Antidepressant‐like effect of riparin II from Aniba riparia in mice: evidence for the involvement of the monoaminergic system

In a previous study conducted by our group, riparin II (ripII) isolated from the green fruit of Aniba riparia presented antianxiety effects in mice. This study investigates a possible antidepressant activity of rip II using two predictive tests for antidepressant activity in rodents: the forced swimming test (FST) and tail suspension test (TST). Additionally, the mechanisms involved in the antidepressant‐like effect in mice were also assessed. Rip II was acute administered by intraperitoneal (i.p.) and oral (p.o) routes to male mice at doses of 25 and 50 mg/kg. Results showed that ripII at both tested doses and administration routes produced a significant decrease of immobility time in FST and TST. The pretreatment of mice with prazosin (1 mg/kg, i.p., an α1‐adrenoceptor antagonist), SCH23390 (15 μg/kg, i.p., a dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), p‐chlorophenylalanine (100 mg/kg, an inhibitor of serotonin synthesis), or NAN‐190 (0.5 mg/kg, a serotonin 5‐HT1A receptor antagonist) completely blocked the anti‐immobility effects elicited by riparin II (50 mg/kg, p.o.) in the FST. This study indicates that riparin II produces significant antidepressant‐like activity in the forced swimming and TSTs, and this effect seems to be dependent on its interaction with noradrenergic, dopaminergic, and serotonergic systems.     

Evidence for the involvement of the serotonergic, noradrenergic, and dopaminergic systems in the antidepressant-like action of riparin III obtained from Aniba riparia (Nees) Mez (Lauraceae) in mice

Previous work has shown that intraperitoneal administration of riparin III (ripIII) reduces immobility time in the forced swimming test (FST), which suggests potential antidepressant activity. As the mechanism of action is not completely understood, this study is aimed at investigating the antidepressant‐like action of ripIII. Following intraperitoneal administration of ripIII at doses of 25 and 50 mg/kg, there were decreases in the immobility time in the FST and tail suspension test without accompanying changes in ambulation (data not shown). The pretreatment of mice with sulpiride (50 mg/kg, i.p.), prazosin (1 mg/kg, i.p.), yohimbine (1 mg/kg, i.p.), and p‐chlorophenylalanine (PCPA, 100 mg/kg, i.p. for, four consecutive days) significantly prevented the anti‐immobility effect of ripIII in the FST. On the other hand, the anti‐immobility effect of ripIII (50 mg/kg, v.o.) was not altered by pretreatment of mice with SCH23390 (15 μg/kg, i.p.) Furthermore, ripIII potentiated the sleeping latency and sleeping time of the pentobarbital‐induced sleeping time test and also potentiated apomorphine (16 mg/kg, i.p.)‐induced hypothermia in mice. In conclusion, the present study provides evidence that the antidepressant‐like effect of ripIII is dependent on its interaction with the serotonergic, noradrenergic (α₁‐ and α₂‐ receptors), and dopaminergic (dopamine D₂ receptors) systems.     

Involvement of monoaminergic system in the antidepressant‐like effect of riparin I from Aniba riparia (Nees) Mez (Lauraceae) in mice

In past studies conducted by our group, riparin I (rip I) isolated from the green fruit of Aniba riparia presented antianxiety effects in mice, while its analogs rip II and III showed anxiolytic and antidepressant‐like actions. This time around, we investigated a possible antidepressant activity of rip I using the forced swimming test (FST) and tail suspension test (TST) as predictive tests for antidepressant activity in rodents. In addition, the involvement of the monoaminergic system in this effect was also assessed. rip I was acutely administered by intraperitoneal (i.p.) and oral (p.o) routes to male mice at doses of 25 and 50 mg/kg. Results showed that rip I at both tested doses and administration routes produced a significant decrease in immobility time in FST and TST. The pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁‐adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂‐adrenoceptor antagonist), SCH23390 (15 μg/kg, i.p., a dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), p‐chlorophenylalanine (100 mg/kg, an inhibitor of serotonin synthesis) or ritanserin (4 mg/kg, a serotonin 5‐HT2_a/2_c receptor antagonist) blocked the anti‐immobility effects elicited by rip I (50 mg/kg, p.o.) in the FST. Taken together, results indicate that rip I produces significant antidepressant‐like activity in the FST and TST, and this effect seems to be dependent on its interaction with noradrenergic, dopaminergic and serotonergic systems.     

