GABA-mediated modification of despair behavior in mice

Summary Gamma-aminobutyric acid (GABA) and GABA agonists exhibited biphasic response on forced swimming-induced despair behavior in mice; smaller doses, GABA (100 mg/kg), muscimol (0.05 and 0.1 mg/kg), baclofen (0.5 and 1 mg/kg), sodium valproate (100 mg/kg), piracetam (25 mg/kg), and fengabine (10 and 20 mg/kg) decreasing forced swimming-induced immobility period, while higher doses enhancing the immobility period. GABA, muscimol, and baclofen also reversed reserpine-induced prolongation of the forced swimming-induced immobility. When GABA was administered with antidepressant agents, it potentiated the effect of some classical antidepressants. Bicuculline and picrotoxin, the GABAergic antagonists, by themselves enhanced the forced swimming-induced immobility period, but they had no significant effect on reserpine-induced prolongation of the immobility period. When animals were chronically exposed to forced swimming, there was a gradual increase of the immobility period which was reduced on treatment with GABAergic agents. It is suggested that GABA has a modulatory role in reversing forced swimming-induced despair and also in potentiating the effect of antidepressants.     

Antidepressant-like activity of the melatonin receptor antagonist, luzindole (N-0774), in the mouse behavioral despair test

The anti-immobility effect of the selective melatonin receptor antagonist, luzindole, was investigated in the behavioral despair test using three different strains (C3H/HeN, C57BL/6J and albino ND/4) of mice. The time of immobility of the C3H/HeN during the 240 s swimming period measured at noon (12:00 to 14:00 h) was 47.8 +/- 3.0 s (n = 63) and at midnight (00:00 to 02:00 h) was 67.7 +/- 2.8 s (n = 68) (P less than 0.001, when compared with the noon value), when the levels of endogenous melatonin are presumably low and high, respectively. Melatonin (30 mg/kg) given i.p. did not modify the time of immobility at either time of measurement. Luzindole (30 mg/kg i.p.) reduced the time of immobility in a dose-dependent manner, the effect being more pronounced at midnight (60% reduction) than at noon (39% reduction). The effect of luzindole was time-dependent, showing a maximal effect at 60 min. The anti-immobility effect of luzindole (10 mg/kg i.p.) was prevented by the administration of melatonin (30 mg/kg i.p.). Luzindole (30 mg/kg i.p.) did not modify the time of immobility either at noon or midnight in the albino ND/4 mouse, or in the C57BL/6J mouse, which does not produce melatonin. Our results suggest that endogenous melatonin plays a role during swimming in the C3H/HeN mouse behavioral despair test. We conclude that luzindole may exert antidepressant-like activity in the C3H/HeN mouse by antagonizing the action of endogenous hormone.     

Purine nucleoside — mediated immobility in mice: Reversal by antidepressants

In the forced swimming-induced immobility (despair) test model, adenosine, and 2-chloroadenosine treatment prolonged the immobilization period in mice. Dipyridamole, which is known to inhibit adenosine uptake, potentiated the adenosine effect. The purinoceptor antagonists caffeine and theophylline blocked purine nucleoside-induced enhancement of immobilization. Tricyclic antidepressants such as imipramine and desipramine, the MAO inhibitor tranylcypromine, and amphetamine, a psychostimulant, reversed purine nucleoside-induced immobility. On the other hand, quipazine, fluoxetine, and amitriptyline failed to reverse purine nucleosides-induced prolongation of immobility. None of the antidepressants in the doses investigated had any effect by themselves.Reserpine also prolonged forced swimming-induced immobility in mice. The antidepressants fluoxetine and quipazine, but not methylxanthine pretreatment, reversed reserpine-induced immobility in this test model. These results indicate that adenosine and 2-chloroadenosine probably reduce norepinephrine outflow through their action on presynaptic purinoceptors on noradrenergic neurons and thereby cause prolongation of immobility in animals.     

