerve regeneration and plasticity, improve cognitive function.

Evaluation of antidepressant-like activity of novel water-soluble curcumin formulations and St. John's wort in behavioral paradigms of despair.

BACKGROUND: Curcumin is the active principle of Curcuma longa, one of the widely used components in the traditional system of medicine in India. Despite its efficacy in experimental studies aiming at neuronal disorders like depression, curcu-min's poor water solubility challenges the production of therapeutic formulations. This study investigates the antidepressant-like activity of novel water-soluble curcumin formulations, dispensed in three different concentrations. Further, the study comparatively evaluates St. John's wort (SJW), another herbal preparation. METHODS: These compounds were evaluated in the forced swimming test in mice, and the corresponding changes in the neurotransmitter levels were measured. RESULTS: Three water-soluble curcumin formulations, C-5, C-20 and C-50 (50-200 mg/kg p.o.) decreased the immobility period, and increased serotonin and dopamine levels in the brain tissues. A subeffective dose (50 mg/kg) of these formulations enhanced the antidepressant-like effect of classical antidepressants with varied mechanisms of action. In addition, an SJW dose of 25 mg/kg showed a significant antidepressant-like effect in all the behavioral studies and also significantly increased brain neurotransmitter levels, especially that of serotonin. The effects produced by C-5 were comparable with those of SJW and fluoxetine, respectively. CONCLUSION: In all these observations, the water-soluble formulations showed a significant antidepressant-like effect, including enhancement of neurotransmitter levels as compared to the similar dose of a conventional curcumin preparation. Thus, these formulations may be used as a novel treatment option in the management of mental depression.

The role of 5-HT1A receptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: a possible antidepressant mechanism.

Epidemiological and dietary studies show that nutritional deficit of omega-3 polyunsaturated fatty acids (ω-3 PUFA) is directly related to the prevalence and severity of depression. Supplementation with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) during critical periods of development (pregnancy and lactation) is essential for cortical maturation, synaptogenesis and myelination, and may also mitigate the risk for cognitive deficits and psychopathologies in young adults. The present study was performed to evaluate the involvement of serotonin (5-HT) receptors, particularly of 5-HT(1A), and hippocampal brain-derived neurotrophic factor (BDNF) expression in the antidepressant effect of ω-3 PUFA supplementation. In Experiment 1, the antidepressant effects of fish oil were assessed by the modified forced swim test in adult rats. The data indicated a robust antidepressant effect produced by this supplementation and that treatment of the rats with WAY 100135 reversed this effect. In Experiment 2, cortical and hippocampal contents of BDNF, 5-HT, dopamine (DA) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC), were determined in animals subjected to the same protocol. Increased BDNF expression in the cortex and hippocampus of both age groups was detected. In 90 day-old rats, 5-HT content in the hippocampus was increased, whereas 5-HIAA formation was diminished in the fish oil group. We suggest the occurrence of a reciprocal involvement of 5-HT(1A) receptors activation and the hippocampal BDNF-increased expression mediated by fish oil supplementation. These data corroborate and expand the notion that supplementation with ω-3 PUFA produces antidepressant effects mediated by an increase in serotonergic neurotransmission, particularly in the hippocampus. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs.

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 µg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC50 = 90 ± 38 nM), serotonin (IC50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

Role for monoaminergic systems in the antidepressant-like effect of ethanol extracts from Hemerocallis citrina.

ETHNOPHARMACOLOGICAL RELEVANCE: Hemerocallis citrina, a traditional herbal medicine, has been used for the improvement of emotions in Eastern-Asia countries. AIM OF THE STUDY: Herein, we explored the antidepressant-like effect and its monoaminergic mechanism of the ethanol extracts from Hemerocallis citrina (HCE). MATERIALS AND METHODS: Effect of HCE (90, 180 and 360 mg/kg, p.o.) on the immobility time was assessed in the mouse forced swim test (FST) and tail suspension test (TST), and locomotor activity was evaluated in the open-field test (OFT). Additionally, the monoamine neurotransmitters serotonin (5-HT), noradrenaline (NA) and dopamine (DA) levels involved in the antidepressant-like effect of HCE were also measured in the mice brain regions of frontal cortex and hippocampus. RESULTS: HCE (90, 180 and 360 mg/kg, p.o.) administration significantly reduced the immobility time in both the FST and TST without accompanying changes in locomotor activity in the OFT. The pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a 5-HT(1A) receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT(2) receptor antagonist), prazosin (62.5 µg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (5 mg/kg, i.p., a ß-adrenoceptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), but not SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) prevented the antidepressant-like effect of HCE (360 mg/kg, p.o.) in the TST. In addition, HCE enhanced 5-HT and NA levels in the frontal cortex and hippocampus as well as elevated DA levels in the frontal cortex. CONCLUSION: The results indicate that the antidepressant-like effect of HCE is dependent on the serotonergic (5-HT(1A) and 5-HT(2) receptors), noradrenergic (α(1)-, α(2)- and ß-adrenoceptors) and dopaminergic (D(2) receptor) systems as well as the elevation of 5-HT, NA and DA levels in the mouse brain.

Peony glycosides reverse the effects of corticosterone on behavior and brain BDNF expression in rats.

Repeated injections of corticosterone (CORT) induce the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in depressive-like behavior. This study aimed to examine the antidepressant-like effect and the possible mechanisms of total glycosides of peony (TGP) in the CORT-induced depression model in rats. The results showed that the 3-week CORT injections induced the significant increase in serum CORT levels in rats. Repeated CORT injections also caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Moreover, it was found that brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex were significantly decreased in CORT-treated rats. Treatment of the rats with TGP significantly suppressed the depression-like behavior and increased brain BDNF levels in CORT-treated rats. The results suggest that TGP produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex.