Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment

Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core symptom of depression, was assessed by measuring consumption of a palatable solution. Exposure to CUS reduced intake of a palatable solution and this effect was prevented by chronic antidepressant treatment. Moreover, chronic antidepressant treatment decreased depressive-like behavior in a modified forced swim test in stressed rats. Present evidence suggests a role for brain-derived neurotrophic factor (BDNF) in depression. BDNF mRNA levels in the ventral and dorsal hippocampus were assessed by in situ hybridization. Exposure to CUS was not correlated with a decrease but rather with an increase in BDNF mRNA expression in both the dentate gyrus of the dorsal hippocampus and the CA3 region of the ventral hippocampus indicating that there is no simple link between depression-like behaviors per se and brain BDNF levels in rats. However, a significant increase in BDNF mRNA levels in the dentate gyrus of the dorsal hippocampus correlated with chronic antidepressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity.     

Functional neural substrates of self-reported physical anhedonia in non-clinical individuals and in patients with schizophrenia

Background

Anhedonia is a negative symptom of schizophrenia that has a detrimental impact on functioning and quality of life. Anhedonia also represents a vulnerability marker for schizophrenia when measured in non-clinical individuals. The investigation of the neural correlates of anhedonia in schizophrenia and non-clinical individuals could provide key insights on the pathophysiology of negative symptoms, as well as on the characterization of neural markers of vulnerability.

Methods

Thirty patients with schizophrenia and twenty-six non-clinical individuals were recruited. We used an event-related functional Magnetic Resonance Imaging paradigm involving an emotional picture viewing task. For each group, separately, we correlated the regional BOLD signal changes during hedonic processing with the Chapman Physical Anhedonia Scale scores. An interaction analysis identified the neural correlates of anhedonia specific to schizophrenia.

Results

We found that anhedonia severity in both groups was inversely correlated with the activity of a limited number of emotion-related regions, including the medial prefrontal cortex. The orbitofrontal cortex and putamen/ventral striatum activity was negatively correlated with anhedonia severity in people with schizophrenia only.

Conclusions

The data first suggest that anhedonia severity is linked to a poor modulation of emotional/attentional brain regions during the processing of hedonic information. The link between anhedonia and the activity of the ventral striatum and orbitofrontal cortex found in schizophrenia could reflect the specific impairment of indirect factors, such as reward anticipation deficits, that influence the measurement of anhedonia severity through self-report questionnaires.     

中文版修订社会快感缺失量表的信效度

目的 分析中文版修订社会快感缺失量表（RSAS-C）的信度和效度.方法 采用RSAS-C对314名正常健康者和204名精神分裂症患者进行评估,随机抽取75名正常者和102名患者间隔两周后进行重测,评估重测信度,以多伦多述情障碍量表（TAS-20）总分和阳性与阴性症状量表（PANSS）的阴性症状分为效标,计算效标关联效度.结果 信度检验：总样本、患者组和正常组RSAS-C的Cronbach α系数分别为0.787、0.804和0.759;分半信度分别为0.715、0.740和0.676;重测信度分别为0.902、0.916和0.831.效度检验：总样本、患者组和正常组RSAS-C得分与TAS-20总分间的相关系数分别为0.261、0.398和0.154,患者组RSAS-C得分与PANSS阴性症状分的相关系数为0.303,差异有统计学意义（均P＜0.01）.精神分裂症患者RSAS-C得分显著高于正常健康者,表明RSAS-C具有较好的实证效度.结论 RSAS-C有较好的信度和效度,可用于中国正常人群和精神分裂症患者人群快感缺失状况的评估.     

精神分裂症患者快感缺失与共情缺陷的相关性

目的 比较精神分裂症患者与正常人的快感缺失程度,探讨快感缺失与共情缺陷的关系.方法 采用中文版修订社会快感缺失量表（RSAS-C）、中文版修订躯体快感缺失量表（RPAS-C）和中文版人际反应指针量表（IRI-C）对200名精神分裂症患者和275名正常人进行评估,分析患者快感缺失与共情能力间的关系.结果 患者组RSAS-C得分[（13.21±6.06）分]和RPAS-C得分[（18.98±8.57）分]显著高于对照组[分别为（10.51±5.20）分和（16.82±7.96）分],差异具有统计学意义（P＜0.05）;患者共情总分、观点采择因子分、想象力因子分和共情性关心因子分显著低于对照组（均P＜0.05）;患者RSAS-C得分（r=-0.170,P＜0.05）和RPAS-C得分（r=-0.275,P＜0.01）与共情总分呈负相关,控制PANSS总分后,快感缺失得分与共情得分间的相关性仍具有统计学意义.结论 精神分裂症患者较正常人存在快感缺失和共情能力缺陷,患者的快感缺失与共情障碍间存在相关,提示两种情绪加工缺陷可能具有共同的病理生理基础.     

Inflammation and the dimensions of depression: A review

Patients with depressive disorders show a wide range of clinical manifestations including cognitive and neurovegetative symptoms. Importantly, these symptoms can differ in terms of biological etiology, and deconstructing depression into specific symptoms may provide valuable insight into the underlying neurobiology. Little research has examined inflammation in the context of depressive dimensions. Here we conduct a narrative review of the existing literature (21 studies) to elucidate whether the depression-inflammation link is symptom specific. Overall, there is evidence that an association exists between neurovegetative symptoms of depression and inflammation, independent of cognitive symptoms. The same cannot be said of cognitive symptoms and inflammation. There is also some evidence of gender differences in the directionality of the relationship between depression and inflammation. Potential explanations for these findings, limitations of the existing literature and recommendations for future research design are discussed.     

Haloperidol and nonreinforcement produce different patterns of response slowing in a food reinforced runway task

Rats were trained to traverse a runway for food reward and speeds were measured in the start, run and goal segments of the alley. After eight days of acquisition training, subjects were tested for four days under conditions of either extinction or haloperidol pretreatment. Although both haloperidol and extinction produced a suppression of the running response, the pattern of this suppression in the three alley segments was quite different for the two conditions. Haloperidol tended to be more effective than extinction in slowing start speeds but less effective than extinction in reducing run and goal speeds. This differential effect of haloperidol and extinction on speeds in different alley segments provides further evidence that haloperidol-induced impairments in performance cannot result entirely from a blunting of primary reinforcement.     

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.     

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is `no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the `taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for `wanting' incentives, but not for `liking' them or for learning new `likes' and `dislikes'.