Lipopolysaccharide-mediated immobility in mice: reversal by cyclooxygenase enzyme inhibitors

Endotoxin (lipopolysaccharide, LPS) is known to activate the hypothalamo-pituitary adrenocortical axis, as well as norepinephrine and indolamine metabolism. In the present study we examined the effects of systemically administered LPS on forced swimming-induced despair behavior in mice. LPS (50 micrograms/mouse i.p.) time-dependently enhanced the forced swimming-induced immobility period. The increase in immobility time was highest after 2 h of LPS administration. Desipramine (10 mg/kg), a tricycle antidepressant, or fluoxetine (10 mg/kg), a serotonin reuptake inhibitor, significantly reversed the LPS-induced increase in immobility time. Cyclooxygenase inhibitors nimesulide (1, 2 and 5 mg/kg), naproxen (10 mg/kg) and rofecoxib (2 mg/kg) did not alter the despair behavior per se. Nimesulide (10 mg/kg) did reverse reserpine-induced immobility. Nimesulide (2 mg/kg), naproxen (10 mg/kg) and rofecoxib (2 mg/kg) significantly reversed LPS-mediated despair behavior. The present study demonstrated that LPS-induced inflammatory responses in the brain may cause despair behavior. Reversal with a cyclooxygenase inhibitor indicates the role of prostaglandins in despair behavior.     

Evidence of beta-adrenergic involvement in forced swimming-induced behavioural despair of mice

Modulation of forced swimming-induced immobility by beta-adrenoceptor activation was investigated in mice. Isoprenaline prolonged the immobility duration of mice in a dose-related manner when the animals were forced to swim for 6 min periods. On the other hand, salbutamol (a beta 2-agonist) reduced the immobility duration of mice. Pretreatment with propranolol (1,2,4,8 and 16 mg/kg, ip), atenolol (10 mg/kg, ip) and metoprolol (10 mg/kg, ip) antagonized the immobility-enhancing effect of isoprenaline. Chronic administration (10 mg/kg/day) for 8 days of propranolol and imipramine protected the animals from isoprenaline-evoked prolongation of immobility. These findings suggest that central beta 1- and beta 2-subtypes of adrenoceptors may be acting in opposite directions to modify the immobility duration of mice. Activation of central beta 1-adrenoceptors may lead to enhanced behavioural despair, whereas a reverse effect may be observed on beta 2-adrenoceptor activation.     

Antidepressant-like effects of apigenin and 2,4,5-trimethoxycinnamic acid from Perilla frutescens in the forced swimming test

We studied the effects of apigenin and 2,4,5-trimethoxycinnamic acid (TMCA) on the behavioral despair test (forced swimming test), and the central noradrenergic, dopaminergic and serotonergic activities in mice. Apigenin at intraperitoneal doses of 12.5 and 25 mg/kg significantly decreased the duration of immobility in the forced swimming test in mice. At 100 mg/kg, the duration of immobility was returned to the control level in the test. On the other hand, TMCA treatment (25-200 mg/kg, i.p.) failed to significantly alter the duration of immobility. Based on the behavioral data, we examined changes in the monoamine turnover in mice having been subjected to forced swimming for 40 min. The monoamine turnover was measured in seven brain regions. Forced swimming exposure induced a significant decrease in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) in the striatum and amygdala and in 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytriptamine (5-HT) in the hypothalamus, and a significant increase in DOPAC/DA in the thalamus and hypothalamus and in 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)/norepinephrine (NE) in the amygdala, frontal cortex, hypothalamus, and midbrain. Apigenin (25 mg/kg) treatment produced attenuation of forced swim test-induced decrease of DA turnover in the amygdala and increase of DA turnover in the hypothalamus. Furthermore, intraperitoneal administration of haloperidol (0.2 mg/kg), a dopamine D(2) antagonist, blocked the apigenin (25 mg/kg)-induced decrease in immobility in the forced swimming test. These behavioral and biochemical results indicate the antidepressant properties of apigenin, which may be mediated by the dopaminergic mechanisms in the mouse brain.     

