Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine

The present study set out to establish the chronic mild stress (CMS) animal model of depression in male CD-1 mice, a commonly used mouse strain. Mice were exposed to a series of mild stressors (e.g. soiled bedding, paired housing, cage tilt, white noise) presented in a continuous unpredictable fashion. Intermittently, CMS was discontinued and the mice were presented with both water and a palatable saccharin solution (0.1% w/v) in a two-bottle choice test overnight (15 h). Repeated exposure of these mice to the stressors led to a reduction in preference for the saccharin solution. This change in preference was attributed to an increase in the consumption of water rather than a decrease in the consumption of saccharin solution. Over time and with extensive testing, CMS no longer affected performance in the two-bottle saccharin preference test. Treatment with the tricyclic antidepressant imipramine (20 mg/kg i.p., once daily) had a varied effect on the CMS-induced change in preference for saccharin, dependent on the timing of initiation of imipramine treatment. In the first instance, following 5 weeks of CMS where a reduction in saccharin preference was established, treatment with imipramine for a further 5 weeks maintained the stress-induced deficit in saccharin preference. However, using a different approach, pre-treatment with imipramine once daily for 2 weeks, prior to onset of CMS, and co-treatment thereafter, attenuated CMS-induced changes in saccharin preference. Finally, when imipramine treatment was scheduled to begin with the CMS procedure, imipramine failed to prevent the CMS-induced reductions in saccharin preference. Changes in behaviour observed after exposure to CMS may be linked to a stress-induced deterioration of the sensitivity of the mice to a rewarding stimulus. Treatment with imipramine can reduce these behavioural changes but is only effective when given repeatedly prior to onset of CMS.     

大豆苷元对慢性应激抑郁大鼠行为学及海马部脑源性神经生长因子表达的影响

目的 探讨大豆苷元抗抑郁作用及其机制. 方法 建立大鼠慢性不可预测应激模型,通过强迫游泳(foced swimming test,FST)、敞箱实验(open field test,OFT)观察应激后各组大鼠行为学的变化. 运用Western bloting观察经药物治疗后各组大鼠海马齿状回部脑源性神经生长因子(brain-derived neurotrophic factor,BDNF)的改变. 结果 经慢性应激14 d后,模型组FST、OFT行为学评分下降,与正常组比较差异有统计学意义(P<0.05),1,3,10 mg&#8226;kg^-1大豆苷元和丙米嗪治疗14 d后,大鼠FST、OFT行为学评分明显改善(P<0.05). 停药7 d后,丙米嗪组、大豆苷元各剂量组FST、OFT评分较模型组均差异无统计学意义(均P>0.05). 同时,在海马齿状回部发现,慢性应激可使BDNF蛋白表达下降,经丙米嗪和大豆苷元治疗后BDNF含量均增加. 停药7 d后,丙米嗪组、大豆苷元各剂量组再次出现BDNF蛋白表达下降. 结论 大豆苷元可能通过增加海马齿状回BDNF的表达改善抑郁模型大鼠行为,产生抗抑郁作用.     

Alnespirone (S 20499), an agonist of 5-HT1A receptors, and imipramine have similar activity in a chronic mild stress model of depression.

A chronic mild stress (CMS) model of depression was used to study an antidepressant-like activity of alnespirone (S 20499), a selective agonist of 5-HT1A receptors. In this model, a substantial decrease in consumption of a palatable sucrose solution over time is observed in rats subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic (5 weeks) treatment with alnespirone, in a dose range between 1-5 mg/kg/day, gradually and dose dependently reversed the CMS-induced reductions in sucrose consumption without any significant effects in the non-stressed control animals. The onset of action of the most active doses (2.5 and 5 mg/kg/day) and the overall efficacy of alnespirone in the CMS model were comparable to those observed following similar administration of imipramine (10 mg/kg/ day). At the lower (0.5 mg/kg/day) and higher (10 and 20 mg/kg/day) doses, alnespirone was ineffective against the CMS-induced deficit in sucrose consumption. These data provide further support for previous suggestions, based on both the clinical observations and animal data, that agonism at 5-HT1A receptors may result in antidepressant action.     

