Extinction-induced "despair" in the water maze, exploratory behavior and fear: effects of chronic antidepressant treatment

In former studies, we found evidence for the hypothesis that withdrawal of negative reinforcement presents a major source for stress and despair. Specifically, the removal of a hidden platform in the water maze induced extinction of previously reinforced escape behavior and behavioral immobility, indicative of "despair", which also correlated with indices of fear. Here, we tested the effects of antidepressants on extinction in the water maze, and expected that such drugs would attenuate the rate of extinction of a conditioned place preference (CPP) and also any emotionally relevant behavior that is induced by the loss of reinforcement, such as immobility. Adult male Wistar rats were trained to escape onto a hidden platform for 10 days. Daily treatment with desipramine hydrochloride (DMI, 10mg/kg) or fluoxetine (FLX, 10 mg/kg) commenced 1 day before the first of 11 extinction trials without the platform, administered 48 h apart, and continued thereafter, as the rats were tested in an open field and elevated-plus maze. As compared to controls, DMI increased the resistance-to-extinction of CPP, attenuated immobility, and increased wall climbing behavior. In the open field, DMI reduced activity levels, but was without effect on traditional fear parameters in the elevated-plus maze. FLX, by contrast, increased immobility during the extinction trials and fear in the elevated-plus maze. The withdrawal of reinforcement induced "despair" that was alleviated by the noradrenaline reuptake inhibitor DMI. The effects of the selective serotonin reuptake inhibitor FLX on immobility and fear may be explained in terms of its side effect profile.     

The prevalence of despair in intractable conflicts: Direct messages of hope and despair affect leftists,but not rightists

In contexts of long-term conflict, it often seems easier to spread despair than to instill hope. The prevalence of despair, an emotion that promotes apathy, in contexts that so desperately need hope, an emotion that promotes conciliation, calls for further investigation. One possibility is that messages of hope and despair have different effects on people based on their political ideology. In the present research we examined the effect of direct despair- and hope-inducing messages (compared to a control condition involving a neutral message) on participants' experience of hope for peace, their sense of urgency to resolve the conflict, and subsequently their support for concession-making as a function of political orientation. Two samples of Jewish-Israelis were collected. Study 1 was collected using snowball methods, while Study 2 replicated and enhanced findings with a more representative sample of Jewish-Israeli society collected using an online survey platform. In both studies, messages of hope or despair yielded no influence on Rightists, whose baseline of hope is inherently low. However, for Leftists (experiencing higher levels of hope for peace) the despair manipulation significantly decreased support for concession-making through decreased hope for peace and sense of urgency to resolve the conflict, providing an explanation to the prevalence of despair over hope in conflict.     

Differential sensitivity to the effects of nicotine and bupropion in adolescent and adult male OF1 mice during social interaction tests

Few studies have compared the action of both nicotine (NIC) and bupropion (BUP), an antidepressant used to treat NIC dependence, on social and aggressive behavior at different ages. This study aims to determine whether these drugs produce differential effects in adolescent (postnatal day: 36-37) and adult (postnatal day: 65-66) mice that have been housed individually for 2 weeks in order to induce aggressive behavior. Mice received BUP (40, 20, or 10 mg/kg), NIC (1, 0.5, and 0.25 mg/kg as base), or vehicle earlier to a social interaction test. BUP (40 mg/kg) decreased social investigation and increased nonsocial exploration in both adolescent and adult mice. The same effects were also observed in adult mice administered with a lower dose of the same drug (20 mg/kg). In adolescents, NIC (1 mg/kg) decreased social investigation, but this effect did not reach statistical significance in adults. In conclusion, a differential sensitivity to the effects of NIC or BUP emerged in some of the behavioral categories when the two age groups were compared.     

Effects of chronic variable stress and antidepressant drugs on behavioral inactivity during an uncontrollable stress: interaction between both treatments.