Antidepressant‐like effect of bis‐eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system

Dehydrodieugenol, known as bis‐eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti‐inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant‐like effect; however, the biological actions of bis‐eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant‐like activity of bis‐eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis‐eugenol was also conducted. Bis‐eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti‐immobility effect of bis‐eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p‐chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2‐adrenoceptor antagonist), SCH23390 (15 μg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high‐performance liquid chromatograph revealed significant increase in the 5‐HT, NE and DA levels in brain striatum. The present study indicates that bis‐eugenol possesses antidepressant‐like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function.     

Anxiolytic‐like effect of Carvacrol (5‐isopropyl‐2‐methylphenol) in mice: involvement with GABAergic transmission

Carvacrol (5‐isopropyl‐2‐methylphenol) is a monoterpenic phenol present in the essencial oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. This work presents the behavioral effects of carvacrol in animal models of elevated plus maze (EPM), open field, Rotarod and barbiturate‐induced sleeping time tests in mice. Carvacrol (CVC) was administered orally, in male mice, at single doses of 12.5; 25 and 50 mg/kg while diazepam 1 or 2 mg/kg was used as standard drug and flumazenil (2.5 mg/kg) was used to elucidate the possible anxiolytic mechanism of CVC on the plus maze test. The results showed that CVC, at three doses, had no effect on the spontaneous motor activity in the Rotarod test nor in the number of squares crossed in the open‐field test. However, CVC decreased the number of groomings in the open‐field test. In the plus maze test, CVC, at three doses significantly increased all the observed parameters in the EPM test and flumazenil was able to reverse the effects of diazepam and CVC. Therefore, CVC did not alter the sleep latency and sleeping time in the barbiturate‐induced sleeping time test. These results show that CVC presents anxiolytic effects in the plus maze test which are not influenced by the locomotor activity in the open‐field test.     

Subchronic administration of riparin III induces antidepressive‐like effects and increases BDNF levels in the mouse hippocampus

Riparin III (Rip III) is an alcamide isolated from Aniba riparia that has presented effects of antidepressant and anxiolytic activities in acute stress behavioral models. The trial's goal was to investigate the activity of Rip III in mice exposed to corticosterone‐induced chronic depression model. Swiss female mice, 22–25 g, were distributed in following experimental groups: control group (vehicle1: saline containing 0.1% dimethyl sulfoxide and 0.1% Tween‐80, SC+ vehicle 2: distilled water emulsified with 2% Tween‐80, PO); stressed group (corticosterone, 20 mg/kg, SC, + vehicle 2, orally); Rip III group (50 mg/kg, orally); and fluvoxamine (Flu) group (50 mg/kg, orally). The mice were exposed to the behavioral tests, and posteriorly, Brain‐derived neurotrophic factor protein levels were assessed in hippocampal samples. Statistical analysis of the data was performed by one‐way anova , followed by Newman–Keuls test. Both administrations of Rip III and Flu significantly reduced the immobility time in tail suspension and forced swimming tests after 21 days without affecting locomotor function. There was also an increase in BDNF protein levels in the mice hippocampus. These findings further support the hypothesis that Rip III could be a new pharmacological target for the treatment of mood disorders.     

