Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies

In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals.The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis.We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT_1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.     

帕罗西汀和西酞普兰对急性应激障碍和创伤后应激障碍的不同预防作用

利用急性强迫游泳(FST)以及单次延长的应激(single-prolonged stress,SPS)模型分别模拟急性应激障碍(ASD)和创伤后应激障碍(PTSD),利用FST中不动时间作为应激障碍指标,评价两种5-HT再摄取抑制剂(SSRIs)帕罗西汀或西酞普兰对ASD和PTSD可能的预防作用。大鼠经过或不经过SPS处理(包括2h束缚,20min FST,休息15min后乙醚麻醉至意识丧失)后,每天通过饮用水给予不同剂量的帕罗西汀(20或40mg/kg)、西酞普兰(20或30mg/kg)或者正常进食水,连续14d后进行20minFST,计算该期限内每5min的不动时间,进行统计学分析,观察帕罗西汀和西酞普兰对动物行为的影响。SPS14d后大鼠的不动时间显著延长(0~5min:P<0.05,vs正常大鼠;5~10min:P<0.01,vs正常大鼠)。连续给予14d20mg/kg帕罗西汀显著缩短动物的不动时间(0~5、5~10和10~15min:P<0.05,vsSPS大鼠)。40mg/kg帕罗西汀以及20/30mg/kg西酞普兰显著缩短0~5min内的不动时间(P<0.05,vsSPS大鼠),但对其余时间点的不动时间没有影响(P>0.05,vsSPS大鼠),相反,40mg/kg帕罗西汀预处理还导致动物在15~20min内的不动时间显著延长。正常大鼠经过14d帕罗西汀或西酞普兰预处理后,0~5和5~10min的不动时间与饮用水对照相比没有显著差异。我们的实验结果提示较低临床剂量帕罗西汀和西酞普兰都可以用于预防ASD,较低剂量帕罗西汀预防PTSD的效果明显好于西酞普兰,同时我们的实验结果还提示对于ASD或PTSD的预防来说,增大抗抑郁药物的剂量,并不一定能取得期望的增加的疗效。     

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity,stress, anxiety,mood, and drug dependence

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.     

Genotype- and experience-dependent susceptibility to depressive-like responses in the forced-swimming test

Abstract Rationale. The forced-swimming test (FST) is utilized to reproduce passive coping responses to stress that may model a relevant aspect of human depression in rodent species. Animals showing high levels of passive responses to the FST are assumed to model pathologically depressed individuals. Objectives. We evaluated sensitivity of FST-induced behavioral responses to the interaction between genetic and environmental influences. Methods. Behavioral responses to FST were evaluated in naive mice of the C57BL/6 and DBA/2 strains, in mice of both strains pre-exposed to FST 14 days before test, and in FST-experienced animals subsequently exposed to 12 days of stress experience (food restriction). Results. C57BL/6 mice are characterized by high propensity to adopt passive coping responses in the FST. Moreover, stress enhances FST-induced immobility in mice of the C57BL/6 strain but reduces this response in DBA/2 mice. Finally, FST-induced immobility in C57BL/6 mice is reduced by chronic treatment with clinically effective antidepressants. Conclusions. These results support the view that behavioral and neural responses to FST exhibited by C57BL/6 mice can be usefully exploited by pre-clinical research on depression. Electronic Publication     

生长发育期光照改变对成年大鼠抑郁相关行为的影响

目的:新近的研究发现光照时间延长会减少大鼠的自主运动,而运动具有全面抗抑郁的特点,因此我们想探讨光照时间的改变对大鼠抑郁相关行为的影响。方法:将50只5 w龄SD雄性大鼠随机分为5组,给予8 w延长、正常和缩短每日光照时间的处理,然后予以正常光照1 w。在光照恢复前和恢复后,用强迫游泳实验和Y-迷宫实验分别测试大鼠的抑郁相关行为和学习记忆能力。结果:延长光照时间使大鼠运动(攀爬+游泳)时间缩短,不动时间延长,学习和记忆的总次数、错误次数以及所花的总时间均显著增多;反之亦然。而且,此改变在恢复正常光照1 w后虽有所恢复,但均未回复到正常水平。结论:光照时间的改变可以影响大鼠在强迫游泳实验和Y-迷宫实验中的心理抑郁程度和学习记忆能力,且不会因短期的正常光照而消除。     

Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression

Ginseng total saponins (GTS) are the major active components of Panax ginseng C.A. Meyer, which has been used as a popular tonic herb for 2000 years in Far East countries. In the present study, two classic animal models: the forced swimming test (FST) and the chronic mild stress (CMS) model were used to evaluate the antidepressant-like activities of GTS. It was observed that GTS at doses of 50 and 100 mg/kg significantly reduced the immobility time in the FST in mice after 7-day treatment. GTS also reversed the reduction in the sucrose preference index, decrease in locomotor activity as well as prolongation of latency of feeding in the novelty environment displayed by CMS rats. In addition, HPLC-ECD and immunohistochemical staining analysis indicated that the CMS-induced decrease in monoamine neurotransmitter concentration and brain-derived neurotrophic factor (BDNF) expression in the hippocampus were almost completely reversed by GTS. In conclusion, GTS exerts antidepressant-like effects in two highly specific and predictive animal models of depression. The activity of GTS in antidepression may be mediated partly through enhancing the monoamine neurotransmitter concentration and BDNF expression in the hippocampus.     