Rats submitted to a chronic variable stress regime exhibited more inactivity during inescapable shock as compared with unstressed rats. Besides, chronic treatments with desipramine, imipramine, clomipramine, or phenelzine reduce the amount of inactivity exhibited during this aversive experience. Furthermore, the combination of both chronic treatments--stress and antidepressants--resulted in a potentiation of the antidepressant effect alone. This higher antidepressant efficacy may result from the interaction of the neural mechanisms triggered by chronic stress exposure and antidepressant drugs.     

应激性抑郁样行为发生中海马5-羟色胺1A受体的作用及其对NMDA受体和AMPA受体的调节

为探讨慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)诱发抑郁样行为发生中海马5-羟色胺1A受体(5-hydroxytryptamine receptor 1A, 5-HT1AR)表达与作用, 及其对谷氨酸N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体和α-氨基羟甲基异恶唑丙酸(α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid, AMPA)受体的影响。通过建立CUMS动物模型, 给应激抑郁模型大鼠海马微量注射5-HT1A受体激动剂、给正常大鼠海马微量注射5-HT1A受体拮抗剂, 测量大鼠体重变化率, 并采用糖水偏爱测试、旷场实验和悬尾实验等方法对大鼠进行行为学检测, 运用Western blot和ELISA方法检测大鼠海马组织中5-HT1AR和NMDAR和AMPAR的关键亚基的表达以及磷酸化水平。结果显示, 与对照组相比, CUMS组大鼠表现出抑郁样行为, 海马5-HT1AR、AMPA受体的GluR2/3亚基表达及磷酸化明显降低, NMDA受体的NR1和NR2B亚基表达及磷酸化显著增加; 正常大鼠海马微量注射5-HT1A受体拮抗剂WAY100635, 动物行为学表现及AMPA受体、NMDA受体表达及磷酸化水平均与CUMS组相同; 注射5-HT1A受体激动剂8-OH-DPAT能逆转应激诱导的上述改变。以上结果表明, CUMS诱发抑郁样行为与海马5-HT1AR表达下降, AMPAR表达量及磷酸化水平降低, NMDAR表达量及磷酸化水平升高有关。5-HT通过5-HT1AR产生抗抑郁作用。5-HT1AR激动剂抗抑郁作用与降低NMDAR表达量及磷酸化水平, 提高AMPAR表达量及磷酸化水平密切相关。     

The impact of a subsequent pregnancy on grief and emotional adjustment following a perinatal loss

The present study examined the impact of a subsequent pregnancy on emotional adjustment associated with a previous perinatal loss and on the following components of parental grief—active grief, difficulty coping, despair. Participants included 25 women and 24 partners who were expecting a baby for the first time since their loss and 25 women and 18 partners who were not expecting and had not had a child or pregnancy after their loss. Depressive symptomatology, anxiety, marital adjustment, as well as active grief, despair, and difficulty coping were measured. Mothers who were not pregnant were experiencing significantly higher levels of despair and difficulty coping than pregnant mothers, independently from the effect of time elapsed since the loss. For the fathers, no significant group effect in emotional distress or intensity of grief was found. Women reported significantly higher levels of negative affectivity than men. A new pregnancy may be associated with a beneficial effect on the mourning process of women with a previous perinatal loss, primarily by decreasing their despair and difficulty coping. However, in our sample, grief intensity remained high, suggesting that the mourning process may not be hindered by a subsequent pregnancy.     

Extinction-induced immobility in the water maze and its neurochemical concomitants in aged and adult rats: a possible model for depression?

Extinction of escape behavior in the water maze due to the removal of the platform, was hypothesized to induce a negative state, including the development of immobility, which is held to reflect a state of "despair" when measured in the forced swimming test. 27 aged and 8 adult animals (26 and 3 months old Wistar rats, respectively) were tested in the water maze during nine days with a platform hidden, followed by 7 days of extinction trials with the platform absent. As expected, both age groups developed immobility over the extinction trials, with the aged showing more than the adults. To examine whether the age difference in immobility was related to performance differences during acquisition, the aged were subdivided into superior, intermediate and inferior learners (n = 9 per group) on the basis of overall times to platform during acquisition, and compared with each other and the adults. Results showed that the aged inferior learners displayed the highest levels of immobility among the aged. Immobility scores were then correlated with post-mortem neurotransmitter contents in the hippocampus and ventral striatum. In the ventral striatum, levels of immobility were correlated with levels of acetylcholine, dopamine and the metabolite dihydroxyphenylacetic acid in the aged, and with norepinephrine in the adults. The data support the hypothesis that multiple extinction trials in the water maze result in immobility that may indicate "behavioral despair," and that striatal neurotransmitter systems correlate with the degree of its expression. The concept of extinction-induced despair is held to provide the promise of a conceptual and empirical model of human depression that is the consequence of loss of reinforcers.     