Tolcapone: a potential new antidepressant detected in a novel animal model of depression

The potential antidepressant properties of tolcapone, a new catechol-O-methyl transferase (COMT) inhibitor, were investigated in a novel animal model of depression. Chronic mild stress (CMS)-induced anhedonia in rats is recognized as a model of depression with predictive and etiological validity. Here, the effects of CMS on the hedonic state of animals were assessed using a self-stimulation paradigm in which rats self-activate the ventral tegmental area. Frequency thresholds for self-stimulation responses were determined prior to, during and after a 19 day period of exposure to a variety of intermittent, unpredictable, mild stressors. In vehicle-treated stressed animals, stimulation threshold was significantly increased after about 12 days, reflecting a gradual development of an "anhedonic" state. This anhedonia persisted throughout the stress period and subsequently disappeared over a 10 day period. This stress-induced anhedonic state was not observed in stressed rats concomitantly treated with tolcapone (10 or 30mg/kg b.i.d.). In non-stressed vehicle- or drug-treated animals, no significant change in self-stimulation threshold was consistently observed. These results suggest that selective, reversible COMT inhibitors such as tolcapone may offer an innovative approach to the treatment of depression, in addition to their potential therapeutic use in Parkinson's disease.     

Effects of the novel antidepressant milnacipran in a chronic mild stress model of depression

The chronic mild stress (CMS) model of depression may serve as a suitable research tool for studying the action of novel antidepressants (i.e., both efficacy and onset of action). The CMS‐induced sub‐sensitivity to reward is reversed by chronic treatment with antidepressant drugs. The effect of the serotonin and norepinephrine reuptake inhibitor (SNRI), milnacipran, was investigated on the CMS model in rats in comparison with imipramine. The CMS model of depression consisted in subjecting rats to several mild stressors for a prolonged period of time, which resulted in a decrease in their responsiveness to rewarding stimuli. This deficit was monitored by a decrease in the consumption of a 1% sucrose solution. Stressed and control animals received daily for 5 weeks injections of vehicle, imipramine (10 mg/kg) or milnacipran (3, 10, and 30 mg/kg). CMS caused a decrease in the consumption of the 1% sucrose solution. The deficit in sucrose consumption in stressed animals was reversed by imipramine and milnacipran. The effect of milnacipran was gradual, dose‐dependent, and was maintained for one week after stopping drug treatment. Neither imipramine nor milnacipran modified the behavior of control animals. Milnacipran is active in the CMS model of depression as expected from its clinically demonstrated antidepressant effect. Drug Dev. Res. 61:101–106, 2004. © 2004 Wiley‐Liss, Inc.     

Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression.

From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.     

Antidepressive effects of the κ-opioid receptor agonist salvinorin A in a rat model of anhedonia

Salvinorin A (SalvA), the hallucinogenic derivative of the plant Salvia divinorum, is a selective κ-opioid receptor agonist that may also have antidepressant properties. Chronic mild stress (CMS) was applied to male and female Long-Evans rats to model anhedonia common in depression. The progressive loss in preference for a sucrose solution over plain water, a measure of anhedonia, and locomotor activity were monitored for 7 weeks. Because antidepressant medications often modify reproductive functions, endocrine glands and hormone-sensitive tissues were assessed at necropsy after the conclusion of the behavioral protocol. Three weeks of CMS exposure led to a decrease in sucrose preference. CMS was continued for 3 additional weeks and animals were randomly assigned to treatment with 1 mg SalvA/kg body weight or to a vehicle control group. The results indicate that SalvA reversed anhedonia whereas control animals continued to show a suppressed preference for the sucrose solution. In addition, no change in sucrose preference was observed in nonstressed rats that were exposed to the same dosage of SalvA. The results indicate that SalvA is an effective antidepressant agent when administered chronically to rats showing symptoms of depression similar to those observed in humans.     

The attenuation of morphine-conditioned place preference following chronic mild stress is reversed by a CCKB receptor antagonist

Chronic exposure to mild unpredictable stress has been found to abolish the acquisition of preference for a distinctive environment paired with morphine, whereas morphine induced conditioning place preference in non-stressed rats. Chronic treatment for 21 days with the tricyclic antidepressant imipramine reversed the motivational effects produced by chronic mild stress, and animals showed a place preference for the morphine-paired compartment. When the CCK_B receptor antagonist PD-134,308 was co-administered with morphine in stressed animals during the conditioning period, the preference for the morphine-paired compartment was also re-established. The CCK_B receptor antagonist given alone did not induce rewarding effects in this paradigm. These findings indicate that the administration of a CCK_B receptor antagonist reversed the effects of chronic mild stress on opiate rewarding properties. Received: 5 October 1996/Final version: 4 December 1996     

Reversal of stress-induced anhedonia by the atypical antidepressants,fluoxetine and maprotiline

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 µg/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.     

Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia

Chronic exposure to very mild unpredictable stress (CMS) has previously been found to reduce the consumption of palatable sweet solutions and to impair place preference conditioning; evidence has been presented that these effects may reflect a dysfunction of the mesolimbic dopamine system. In the present study, rats were subjected to CMS for a total of 9 weeks. CMS reduced the consumption of a 1% sucrose solution. During weeks 6 and 7, animals received quinpirole (0–400 µg/kg) twice weekly. Both CMS-treated animals and controls showed sensitization to the locomotor stimulant effects of quinpirole. Subsequently, a sustained recovery of sucrose drinking was observed in quinpirole-treated stressed animals. During week 8, all animals received a single pair of place preference conditioning trials, in which quinpirole (200 µg/kg) was administered in a distinctive environment, and vehicle in a different environment. Non-stressed animals showed an increase in preference for the environment associated with quinpirole, as did stressed animals that had been sensitized to quinpirole; this effect was absent in untreated stressed animals. Finally, in week 9, acute administration of raclopride (150 µg/kg) was found to reverse the recovery of sucrose drinking in quinpirole-treated stressed animals, suggesting that these effects are mediated by an increase in dopamine function.     

The selective sigma2 ligand Lu 28-179 has an antidepressant-like profile in the rat chronic mild stress model of depression

The selective sigma2 (sigma2) ligand Lu 28-179, or 1'-[4[1-(4-fluorophenyl)-1H-indol-3-yl]-l-butyl]spiro[isobenzofuran++ +-1(3H),4'-piperidine], was studied in the chronic mild stress (CMS) model of depression. The CMS test procedure consists of sequential exposures to a variety of mild stressors for a prolonged period of time and results in behavioural hedonic deficits, which can be measured as decreased consumption of a palatable sucrose solution. In rats, exposure to CMS treatment with citalopram or imipramine for 2 or 4 weeks, respectively, normalized the sucrose intake. Similarly, Lu 28-179 (1.0 mg/kg subcutaneously per day) normalized sucrose intake in rats exposed to CMS. This effect was found in two separate experiments and was achieved after 3 and 4 weeks of treatment, respectively. This suggests an antidepressant potential for Lu 28-179. Doses of 0.01 and 0.1 mg/kg were inactive. Groups exposed to CMS and treated with 0.5, 2.0 or 3.0 mg/kg showed a significantly increased sucrose intake compared with vehicle-treated stressed animals at week 5. However, this effect was confounded by decreased intake in the vehicle controls. Lu 28-179 did not affect sucrose intake in non-stressed rats at any of the doses tested.     

Icariin from Epimedium brevicornum attenuates chronic mild stress-induced behavioral and neuroendocrinological alterations in male Wistar rats

Chronic mild stress (CMS) is suggested to produce abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamus-pituitary-thyroid (HPT) axis. Therefore, compound that attenuates the neuroendocrinological alterations may have potential as antidepressant. The behavioral and neuroendocrinological effects of icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, were investigated in the CMS model of depression in male Wistar rats. CMS procedure caused an anhedonic state in rats resulted in increased corticotropin-releasing factor (CRF) concentrations in dissected brain regions and serum, decreased total triiodothyronine (tT3) in serum with no significant changes in serum adrenocorticotrophic hormone (ACTH) and thyroxine (tT4). Administration of icariin reversed CMS-induced sucrose intake reduction and CRF elevation. These results suggested that icariin possessed potent antidepressant-like activities which were at least in part mediated by improving the abnormalities in the HPA axis functions. However, we did not find a clear correlation between the HPT axis and icariin treatment in the CMS-treated rats.     

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats.

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.     

Effects of imipramine on serotonergic and beta-adrenergic receptor binding in a realistic animal model of depression

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. In the present study, in addition to confirming these behavioural observations, the binding properties of cortical beta-adrenergic and 5HT₂ receptors, and hippocampal 5HT_1A receptors were studied (using the ligands [³H]-dihydroalprenolol, [³H]-ketanserin and [³H]-8-OH-DPAT, respectively), following 7 weeks of CMS and 4 weeks of imipramine treatment (10mg/kg per day). CMS increased B_max for all three receptor systems. Impramine decreased B_max, reversing the effect of CMS, for beta-adrenergic and 5HT₂ receptor binding, but increased B_max for 5HT_1A receptor binding. K_Ds were unaffected by either treatment. The beta-receptor and 5HT₂ receptor binding data are consistent with accounts of antidepressant action derived from studies in normal animals, but the 5HT_1A receptor binding data are more difficult to reconcile. In no case was there a good correlation between receptor binding and behavioural data.     