Tauroursodeoxycholic acid produces antidepressant‐like effects in a chronic unpredictable stress model of depression via attenuation of neuroinflammation,oxido‐nitrosative stress,and endoplasmic reticulum stress

Depression is a common psychiatric disorder with heavy economic and social burdens. Searching new agents with better antidepressant‐like activities is of great significance for depression therapy. Tauroursodeoxycholic acid (TUDCA), a clinical drug for gallstone treatment, possesses neuroprotective effects in different brain disorders. However, whether it affects depression remains unclear. We addressed this issue by evaluating the effect of TUDCA on depression induced by chronic unpredictable stress (CUS). Results showed that TUDCA treatment at 200 but not 100 mg/kg prevented the 5 weeks of CUS‐induced increases in the immobile time of C57BL6/J mice in the experiments of forced swimming test and tail suspension test as well as the CUS‐induced decrease in sucrose intake and crossing numbers in the open‐field test, and did not enhance the antidepressant‐like effect of fluoxetine. Attenuation of neuroinflammation may be involved in the antidepressant‐like effect of TUDCA, as TUDCA treatment (200 mg/kg) normalized the levels of tumor necrosis factor‐α and interleukin‐6 in both hippocampus and prefrontal cortex. The increases in inflammasome and microglial activation markers, including interleukin‐β, nod‐like receptor protein 3, and Iba‐1, in CUS‐treated mice were reduced by TUDCA treatment (200 mg/kg). TUDCA treatment (200 mg/kg) also normalized the changes in markers reflecting the oxidative–nitrosative and endoplasmic reticulum (ER) stress induced by CUS, such as nitric oxide, reduced glutathione, malondialdehyde, glucose‐regulated protein 78, and C/EBP homologous protein. These results revealed that TUDCA improved the CUS‐induced depression‐like behaviors likely through attenuation of neuroinflammation, oxido‐nitrosative, and ER stress.     

Protective effects of antidepressants against chronic fatigue syndrome – induced behavioral changes and biochemical alterations

Chronic fatigue syndrome (CFS) is characterized by profound fatigue, which substantially interferes with daily activities. The aim of this study was to explore the protective effects of antidepressants in an animal model of CFS in mice. Male albino mice were forced to swim individually for a period of 6-min session each for 7 days. Imipramine (10 and 20 mg/kg), desipramine (10 and 20 mg/kg) and citalopram (5 and 10 mg/kg) were administered 30 min before forced swimming test on each day. Various behavior tests (immobility time, locomotor activity, anxiety-like behavior by plus maze and mirror chamber) followed by biochemical parameters (lipid peroxidation, reduced glutathione, catalase and nitrite level) were assessed in chronic stressed mice. Chronic forced swimming for 7 days significantly caused increase in immobility period, impairment in locomotor activity, anxiety-like behavior, and oxidative stress (raised lipid peroxidation, nitrite activity and reduced glutathione and catalase activity) as compared with naïve mice ( P  < 0.05). Seven days of pretreatment with imipramine (10 and 20 mg/kg), desipramine (10 and 20 mg/kg), and citalopram (5 and 10 mg/kg) significantly reduced immobility time, improved locomotor activity and anti-anxiety effect (in both plus maze and mirror chamber test), and attenuated oxidative stress in chronic stressed mice as compared with control (chronic fatigues) ( P  < 0.05). These results suggested that these drugs have protective effect and could be used in the management of chronic fatigue like conditions.     

Antidepressant‐like activity of gallic acid in mice subjected to unpredictable chronic mild stress

This study was designed to evaluate antidepressant‐like activity of gallic acid in Swiss young male albino mice subjected to unpredictable chronic mild stress and to explore the possible underlying mechanisms for this activity. Gallic acid (5, 10, 20 mg/kg, i.p.) and fluoxetine (10 mg/kg, i.p.) per se were administered daily to unstressed mice and other groups of mice subjected to unpredictable mild stress, 30 min after the injection for 21 successive days. The antidepressant‐like activity was evaluated using forced swim test (FST) and sucrose preference test. Stress significantly increased immobility period of mice in FST. Gallic acid (10 and 20 mg/kg, i.p.) and fluoxetine significantly decreased immobility period of unstressed and stressed mice in FST and prevented the stress‐induced decrease in sucrose preference, indicating significant antidepressant‐like activity. There was no significant effect on locomotor activity of the mice by the drugs. Gallic acid (10 and 20 mg/kg, i.p.) significantly decreased Monoamine oxidase‐A (MAO‐A) activity, malondialdehyde levels, and catalase activity in unstressed mice; and significantly prevented the stress‐induced decrease in reduced glutathione and catalase activity; and also significantly prevented stress‐induced increase in MAO‐A activity, malondialdehyde levels, plasma nitrite, and corticosterone levels. Thus, gallic acid showed antidepressant‐like activity in unstressed and stressed mice probably due to its antioxidant activity and through inhibition of MAO‐A activity and decrease in plasma nitrite levels. In addition, gallic acid also showed antidepressant‐like activity in stressed mice probably through decrease in plasma corticosterone levels.     