丹参酮的抗抑郁作用研究

目的：研究丹参酮的抗抑郁作用。方法：丹参酮灌胃给药。通过尾静脉注射利血平（2mg·kg-1）复制小鼠抑郁模型,观察眼帘下垂动物数、运动不能动物数,测肛温;腹腔注射丁苯那嗪（40mg·kg-1）复制小鼠抑郁模型,观察眼帘下垂动物数和僵住动物数;尾静脉注射利血平（2mg·kg-1）后进行悬尾、强迫游泳实验,复制小鼠获得性绝望模型,观察小鼠悬尾不动时间和游泳不动时间;通过静脉注射单胺氧化酶抑制剂（盐酸色胺）复制大鼠惊厥模型,观察大鼠动作平均分值、拍打动作持续时间。结果：60、30、20mg·kg-1丹参酮可显著减少利血平复制的抑郁模型小鼠眼帘下垂、运动不能动物数,显著升高模型小鼠肛温（P〈0.05）;60、30mg·kg-1丹参酮可显著减少丁苯那嗪复制的抑郁模型小鼠眼帘下垂、僵住动物数（P〈0.01或P〈0.05）;60、30mg·kg-1丹参酮可显著缩短绝望模型小鼠悬尾不动、游泳不动时间（P〈0.01）;42、21、14mg·kg-1丹参酮可显著降低盐酸色胺复制的惊厥模型大鼠动作平均分,42、21mg·kg-1丹参酮可显著缩短模型大鼠拍打动作持续时间（P〈0.01或P〈0.05）。结论：丹参酮有一定抗抑郁作用。     

Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models

Aim:

To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice.

Methods:

In the learned helplessness test (LH), Neu-P11 or melatonin (25–100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25–100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25–100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed.

Results:

In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon.

Conclusion:

The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.     

Forced swimming test in rats: effect of desipramine administration and the period of exposure to the test on struggling behavior, swimming, immobility and defecation rate

The effect of desipramine administration and the duration of the daily exposure to forced swimming on some variables has been studied in adult male rats. Desipramine administration (15 mg/kg) significantly increased struggling behavior in the first and second 5-min periods of a single exposure to forced swimming. Swimming was reduced in the first 5 min and remained unchanged thereafter. Immobility was decreased in the second and the third 5-min periods. After a pre-exposure to forced swimming for 15 min the day before, the drug was effective in increasing struggling behavior and reducing immobility during a subsequent 5-min test. Swimming was not modified. Daily exposure to forced swimming for 3 days caused a decline in struggling behavior and swimming, while increasing immobility and the defecation rate. The duration of daily exposure to forced swimming did not alter the changes in the variables measured. The present results indicate that a one-day test can be used to discriminate between saline- and desipramine-treated rats, and that struggling behavior could be a reliable measure of the positive action of antidepressants. The finding that behavioral changes over the 3 days were independent of the duration of exposure to swimming argues against the interpretation of the results which suggest that the responses are caused by the appearance of a behavioral despair state, and suggests that these behaviors might be trait-markers in the rat. In addition, the changes in struggling behavior and immobility over the 3 days cannot be attributed to a behavioral adaptation to the test because the defecation rate increased rather than decreased during successive forced swimming tests.     

Non-specificity of "behavioral despair" as an animal model of depression

When mice are forced to swim in a restricted space, they will cease attempts to escape and adopt a characteristic immobile posture which can be readily identified and timed. Imipramine decreased the duration of immobility in a 4 min swimming test in a dose-related manner. Likewise, caffeine, triiodothyronine and pentobarbital reduced immobility. These latter findings shed doubt upon the specificity of the behavioral despair swimming test to identify substances with antidepressant activity.     

Possible contributory role of the central histaminergic system in the forced swimming model.

Forced swimming is considered to bring about a depressive or despair state in experimental animals, usually manifested as immobility. Levoprotiline (CAS 76496-68-9), a new antidepressant, clearly reduced the duration of immobility in the forced swimming model in mice. As levoprotiline does not inhibit noradrenaline or serotonin reuptake, this effect did not seem to have been brought about through central monoaminergic systems. Histamine and tele-methylhistamine levels, the main metabolite of histamine in the cerebral cortex, were found to be significantly increased in the forced swimming model. Since the only significant known effect of levoprotiline on the neurotransmitter system is its histamine H1 receptor antagonism, a possible contribution of the central histaminergic system to the forced swimming model is proposed. The action of mepyramine, a histamine H1 receptor antagonist in reducing the duration of immobility seemed to support this proposition. It should be noted that antihistaminergic properties are shared by many antidepressant drugs.     