Deaths of Despair: Conceptual and Clinical Implications

Since the late 1990s, mortality rates for middle-aged (45-55), White non-Hispanic (WNH) Americans began to rise while rates declined for all other demographic and age groups. Coinciding with the rise in mortality, rates of death due to suicide, drug- and alcohol-related overdoses, and alcohol-related liver diseases increased as well for this demographic. Research suggests these causes of death (i.e., suicide, poisoning, alcohol-related liver disease) are driving the overall mortality rate for middle-aged WNHs and have been described as “deaths of despair” in the literature. In the current paper, we describe the social and clinical features of “deaths of despair,” explore theoretical models of psychopathology (e.g., depression, posttraumatic stress disorder) that may inform our understanding of mechanisms of risk for negative mental health outcomes, and propose an initial conceptual model of “deaths of despair” to identify intervention targets. We then review an applied case example demonstrating how this model could be used for clinical application. We conclude our paper by describing how current cognitive-behavioral interventions may address these mechanisms of “despair.”     

Construct validity of the Kendrick Battery with institutionalized aged

In this study, we attempted to explore the construct validity of the Kendrick Battery by using an American sample and psychometric tests as indexes of diffuse organicity, depression, and normality. Institutionalized residents (N = 53) were tested twice (6-week interval). When organicity was defined by disorientation and memory deficits, then both the Object Learning test and the Digit Copying test were accurate in differentiating preestablished criterion groups. When organicity was defined more broadly, including sensorimotor function, the Digit Copying test alone was more accurate when depression was defined in terms of irritability, restlessness, and despair. These data suggest that although the Kendrick scales appeared to be sensitive to organicity and depression in this sample, their validity varied with the criteria for each when such were defined psychometrically.     

“Age is opportunity”: Women’s personality trajectories from mid- to later-life

Previous scholarship examining Erikson’s (1980) constructs of generativity versus stagnation, and ego integrity versus despair has primarily focused on generativity or ego integrity, with little examination of stagnation or despair. The current study uses four waves of longitudinal data from a total of 166 women, ages 43–72, to assess whether these characteristics are best measured via four separate or two bipolar dimensions, and to examine developmental trajectories in resulting scales. We hypothesized developmental trajectory increases for generativity and ego integrity, and declines for stagnation and despair. Results indicated that generativity and ego integrity showed linear increases with no significant decline; however, stagnation and despair showed curvilinear patterns. Findings highlight the importance of examining these constructs independently and longitudinally.     

Antidepressant treatment of children: clinical relapse is unrelated to tricyclic plasma concentrations

Plasma concentrations of imipramine and amitriptyline and their desmethylated metabolites were measured in 20 children being treated for major depressive illness 2 wk. and 5 to 10 wk. after achieving drug dosages of 2.25 mg/kg body weight. At 2 wk. all children had exhibited clinical improvement, but by 10 wk. 4 of the 10 children treated with imipramine and 5 of the 10 children treated with amitriptyline had experienced clinical relapse of depressive symptoms. Tricyclic antidepressant plasma concentrations and ratios were comparable in the subgroups of children who maintained their clinical improvement and those who relapsed. There was no evidence of a systematic decline in plasma tricyclic antidepressant concentrations in those children who relapsed.     