Anti-immobility activity of different antidepressant drugs using the tail suspension test in normal or reserpinized mice

Summary— The tail suspension test is a screening procedure recently used in mice to detect antidepressant activity of drugs. The ability of amine re-uptake inhibitors to decrease immobility in non-reserpinized and in reserpinized mice was studied. Reserpine (4 mg/kg ip) was injected 4 h previously. Anti-depressants were administered ip, 60 min before tail suspension. Animal activity was recorded for 6 min. Preferential serotonin re-uptake blockers (fluoxetine, fluvoxamine, clomipramine) were poorly active in non-reserpinized mice and inactive in reserpine-treated mice. Noradrenergic drugs (desipramine, demexiptiline, viloxazine) were more efficient in reserpinized than in non-reserpinized mice. The mixed serotonin- noradrenaline re-uptake inhibitor (imipramine) shows an activity which should be considered between serotonin re-uptake inhibitors and noradrenaline re-uptake inhibitors. DA re-uptake inhibitors (amineptine, GBR 12909) exhibited the highest anti-immobility effect in non reserpinized animals but were of low efficacy after reserpine treatment. Amphetamine differed from dopamine re-uptake inhibitors by its better activity in reserpinized animals. Moreover, it was the only drug showing an equal anti-immobility effect in non reserpinized and reserpinized mice because the dose of 8 mg/kg of amphetamine reduced immobility in reserpinised mice with the same intensity as the dose of 4 mg/kg in non reserpinised mice whereas no other drugs tested in this study achieved the same effect. Comparison of anti-immobility activities of putative antidepressants in non-pre-treated and in reserpine-pre-treated mice, using the tail suspension test, may be useful to discriminate amphetamines from antidepressant drugs and to differentiate between categories of amine re-uptake blockers.     

Felbamate produces antidepressant‐like actions in the chronic unpredictable mild stress and chronic social defeat stress models of depression

Felbamate is an anticonvulsant used in the treatment of epilepsy. In this study, we investigated the antidepressant‐like actions of felbamate in mice. The effects of felbamate were first assessed using the forced swimming test (FST) and tail suspension test (TST), and then investigated in the chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models of depression. The changes in the hippocampal brain‐derived neurotrophic factor (BDNF) signaling cascade after chronic stress and felbamate treatment were also examined. It was found that felbamate exhibited antidepressant‐like activities in the FST and TST without affecting the locomotor activity of mice. Felbamate was also effective in both the CUMS and CSDS models of depression. Moreover, felbamate administration fully restored the decreased hippocampal BDNF signaling pathway in both the CUMS‐stressed and CSDS‐stressed mice. Collectively, felbamate has antidepressant‐like actions in mice involving the hippocampal BDNF system.     

Les effets de l’ayahuasca sur le système nerveux central: étude comportementale

An ayahuasca beverage sample, containing harmalol, harmol, harmane and N,N-Dimethyltryptamine alkaloids, was evaluated in the forced swimming and open field tests. In the forced swimming test, the doses have decreased the immobility time in inverse dose-dependant way. Doses of 2.5mg/kg and 10mg/kg of ayahuasca also decreased the locomotor activity and vertical exploration on open field test. The 2.5mg/kg dose decreased the locomotor activity in 44.95% and the vertical exploration in 62.12%. It is possible to suggest that doses are relationed in inverse dose-dependent way, and the 2.5mg/kg dose presented antidepressant activity.     

Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies

The excellent pharmacological profile displayed by the selective nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] in vitro prompted us to investigate the actions of this compound in vivo. In the mouse tail withdrawal assay, SB-612111 given i.p. up to 3 mg/kg did not modify per se tail withdrawal latencies but was able to prevent the pronociceptive and the antinociceptive action of 1 nmol of N/OFQ given i.c.v. and i.t., respectively. In food intake studies performed in sated mice, SB-612111 (1 mg/kg i.p.) had no effect on food consumption but fully prevented the orexigenic effect of 1 nmol of N/OFQ i.c.v. In 17-h food-deprived mice, the opioid receptor antagonist naltrexone (1 mg/kg s.c.), but not SB-612111 (1 and 10 mg/kg i.p.), produced a statistically significant reduction of food intake. In the mouse forced swimming and tail suspension tests, SB-612111 (1-10 mg/kg) reduced immobility time. The antidepressant-like effect elicited by SB-612111 in the forced swimming test was reversed by the i.c.v. injection of 1 nmol of N/OFQ and no longer evident in mice knockout for the NOP receptor gene. In conclusion, the present findings demonstrate that SB-612111 behaves in vivo as a potent and selective NOP antagonist and suggest that the N/OFQ-NOP receptor endogenous system plays an important role in regulating mood-related behaviors. The use of SB-612111 in future pathophysiological studies will certainly contribute to define the therapeutic potential of selective NOP receptor antagonists in different disease areas.     

应用高通量筛选体系寻找抗抑郁新药的实验研究

背景目前抑郁症发病率日益趋高,运用新技术新方法开发新型高效低毒抗抑郁药具有重要意义.目的通过高通量筛选与体内试验相结合,建立寻找抗抑郁新药先导化合物的研究体系.设计随机对照实验.地点、材料和干预本研究地点为中国医学科学院药物研究所.实验选用昆明种雄性小鼠70只,体质量(20±2)g.雄性Wistar大鼠10只,体质量(200±20)g.取雄性Wistar大鼠,断头处死,快速取脑用于5羟色胺重摄取实验.将小鼠随机分为对照组、氟西汀组(2.6 mg/kg)、J01113组(30 mg/kg),J01114组(30 mg/kg),J10745组(30 g/kg).连续灌胃给药5 d,每天给药1次,从给药第2天开始隔日进行小鼠悬尾试验.比较给药组及对照组小鼠自挂上后6 min内的不动时间.分组给药同小鼠悬尾实验,隔日进行小鼠强迫游泳实验.比较给药组及对照组小鼠在后4 min内的不动时间.主要观察指标突触体5-羟色胺重摄取抑制活性,抑郁模型小鼠静止时间.结果体外试验表明5 000多种化合物经高通量筛选后,J01113,J01114和J10745均显示较强的5羟色胺重摄取抑制活性.J01113,J01114和J10745的半数有效剂量(IC50)分别为(1.304×10-10),(9.036×10-10),(1.447×10-7)mol/L.小鼠悬尾试验结果显示J01113连续给药3 d或5d悬尾小鼠的静止时间[(67.2 ±47.33),(95.2±47.5)s]明显少于对照组[(117.8±33.2),(170.2±40.47)s](t=2.77,P＜0.05;t=3.8,P＜0.01).小鼠游泳试验结果表明,J01113组小鼠连续给药3天或5天静止时间[(9.8±16.59),(19.4±24.64)s]也显著低于对照组[(63.7±35.4),(48.7 ±33.9)s](t=4.36,P＜0.01;t=2.21,P＜0.05).在这两种模型中J01114,J10745与对照组比静止时间虽有减少趋势,但均差异无显著性意义(P＞0.05).结论应用高通量筛选体系,可实现大规模高效率抗抑郁药先导化合物的发现,活性化合物J01113可能是潜在的一种新型抗抑郁药.     

Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice

The development of serotonin receptor knockout mice has provided an opportunity to study antidepressant drug effects in animals with targeted genetic deletion of receptors involved in antidepressant responses. In the current study, the effects of two types of antidepressant drugs, the selective serotonin reuptake inhibitors fluoxetine and paroxetine and the selective norepinephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptamine (5-HT)(1A) and 5-HT(1B) receptor mutant mice using the tail suspension test (TST). Under baseline conditions, the immobility of 5-HT(1A) receptor mutant mice, but not 5-HT(1B) receptor mutant mice, was significantly lower than that of wild-type mice. The decreased baseline immobility in 5-HT(1A) receptor mutant mice was reversed by pretreatment with alpha-methyl-para-tyrosine, but not by para-chlorophenylalanine, suggesting mediation by enhanced catecholamine function. In wild-type mice, fluoxetine (10.0--20.0 mg/kg i.p.) and desipramine (5.0--20.0 mg/kg i.p.) both significantly decreased immobility in the TST. In 5-HT(1A) receptor mutant mice, desipramine (20.0 mg/kg i.p.) significantly decreased immobility, whereas fluoxetine (20.0 mg/kg i.p.) and paroxetine (20.0 mg/kg i.p.) had no effect. The immobility of 5-HT(1B) receptor mutant mice was decreased similarly by desipramine (5.0--20.0 mg/kg i.p.). However, the effect of low doses of fluoxetine were significantly augmented in the 5-HT(1B) receptor mutant mice (2.5--20.0 mg/kg i.p.) compared with wild-type mice. Administration of selective 5-HT receptor antagonists in wild-type mice partially reproduced the phenotypes of the mutant mice. These results suggest that 5-HT(1A) and 5-HT(1B) receptors have different roles in the modulation of the response to antidepressant drugs in the TST.     

衰老对应激前后小鼠抑郁及焦虑样行为的影响

目的:探讨不同年龄段小鼠应激造模前后的抑郁及焦虑样行为.方法:54只C57BL/6J小鼠分为正常对照(NC)组和慢性束缚应激(CRS)组,再根据年龄分为青年亚组、中年亚组、老年亚组,共6亚组,每亚组9只.通过检测各组小鼠的行为学改变,包括体质量、悬尾试验、强迫游泳试验、糖水偏好试验、开放旷场实验,观察小鼠抑郁样及焦虑样...     

Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2C) receptors

The role of the 5-HT(2C) receptor in mediating active behaviors in the modified rat forced swim test was examined. Three novel selective 5-HT(2C) receptor agonists, WAY 161503 (0.1-3.0 mg/kg), RO 60-0175 (2-20 mg/kg), and RO 60-0332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reuptake inhibitor fluoxetine (5-20 mg/kg). However, the prototypical but nonselective 5-HT(2C) receptor agonist m-chlorophenylpiperazine (1-10 mg/kg) increased immobility scores in the forced swim test. The selective 5-HT(2C) receptor antagonist SB 206533 was inactive when given alone (1-20 mg/kg). However, SB 206533 (20 mg/kg) blocked the antidepressant-like effects of both WAY 161503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (noradrenergic alpha(2) and 5-HT(2C) receptor antagonist) mianserin reduced immobility and increased climbing at 30 mg/kg. At a behaviorally subactive dose (10 mg/kg), mianserin abolished the effects of WAY 161503 (1 mg/kg) on both swimming and immobility scores. Mianserin blocked the effects of fluoxetine (20 mg/kg) on swimming only; mianserin plus fluoxetine reduced immobility and induced a switch to climbing behavior, suggesting activation of noradrenergic transmission. These data exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotonergic and noradrenergic effects. Taken together, the results strongly implicate a role for 5-HT(2C) receptors in the behavioral effects of antidepressant drugs.     

Imipramine reverses the depressive symptoms in sepsis survivor rats

Objective To evaluate the antidepressant effect of imipramine on depressive symptoms observed in sepsis survivors rats. Design and setting Prospective, controlled experiment in an animal basic science laboratory. Subjects Male Wistar rats weighing 300–350 g. Interventions The rats underwent cecal ligation and perforation (CLP; sepsis group) with “basic support” (saline at 50 ml/kg immediately and 12 h after CLP plus ceftriaxone at 30 mg/kg and clindamycin at 25 mg/kg 6, 12, and 18 h after CLP) or sham-operated (control group). After 10 days of recovery rats received intraperitoneal injections of imipramine 10 mg/kg or saline and were subjected to the forced swimming test. Measurements and results The observed increase in the immobility time in the forced swimming test in animals subjected to CLP, as a parameter of depressive behavior, was reversed by imipramine. Conclusions The depressive symptoms evaluated by forced swimming test had been reversed after imipramine administration. Our data provide evidence that CLP-induced depressive symptoms are sensitive to antidepressants. This research was supported in part by UNESC (Brazil), FAPESC (Brazil), and CNPq (Brazil).     