酸枣仁总皂苷抗抑郁作用的实验研究

目的研究酸枣仁总皂苷对行为绝望小鼠抑郁模型的影响。方法采用小鼠强迫游泳实验和悬尾实验抑郁模型,小鼠行为绝望的不动时间作为指标,考察酸枣仁总皂苷抗抑郁活性。结果酸枣仁总皂苷中、高剂量组均能减少小鼠强迫游泳和悬尾不动时间,与空白对照组比较差异有统计学意义(P<0.05,P<0.01)。结论酸枣仁总皂苷具有一定的抗抑郁作用。     

Clonidine — induced behavioural despair in mice: Reversal by antidepressants

The effects of various alpha₂ adrenoceptor agonists on forced swimming — induced despair behaviour were studied in mice. Clonidine, B-HT 920 and guanfacine significantly prolonged the total immobility duration. Clonidine-induced behavioural despair was antagonized by prior treatment with yohimbine. The tricyclic antidepressants imipramine, desipramine, trimipramine, amitriptyline, nortriptyline and doxepin, the MAO inhibitor tranynlcypromine, and the antimanic agent lithium reversed clonidine-induced behavioural despair. Chronic treatment with imipramine evoked more pronounced reversal as compared to acute treatment. Amphetamine, a psychostimulant, inhibited clonidine-induced enhancement of immobility duration but diazepam, a skeletal muscle relaxant was without any effect. On the other hand, adenosine showed potentiation of the submaximal response of clonidine. These observations suggest that clonidine-induced behavioural despair is probably mediated through its presynaptic action on alpha₂ adrenoceptors, resulting in reduced central noradrenergic outflow. The present data proposes a simple test system to induce depression-like syndrome in animals, sensitive to antidepressant therapy.     

百合地黄汤抗抑郁活性部位的筛选

 目的：筛选百合地黄汤抗抑郁活性部位。方法：选用小鼠行为绝望模型评价百合地黄汤醇提取物及其4个不同极性部位的抗抑郁作用。结果：百合地黄汤醇提取物及其4个不同极性部位均不同程度地缩短绝望模型中小鼠悬尾和强迫游泳的不动时间,其中以百合地黄汤醇提取物(P<0.01)和正丁醇部位(P<0.001)最为显著。结论：百合地黄汤具有抗抑郁作用,活性成分主要分布在正丁醇部位。     

Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test

The role of genotype in the effects of selective D1 and D2 dopamine agonists and antagonists on behavioural despair (Porsolt's test) was studied. Mice of nine inbred strains showed significant interstrain differences in duration of immobility. The influence of dopaminergic drugs was assessed in six strains characterized by different levels of swimming activity. SKF 38393 (10 mg/kg), an agonist at D1 dopamine receptors, increased swimming activity, while the D1 antagonist SCH 23390 (0.2 and 0.5 mg/kg) reduced it, the effects being genotype dependent. The involvement of D2 dopamine receptors in the regulation of mouse behaviour in the forced swimming test was not so evident; the D2 agonist bromocriptine (10 mg/kg) produced no significant effect. The D2 agonist quinpirole (2.5 mg/kg) increased immobility in the majority of the mouse strains studied, while in CBA mice it resulted in a marked reduction of immobility. The D2 antagonist sulpiride (20 mg/kg) decreased immobility and increased active swimming only in two strains. The present results suggest a different role for D1 and D2 dopamine receptors in the regulation of swimming in the mouse.     