Antidepressant-like effect of magnetic resonance imaging-based stimulation in mice

INTRODUCTION: It has been reported that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) may show antidepressant effects. We examined whether the two routine diagnostic protocols of MRI [T1 and echo planar diffusion weighted imaging (EPI-DWI)], have antidepressant-like effects in an animal model of depression. METHODS: The effects of standard EPI-DWI and T1 MRI on immobility, swimming and climbing times in the modified forced swimming test (FST) in mice were examined. After exposure to the first session of modified forced swimming test, we randomly divided the mice into four groups. The first group (T1 MRI group, n=21) received a 15-minute stimulation of T1 sequence. The second group (EPI-DWI MRI group, n=21) received a 15-minute stimulation of EPI-DWI protocol. The third group (sham group, n=21) spent 15 min in a tunnel similar to the MRI gantry in terms of size, temperature and light intensity and received recorded sounds from a normal session of EPI-DWI with similar duration and intensity. The fourth group acted as controls (n=21).The second session of the modified FST was conducted twelve hours later. The mean of immobility, swimming and climbing times in this session were compared to the control group. RESULTS: T1 weighted and EPI-DWI MRI groups showed a reduction in immobility time compared to the control group (P value<0.002, P value<0.017 respectively). This effect is comparable to that seen in the FST after the administration of antidepressant agents. The climbing time in the group subjected to EPI-DWI MRI was longer than the control group (P value<0.035). Previous studies showed similar effects after the administration of antidepressant drugs affecting the catecholamine systems. The swimming time in the T1 MRI group was significantly longer than the control group (P value<0.037). Previous studies showed qualitatively similar effect to that of anti-depressant drugs affecting the serotoninergic systems. The swimming, climbing and immobility times in the sham and control groups showed no significant difference. CONCLUSIONS: Our findings raise the possibility that MRI-based stimulation may have antidepressant-like effects in mice. This is likely to be through different mechanisms in T1 weighted and EPI-DWI protocols. However the possible biological basis of this effect is not yet understood and we would advocate further studies of MRI-based stimulation effects on transmitters in the different organs in the body specially the brain.     

Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D2/D3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D2/D3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain using high-performance-liquid chromatography (HPLC) with electrochemical detectors (ECD). In the mouse forced swim test (FST) or tail-suspension test (TST), ropinirole (1-10 mg/kg, i.p.) produced S-shaped dose-response curve in the percentage decrease in immobility period. Compared with vehicle, ropinirole (10 mg/kg., i.p.) had a significant anti-immobility effect without affecting locomotor activity. The reduction in the immobility period elicited by ropinirole (10 mg/kg, i.p.) in the FST was reversed by dopaminergic and sigma receptor antagonist, haloperidol (0.5 mg/kg, i.p.), and specific D2 dopamine receptor antagonist sulpiride (5 mg/kg i.p.), but not by SCH 23390 (0.5 mg/kg i.p), a D1 dopamine receptor antagonist. Rimcazole (5 mg/kg i.p.) (a sigma receptor antagonist), progesterone (10 mg/kg i.p.) (a sigma receptor antagonistic neurosteroid), BD 1047 (1 mg/kg i.p.) (a novel sigma receptor antagonist with preferential affinity for sigma-1 sites) also reversed the anti-immobility effect of ropinirole (10 mg/kg i.p.). The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels. The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.     

Hybridizing behavioral models: A possible solution to some problems in neurophenotyping research?

The use of batteries of single-domain tests for neurophenotyping research is a common strategy to achieve higher data density and explore different behavioral domains. This approach, however, is accompanied by several methodological challenges, briefly discussed here. As an alternative, this paper advocates the wider use of extensive "hybrid" protocols that assess multiple domains in parallel, or logically/logistically combine experimental paradigms, in a way that disproportionately maximizes the number of tested phenotypes per experimental manipulation. Several examples of this approach are given in this paper, demonstrating the potential to reduce time, cost and subject requirements for the experiments. Offering behavioral analyses that are lacking in the standard single-domain tests, such "hybrid" models enable innovative modeling of neuropsychiatric disorders by more thorough and broader investigation of complex phenotypical characteristics.