Does Exposure and Response Prevention Behaviorally Activate Patients With Obsessive-Compulsive Disorder? A Preliminary Test

Exposure and response prevention (ERP) and behavioral activation (BA) are effective treatments for obsessive-compulsive disorder (OCD) and depression, respectively. Patients with OCD often exhibit depression; furthermore, ERP for OCD is associated with reduced depressive symptoms. To our knowledge, no study has examined whether ERP itself functions to behaviorally activate patients with concurrent OCD and depressive symptoms. This prospective study was designed to test the hypotheses that (a) OCD exposure hierarchy completion, increased BA, and depressive symptom reduction would all be related, and (b) pre- to posttreatment changes in BA would mediate the direct effect of OCD hierarchy completion on posttreatment depressive symptoms, even after controlling for pretreatment depressive symptoms, pretreatment BA, pre- to posttreatment reductions in OCD symptoms, treatment duration, and antidepressant medication use. Patients (N = 90) with a primary diagnosis of OCD who received residential ERP for OCD completed a self-report battery at pre- and posttreatment. Exposure hierarchy completion, increases in BA, and decreases in depression were all significantly correlated (rs ranged .33 to .44). The effect of hierarchy completion on posttreatment depressive symptoms was fully mediated by pre- to posttreatment changes in BA. Findings highlight the potential for ERP to exert antidepressant effects by behaviorally activating patients. Limitations, clinical implications, and future directions are discussed.     

Substance P antagonists: meet the new drugs,same as the old drugs? Insights from transgenic animal models

Antidepressants that primarily target the reuptake of monoamines have been highly successful treatments. However, therapies with these drugs still have several drawbacks, namely severe side effects, delays in the onset of action, and a significant percentage of non-responders. Recently, non-peptidic antagonists of the neurokinin 1 receptor, or substance P antagonists, have emerged as a novel class of drugs with antidepressant efficacy that is comparable to current drugs, but a potentially reduced side effect profile. This review summarizes the pre-clinical evidence derived from pharmacological and transgenic animal studies that suggests an important role for the substance P/neurokinin 1 system in anxiety and depression. Also, potential mechanisms by which substance P antagonists may produce their therapeutic effects are discussed.     

Extinction-induced "despair" in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.     

Fluoxetine activity on muricidal aggression induced in rats by p-chlorophenylalanine

Fluoxetine is a selective inhibitor of serotonin uptake into serotonergic presynaptic terminals of rat brain. This compound was shown to develop a clinical antidepressant activity. Rat muricidal aggression, which is believed to involve a decrease of brain serotonergic inhibitory control, is also believed to represent a good experimental tool to study the efficacy of antidepressant drugs, which usually inhibit this behavior. In this framework, fluoxetine is also capable of significantly reducing muricidal aggression induced by p-chlorophenylalanine in male Wistar rats.     

休息对自我损耗的补偿作用

两个实验旨在检验自我损耗效应并探讨休息对自我损耗的补偿作用。在实验1中,损耗组被试通过观看注意控制视频诱发自我控制资源的损耗,然后完成Stroop任务。实验2与实验1的不同之处在于,诱发自我损耗后进行不同时间（5分钟、10分钟）的休息处理。两个实验结果发现：（1）注意控制视频成功诱发了自我损耗效应;（2）休息对自我损耗具有补偿作用;（3）在损耗状态下,休息5分钟即对自我控制资源具有补偿作用。研究结果证实了自我损耗的资源枯竭观。     

Conditioned activity and the interaction of amphetamine experience with morphine's activity effects

This experiment assessed the transfer effect of Pavlovian conditioning with d-amphetamine sulfate (1 mg/kg) on morphine's activity effects. Prior experience with amphetamine resulted in higher levels of activity when challenged with morphine (10 and 20 mg/kg). This interactive effect of amphetamine, however, was present only in those animals who had experienced amphetamine paired with the activity test situation. Animals who had received equivalent doses of amphetamine unpaired with the testing environment did not differ from drug-naive control animals. Analysis of predrug activity levels revealed a conditioned activity response in paired animals compared to the controls. These findings suggest that the response interaction between drug conditioned responses and drug unconditioned responses is an important determinant of cross-drug effects between drugs of different pharmacological classes.