Combination therapy of imipramine and melatonin: additive antidepressant effect in mouse forced swimming test

Although there are tools to treat depressive patients, a considerable amount of the cases remains to be untreated. These drug-resistant patients need new drugs or drug combinations to overcome this problem. Thus, the potential synergistic effect of melatonin on a classical drug, imipramine was evaluated in the present study. To test this hypothesis, porsolt swim test, a test predictive of antidepressant-like action, was conducted in mice. Imipramine at doses of 20 and 40 mg/kg caused no alteration and statistically significant reduction in the duration of immobility in forced swim test, respectively. While 5 mg/kg melatonin had no effect, 10 mg/kg melatonin slightly reduced the duration of immobility. When sub-effective doses of imipramine and melatonin (20 and 5 mg/kg, respectively) were co-administered, there was no alteration in responses compared with those of each drug alone. Likewise, the effective dose of melatonin (10 mg/kg) did not cause any increase in responses to 20 mg/kg imipramine. Although combination of imipramine (40 mg/kg) and melatonin (5 mg/kg) did not exert an antidepressant effect above that of imipramine alone, co-administration of the effective doses (10 and 40 mg/kg for melatonin and imipramine, respectively) displayed an additive effect. There were no significant differences between groups in relation with locomotor activity test. The results show that co-administration of imipramine and melatonin exhibits an additive effect and that there seems to be no interaction between the drugs.     

Effects of acute or chronic administration of substituted benzamides in experimental models of depression in rats

The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose–response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose–response relationship suggests that these drugs in small doses act on presynaptic dopamine D₂ receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.     

Studies on the neuropsychopharmacological profile of fengabine (SL 79229) in mice

The effect of fengabine (a novel benzylidene derivative) on neuropsychopharmacological parameters was investigated in mice. On acute systemic administration, it showed modulatory effects on 1) forced swimming-induced immobility, 2) foot shock-induced aggression, 3) electromaximal shock-induced convulsion, 4) radiant heat-induced nociception and 5) locomotor activity. However, it has no effect on the muscle strength of the animal. The GABAA receptor antagonists reversed its effects on forced swimming-induced immobility and foot shock-induced aggression, implicating a GABAergic involvement in its mechanism of action. But these antagonists failed to reverse its potentiating effect on morphine antinociception, suggesting a possible interaction of the drug with opioid receptors. A potential clinical usefulness of the drug and of GABA agonists in general is commented upon.     

Antidepressant-like effect of icariin and its possible mechanism in mice

The behavioral, neurochemical and neuroendocrine effects of icariin isolated from Epimedium brevicornum were investigated in behavioral despair models of KunMing strain of male mice. Icariin was found to significantly shorten immobility time in the forced swimming test (FST) after orally administration for 21 consecutive days. Icarrin also produced a marked reduction in immobility time in the tail suspension test (TST) when administered for at least 7 consecutive days. The preferable antidepressant action by icariin was obtained at 17.5 and 35 mg/kg in the present study. Moreover, it was observed that the stress of FST exposure induced increases in brain monoamine oxidase (MAO) A and B activities, serum corticotropin-releasing factor (CRF) levels, as well as decreases in brain monoamine neurotransmitter levels. Treatment of icariin for 21 consecutive days mainly reversed the above effects in the mouse FST. These results suggested that icarrin possessed potent antidepressant-like properties that were mediated via neurochemical and neuroendocrine systems.     

花椒多酚类化合物急性给药的抗抑郁作用及机制研究

目的探讨花椒多酚类化合物总提取物（ZPPC）急性给药对ICR小鼠抑郁模型的拮抗作用及可能的机制。方法采用经典的行为绝望抑郁模型,即小鼠悬尾实验和强迫游泳实验,观察ZPPC急性给药对应激小鼠绝望不动时间的影响;同时观察ZPPC对小鼠自主活动的影响,采用荧光分光光度法测定ZPPC对小鼠脑内单胺氧化酶活性的影响。结果与空白组比较,ZPPC（50,100,200mg·kg-1,i.g.）明显缩短小鼠悬尾和强迫游泳实验中的不动时间,其作用类似于阳性对照药丙咪嗪（10mg·kg-1,i.p.）;ZPPC还明显抑制脑内单胺氧化酶的活性。结论 ZPPC急性给药在小鼠行为绝望模型中显示出明显的抗抑郁作用,其作用机制可能与抑制脑内单胺氧化酶活性有关。