An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress

Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, anddl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.     

Electroconvulsive stimulation reverses anhedonia and cognitive impairments in rats exposed to chronic mild stress

Electroconvulsive therapy remains the most effective treatment for depression including a fast onset of action. However, this therapeutic approach suffers from some potential drawbacks. In the acute phase this includes amnesia. Electroconvulsive stimulation (ECS) has previously been shown to reverse a depression-like state in the chronic mild stress model of depression (CMS), but the effect of ECS on cognition has not previously been investigated. In this study the CMS model was used to induce a depressive-like condition in rats. The study was designed to investigate the acute effect of ECS treatment on working memory and the chronic effect of repeated ECS treatments on depression-like behavior and working memory. The results indicated that, in the acute phase, ECS treatment induced a working memory deficit in healthy controls unexposed to stress, while repeated treatments reversed stress-induced decline in working memory, as well as recovering rats submitted to the CMS paradigm from the anhedonic-like state. Like in the clinical setting, a single ECS exposure was ineffective in inducing remission from a depression-like state.     

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     

Voltammetric evidence that subsensitivity to reward following chronic mild stress is associated with increased release of mesolimbic dopamine

Chronic exposure to mild unpredictable stress caused a decrease in rats' consumption of a palatable weak sucrose solution, which was reversed by chronic (5 weeks) administration of imipramine (5 mg/kg/day). Dopamine (DA) release in the nucleus accumbens (NAc) and caudate putamen (CPu) was measured in vivo using fast cyclic voltammetry, following electrical stimulation of the medial forebrain bundle. Experiments were performed under chloral hydrate anaesthesia 48 h after the termination of stress and the final imipramine injection. DA release was increased in the NAc of both stressed and imipramine-treated animals; imipramine did not normalize the increased DA release in stressed animals. In a further experiment, brain slices from stressed animals tended to be subsensitive to the inhibition of DA release in the NAc by quinpirole. No changes were observed in the CPu in any experiment. We discuss the relationship of these effects to stress-induced anhedonia.     

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).     

Behavioral and biochemical evidences for antidepressant-like activity of palmatine in mice subjected to chronic unpredictable mild stress

BackgroundIn the present study, antidepressant-like activity of palmatine was evaluated in unstressed and stressed young male Swiss albino mice.MethodsThe animals were subjected to unpredictable mild stress daily for 21 successive days to induce depression-like behavior. Palmatine (0.25, 0.5, 1 mg/kg, ip) was administered for 21 successive days to unstressed and stressed mice. The antidepressant-like activity was evaluated using the tail suspension test, forced swim test and sucrose preference test.ResultsPalmatine (0.5 and 1 mg/kg, ip) significantly decreased immobility periods of unstressed and stressed mice in the forced swim test and tail suspension test, thus indicating its significant antidepressant-like activity. Only the highest dose (1 mg/kg) of palmatine significantly reversed the stress-induced decrease in sucrose preference. There was no significant effect on locomotor activity of the mice by palmatine and fluoxetine. The antidepressant-like activity of palmatine was found to be comparable to fluoxetine (10 mg/kg) administered for successive 21 days. Palmatine (0.5 and 1 mg/kg, ip) significantly reversed the stress-induced increase in brain catalase levels, MAO-A activity, lipid peroxidation, plasma nitrite and corticosterone levels.ConclusionsPalmatine showed significant antidepressant-like activity in unstressed and stressed mice probably through inhibition of MAO-A activity, decrease in plasma nitrite levels and due to its antioxidant activity. In addition, palmatine also showed antidepressant-like activity in stressed mice probably through decrease in plasma corticosterone levels.     

Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine

Chronic sequential exposure to a variety of mild stressors has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions, associated with abnormalities of dopaminergic neurotransmission in the nucleus accumbens. In the present study, 5 weeks of treatment with imipramine (10 mg/kg b.i.d.) reversed the decreased sucrose intake of rats exposed to chronic mild stress. Stress also caused a decrease in D₂-receptor binding in the limbic forebrain (but not the striatum), which was completely reversed by imipramine. In nonstressed animals, imipramine decreased D₁-receptor binding in both regions. However, in stressed animals, imipramine did not significantly alter D₁-receptor binding in either area. Stress alone slightly increased D₁-receptor binding, in striatum only. Scatchard analysis showed that all changes in receptor binding resulted from changes in receptor number (B_max) rather than receptor affinity (K_D). The results support the hypothesis that changes in D₂-receptor function in the nucleus accumbens are responsible for chronic mild stress-induced anhedonia and its reversal by antidepressant drugs. They do not support the hypothesis that the sensitization of D₂-receptors seen following chronic antidepressant treatment is caused by a down-regulation of D₁-receptors.     

Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment

RATIONALE: Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning. MATERIALS AND METHODS: Mice (C57BL/6) were exposed to CMS for 6 weeks and anhedonia was evaluated by weekly monitoring of sucrose intake. Paroxetine (10 mg kg(-1)day(-1) i.p.) or saline were administered the last 3 weeks of CMS and continued for 2 weeks thereafter. Behavioral tests were performed over the last week of CMS (acute effects) and 1 month later (long-term effects). RESULTS: Mice exposed to CMS displayed both acute and long-term decreased sucrose intake, increased immobility in the forced swimming test (FST) and impaired memory in the novel object recognition test. It is interesting to note that a correlation was found between the cognitive deficits and the helpless behavior in the FST induced by CMS. During the CMS procedure, paroxetine treatment reverted partially recognition memory impairment but failed to prevent the increased immobility in the FST. Moreover, it decreased on its own sucrose intake. Importantly, the long-term effects of CMS were partially prevented by chronic paroxetine. CONCLUSIONS: CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.     

Individual differences in sucrose consumption in the rat: motivational and neurochemical correlates of hedonia

RATIONALE: Rats exhibit marked individual differences in consumption of freely available sucrose; however, the underlying mechanism(s) contributing to such interindividual differences remain unclear. OBJECTIVES: The current study examined whether: 1) motivational differences (as reflected by the degree of operant output to procure sucrose reward) underlie variability in sugar consumption, and 2) whether potential differences in dopaminergic and/or opioidergic systems contribute to such differences. METHODS: In the initial experiment, Sprague-Dawley rats were divided into those that spontaneously consumed High or Low amounts of sucrose, based on the consumption of freely available sugar (+/-2 SD from group median) over 7 consecutive test days. The potential differences in their motivation to seek and "earn" sucrose solution rewards were measured using the progressive ratio (PR) schedule of reinforcement. RESULTS: Performance of both groups on the PR schedule was sensitive to the concentration of sucrose (i.e. the higher the concentration, the greater the behavioral output). Furthermore, the High sucrose consumers earned a greater number of reinforcements (20% sucrose solution) than the Low group. Parenthetically, the degree of behavioral output by the High (but not the Low) group was comparable to that emitted for water under water-deprived condition. Treatment with the opioid antagonist, naloxone, attenuated PR performance for sucrose, whereas d-amphetamine (0.5 mg/kg) enhanced it. Furthermore, naloxone attenuated amphetamine-enhanced responding for sucrose reward, suggesting an interaction between the dopaminergic and opioidergic systems in the mediation of sucrose reward. CONCLUSIONS: These results support the contention that motivational differences may partially account for individual variability in sucrose consumption, and that dopaminergic and/or opioidergic agents differentially affect the "wanting" and/or "liking" of sucrose in the High and Low sucrose consumers.     

Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine

The anxiety/defense test battery has been developed to assess defensive reactions in rats to situations associated with a natural predator, the domestic cat. This comprises three paradigms designed to study the effects of cat exposure on general activity and location with respect to the cat (proxemic avoidance), the effects of cat exposure on non-defensive consummatory behavior, and the behavioral response to cat odor. In the present study subjects were exposed to 21 days pretreatment with imipramine (0, 5, and 15 mg/kg), before being assessed in the three experimental paradigms (carried out over a total period of 7 days). Imipramine treatment was maintained on a daily basis during the 7 days taken to complete the series of tests. The data indicated a behaviorally specific profile consistent with anxiety/fear reduction, but not with sedation, in three different paradigms, following treatment with 15 mg/kg imipramine. These behavioral changes included a reduction in freezing, proxemic avoidance and a disinhibition of suppressed feeding in response to cat presentation. Similarly, imipramine treatment (15 mg/kg) significantly reduced behaviors associated with risk assessment (e.g. flat back approach, stretch attend) during presentation of a cat odor stimulus. This behavioral profile suggests that chronic pretreatment with imipramine produces an attenuation of antipredator defensive behavior.Supported by NIH MH42803 and RCMI Grants RR03061 and RR01825.     

Effects of neuronal and inducible NOS inhibitor 1-[2-(trifluoromethyl) phenyl] imidazole (TRIM) in unpredictable chronic mild stress procedure in mice

Nitric oxide is an intracellular messenger which is involved in several functions and pathologies such as depression, anxiety, learning and memory. In many studies nitric oxide synthase inhibitors (NOSI) were shown to possess antidepressant-like effects in animal models of depression. The aim of this study is to investigate the effects of a selective neuronal and inducible nitric oxide synthase inhibitor TRIM (30 mg/kg/day, 35 days) in mice subjected to unpredictable chronic mild stress and then compare it's effect with a conventional selective serotonin reuptake inhibitor fluoxetine (15 mg/kg/day, 35 days). Stressed vehicle animals showed a significant disturbed coat state when compared with nonstressed animals and this effect was reversed by TRIM or fluoxetine. Both TRIM and fluoxetine prevented the stress-induced deficit in the grooming behaviour in the splash test. TRIM and fluoxetine also significantly decreased the attack frequency when compared to the stressed control group in the resident-intruder test. These results support the assumption that NOS inhibitors can be a new class of antidepressant drugs possibly acting on neuronal NOS.     

Phencyclidine (PCP) produces sexually dimorphic effects on voluntary sucrose consumption and elevated plus maze behavior

Previous research in our laboratory indicates that the psychotomimetic drug phencyclidine (PCP) reduces voluntary sucrose consumption in male rats, potentially modeling the schizophrenic symptom of anhedonia. Given reports from the clinical literature that schizophrenia has a later age of onset and more favorable outcome in females, PCP might be expected to have sexually dimorphic effects in animal models of schizophrenia such as PCP-induced decreases in voluntary sucrose consumption. Young adult (66 days old) and adult (109 days old) male and female rats were trained to drink sucrose during a 30 min/day presentation protocol. On the day prior to the test day, animals were treated with PCP (15 mg/kg) or saline four hours after the onset of the sucrose presentation (20 h prior to the sucrose on the test day). PCP decreased sucrose consumption on the test day similarly in adult males and females, although females also showed decreased water consumption. In young animals, PCP decreased sucrose consumption in males but not in females. These results are consistent with the prediction that females will be less sensitive to the schizophrenia-like behavioral effects of PCP. In a separate study, the same animals were tested in an elevated plus maze one to two months after testing for voluntary sucrose consumption. Significant sex × drug interaction effects on a number of measures in the elevated plus maze indicated that prior exposure to PCP had an anxiolytic effect in females and an anxiogenic effect in males. While unexpected, this finding indicates an additional sexually dimorphic effect of PCP on behavior and its potential relevance to the PCP model of schizophrenia is discussed.     