丙泊酚对脂多糖诱导的脓毒血症小鼠抑郁样行为和海马炎症反应的影响

目的:观察丙泊酚预处理在脂多糖(LPS)诱导的脓毒血症小鼠抑郁样行为和海马炎症反应中的作用,并探讨其可能的作用机制。方法:60只健康ICR小鼠随机分为6组:对照组(C组),丙泊酚组(P1组),LPS组(L5组),丙泊酚+LPS组(L5P1、L5P2、L5P5组),每组10只。P1组注射10 mg/kg丙泊酚;L5组注射5 mg/kg LPS;L5P1组、L5P2组和L5P5组分别注射10 mg/kg、20 mg/kg和50 mg/kg丙泊酚预处理,30 min后注射5 mg/kg LPS。所有药物均选择腹腔注射,C组注射同等剂量的生理盐水。24 h后依次采用糖水偏好实验、悬尾实验和强迫游泳实验对小鼠进行抑郁样行为测试;行为学测试后处死小鼠,采用免疫印迹法检测脑炎性因子Toll样受体4(TLR4)、核转录因子κB(NF-κB)主要蛋白P65、髓样分化因子-2(MD-2)表达水平。结果:与C组比较,L5组糖水摄取量减少,悬尾静止时间延长,TLR4、P65、MD-2表达量升高(P<0.05)。与L5组比较,L5P1组糖水摄取量增加,TLR4、P65、MD-2表达量降低(P<0.0...     

Further analysis of acute antinociceptive and anti‐inflammatory actions of 4‐phenylselenyl‐7‐chloroquinoline in mice

A new quinoline containing selenium, 4‐phenylselenyl‐7‐chloroquinoline (4‐PSQ), was described and synthetized by our research group. Recently, we demonstrated the potential antinociceptive and anti‐inflammatory of 4‐PSQ. For this reason, the first objective of this study was to expand our previous findings by investigating the contribution of glutamatergic, serotonergic, and nitrergic systems to the acute antinociceptive action of this compound. Pretreatment with 4‐PSQ (0.01–25 mg/kg, p.o.) reduced the nociception induced by glutamate. MK‐801 (an uncompetitive antagonist of the N‐Methyl‐d ‐aspartate (NMDA) receptor) blocked the antinociceptive effect exerted by 4‐PSQ (25 mg/kg, p.o.) in the acetic acid‐induced abdominal writhing test. The pretreatment with WAY100635 (a selective antagonist of 5‐HT_1A receptor), ketanserin (a selective antagonist of 5‐HT_2A/2C receptor), and pindolol (a nonselective antagonist of 5‐HT_1A/1B receptors) partially blocked the antinociceptive effect caused by 4‐PSQ (25 mg/kg, per oral, p.o.) in the acetic acid‐induced abdominal writhing test. Nitric oxide precursor, l ‐arginine hydrochloride, partially reversed antinociception caused by 4‐PSQ or ω‐nitro‐l ‐arginine (l ‐NOARG). Treatments did not modify the locomotor and exploratory activities of mice. Additionally, the acute anti‐inflammatory effect of 4‐PSQ in a model of pleurisy induced by carrageenan in mice was investigated. 4‐PSQ reduced the cellular migration, pleural exudate accumulation, and myeloperoxidase activity induced by carrageenan exposure. 4‐PSQ protected against the increase in reactive species levels and reduction of nonprotein thiol levels induced by carrageenan. Data presented here showed that the modulation of serotonergic, nitrergic, and glutamatergic systems contributed to the antinociceptive effect of 4‐PSQ and it reinforced the therapeutic potential of this quinolinic compound for acute inflammation.