Inhibition of NMDA receptor and GSK3β vmediates the fast onset of antidepressant like natural product

OBJECTIVE To investigate the fast antidepressant effect and the underlying mechanism of it.METHODS C57BL/6 mice were exposed to a 6-week chronic unpredictable mild stress(CUMS)protocol,and treated with YY-23 or a positive drug fluoxetine in the last 3weeks,behavioral assessments proceed every week.NMDA-induced current were recorded by whole-cell patch clamp on dissociated hippocampal CA1 neurons of Sprague-Dawley rats.Phosphorylation of the signaling proteins was evaluated by Western blotting.RESULTS The electrophysiological results showed that YY-23 is a non-competitive NMDA receptor antagonist,neither in′use-dependent′nor′voltage-dependent′way,with no prominent effect on AMPA induced current.This antagonism of YY-23 could be partially prevented by proven blockers MK801 and Mg2+,laterally indicating the nature of NMDA receptor antagonist both pharmacologically and physiologically.Behavioral and Biochemical study showed that YY-23 could act as antidepressant and exerted strong inhibitory effect on GSK3β in PFC of CMS depression mice model.CONCLUSION YY-23 showed promising antidepressant effect with rapid onset,which might be related to NMDA receptor antagonism and GSK3β inhibition.     

Antidepressant-like action of AGN 2979, a tryptophan hydroxylase activation inhibitor, in a chronic mild stress model of depression in rats.

Chronic mild stress (CMS) procedure was used to study an antidepressant-like activity of AGN 2979, a selective inhibitor of tryptophan hydroxylase (TH) activation. At the dose of 4 mg/kg, AGN 2979 fully reversed the CMS-induced reduction in the consumption of 1% sucrose solution. This effect was maintained for at least 1 week after cessation of treatment and no signs of withdrawal were observed in either stressed or control animals receiving AGN 2979. The lower (1 mg/kg) and higher (16 mg/kg) doses were ineffective. The magnitude of action of AGN 2979 in the CMS model was comparable to that of imipramine (10 mg/kg) but its onset of action appears to be faster since the inhibition of sucrose intake in stressed animals was already reversed after the 1st week of AGN 2979 administration while imipramine required 3 weeks of treatment to cause similar effect. These results provide support for the hypothesis that inhibition of TH activation may result in a potent antidepressant activity.     

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT_1A receptor agonist and 5-HT₂ receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D₂/D₃ receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D₂/D₃ receptor-mediated transmission.     

Quetiapine prevents anhedonia induced by acute or chronic stress.

The role of atypical antipsychotics as add-on treatments and as primary mood stabilizers in different phases of bipolar disorder is an important current research area. Although in bipolar patients the main therapeutic indication of quetiapine (QTP) is the management of acute mania, several observations suggest that this agent may exert antidepressant as well as antimanic effects. However, in our knowledge, there are no preclinical studies supporting this hypothesis. Thus, the main goal of the present work was to evaluate the putative antidepressant effect of QTP (0.4, 2.0, or 10 mg/kg/day), in comparison to amitriptyline (AMI) (2 or 5 mg/kg/day), in rats exposed to acute or chronic stress. The administration of QTP, 2 mg/kg/day, prevents the onset of anhedonia in rats exposed to a 6-week chronic mild stress (CMS) protocol. The effect of QTP has a slow onset, beginning at week 5, and causes a complete recovery from anhedonia. In this respect, the effect of QTP is similar to that obtained after chronic administration of AMI 2 or 5 mg/kg/day. Our findings also indicate that a 6-week administration of QTP, 2 or 10 mg/kg/day, has protective effects against the onset of anhedonia caused by the exposure to an acute subthreshold stressful event in rats that have previously experienced the CMS procedure. The results suggest that QTP is able to prevent both the transient mood depression caused by acute stress and the long-lasting anhedonic state induced by exposure, over a period of weeks, to a variety of unpredictable mild stressors.     

Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer

Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (±)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (±)-mianserin (2.5 mg/kg), and the other enantiomer, (–)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (±)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (±)-mianserin (2.5 mg/kg) or by (–)-mianserin. Raclopride (100 µg/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with (±)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.These data were presented at the joint meeting of the British Association for Psychopharmacology and the European Behavioural Pharmacology Society held in Cambridge, UK in July 1992 (Cheeta et al. 1992).