The number of granule cells in rat hippocampus is reduced after chronic mild stress and re-established after chronic escitalopram treatment

Stress and depression cause structural changes in the hippocampal formation. Some of these can be reversed by chronic antidepressant treatment. In the present study, we examined the changes in the total number of granule cells and the volume of the granule cell layer after exposing rats to chronic mild stress and chronic escitalopram treatment. Furthermore, we investigated which classes of immature granule cells are affected by stress and targeted by escitalopram. Rats were initially exposed to 2 weeks of CMS and 4 weeks of escitalopram treatment with concurrent exposure to stress. The behavioral changes, indicating a decrease in sensitivity to a reward, were assessed in terms of sucrose consumption. We found a significant 22.4% decrease in the total number of granule cells in the stressed rats. This decrease was reversed in the stressed escitalopram treated rats that responded to the treatment, but not in the rats that did not respond to escitalopram treatment. These changes were not followed by alterations in the volume of the granule cell layer. We also showed a differential regulation of dentate neurons, in different stages of development, by chronic stress and chronic escitalopram treatment. Our study shows that the anhedonia-like state in the CMS rats is associated with a reduced number of granule cells. We conclude that escitalopram acts on specific cellular targets during neuronal differentiation and that recovery from anhedonia-like behavior in rats may be the consequence of an escitalopram mediated increase in specific subtypes of immature dentate neurons.     

Effects of chlordiazepoxide,amitriptyline, imipramine,and their combinations on avoidance behaviour in mice

Chlordiazepoxide, imipramine, and amitriptyline, given alone or in combination, were tested in mice subjected to 5 daily 100-trial avoidance sessions in the shuttle-box. When the drugs were given alone, chlordiazepoxide and the lower doses of imipramine facilitated avoidance behaviour. The higher doses of the two antidepressants impaired avoidance behaviour. Mixtures of chlordiazepoxide and imipramine produced some facilitating effects, while depressant effects prevailed in the chlordiazepoxide-amitriptyline combinations.     

木兰花碱减轻慢性应激小鼠抑郁样行为及对脑部LSD1组蛋白修饰的影响

目的 探索木兰花碱对慢性不可预见性温和应激所致抑郁小鼠行为学的影响机制。方法 将 ICR小鼠随 机分为正常对照组（control组）、抑郁模型组（PG组）、木兰花碱高剂量组（MH组）和木兰花碱低剂量组（ML组）。采用 慢性不可预见性温和刺激方法建立抑郁小鼠模型,检测各组小鼠行为学的变化,并用实时定量 PCR、Western blot检 测小鼠脑部赖氨酸特异性组蛋白去甲基化酶 1（LSD1）mRNA及蛋白表达水平的变化。免疫组化染色法检测小鼠脑 部 LSD1阳性细胞数量。结果 木兰花碱在行为学上改善了小鼠的抑郁状况,与 PG组相比,MH组和 ML组悬尾不动 时间、强迫游泳不动时间明显缩短（P＜0.05）。实时定量 PCR及 Western blot结果显示,与 control组相比,PG组 LSD1 mRNA表达差异无统计学意义,蛋白表达明显降低（P＜0.05）,ML组 LSD1 mRNA和蛋白表达明显升高（P＜0.05）;与 PG组相比,ML组 LSD1 mRNA和蛋白表达明显升高（P＜0.05）。免疫组化结果显示,与 control组相比,PG组小鼠脑部 LSD1阳性细胞数量减少,而 ML组较 PG组增加。结论 在木兰花碱治疗抑郁小鼠的过程中,LSD1可能起到了重要 的调节作用。     

脱氢表雄酮对慢性轻度应激小鼠认知功能的影响

目的 :观察慢性轻度应激 (CMS)小鼠模型的自发活动与认知行为变化 ,中枢胆碱能毒蕈碱型(M)受体的改变及药物脱氢表雄酮 (DHEA)的干预作用。方法 :连续 3wk对小鼠采用 7种不可预知的应激原建立CMS模型 ,设DHEA低、高两个药物治疗组 ,用自发活动和水迷宫法测定行为改变 ,用放射性配基法测定皮层、海马、下丘脑和小脑的M受体改变。结果 :CMS组小鼠自发运动明显减少 ,寻找平台潜伏期明显延长 ,DHEA补充后可有效改善上述行为变化 ;CMS组小鼠大脑皮层、海马的M受体特异性结合与正常对照组比较显著减少 (P <0 .0 5)。使用DHEA后 ,恢复至正常水平。结论 :CMS可使动物的自发运动减少 ,并使其空间学习记忆功能减退 ,该变化与脑内胆碱能受体活性低下有关。补充DHEA可有效缓解上述变化 ,以低剂量效果好     

Dopamine receptor binding in rat striatum: Ultradian rhythm and its modification by chronic imipramine

To investigate diurnal variations in dopamine receptor binding, the amount of specifically bound ³H-spiroperidol was measured at 4-h intervals over a 24-h period in the striatum of rats which had been housed under a controlled 12-h light-dark cycle (lights on 7 a.m.). A highly significant ultradian rhythm with peaks at 2 a.m. and 2 p.m. was found with an amplitude of about 75%. Chronic imipramine modified the rhythm such that the two peaks occurred 4 h later and amplitude as well as 24-h mean of binding decreased. Scatchard analysis at times of least and greatest binding indicated that the differences in binding were due not to changes in the affinity, but in the number of binding sites. These results are interpreted with regard to the mode of action of psychoactive drugs and to postulated changes of receptor sensitivity in neurological and psychiatric disorders.     

Hedonic sensitivity in adolescent and adult rats: Taste reactivity and voluntary sucrose consumption

Adolescents have been hypothesized to exhibit an age-related partial anhedonia that may lead them to seek out natural and drug rewards to compensate for this attenuated hedonic sensitivity. In the present series of experiments, taste reactivity (TR) and 2 bottle choice tests were used to assess hedonic reactions to sucrose.In Exp 1, total positive taste responses to 10% sucrose solution were significantly higher in adolescent than adult rats during the infusion period. In Exp 2, adolescent animals exhibited a concentration-effect shift that was consistent with a greater hedonic sensitivity compared to adults. Conversely, adolescents exhibited fewer negative responses to quinine. Using a shortened infusion period, adolescents in Exp 3 exhibited a trend for greater positive TR than adults in response to 10 and 34% sucrose. Consistent with the TR results of Exp 1-3, adolescents consumed significantly more sucrose solution (ml/kg) than adults, although no significant age difference in sucrose preference rates emerged.The results of the current series of experiments do not support the hypothesis that adolescents exhibit an age-related, partial anhedonia, with adolescent animals, under a number of test circumstances showing greater positive taste reactivity and reduced negative responding.     

Attenuated feed-back inhibition of brain serotonin synthesis following chronic administration of imipramine

Summary Acute administration of imipramine (IMI), 15 mg/kg i.p., significantly reduced the accumulation of 5-hydroxytryptophan (5-HTP) in various parts of the rat brain during 30 min following treatment with NSD 1015, 100 mg/kg i.p., and inhibitor ofl-aromatic amino acid decarboxylase. The simultaneously measured accumulation of 3,4-dihydroxyphenylalanine (Dopa) was increased in the dopamine (DA) dominated brain parts but, if anything, slightly reduced (10%) in the noradrenaline (NA) rich hemispheres. Twelve hours after cessation of a chronic IMI-regimen (10 mg/kg i.p., 12 h intervals, 14 days), the 5-HTP- and Dopa-accumulations in the various brain parts were not different from those in saline-treated controls. However, when IMI, 15 mg/kg i.p., was administered to the chronically IMI-treated rats, 12h after the last injection, no significant reduction in 5-HTP accumulation was obtained in any of the brain parts analyzed (limbic system, corpus striatum, hemispheres and brain stem). In the NA-rich brain parts, there was no reduction in the Dopa accumulation, whereas in the DA-dominated regions the same increase in Dopa accumulation was seen as when IMI, 15 mg/kg, was given to naive rats. In conclusion, the data show that the feed-back inhibition of central 5-hydroxytryptamine (5-HT) synthesis by IMI is attenuated by chronic IMI treatment.