Baroreflex mechanisms in major depression

BACKGROUND: Recent studies have shown that depressive disorder is associated with impaired baroreceptor or baroreflex sensitivity, which is proposed to be a predisposing factor for sudden death in patients with manifest cardiac disease. These studies have not evaluated the afferent and efferent components of the cardiac baroreflex loop or other baroreflex mechanisms that regulate target processes (cardiac metabolism and blood pressure variability) related to the impairment. The objective of this study was to gain more insight into autonomic functioning in depressive disorder to more fully examine the potential basis for increased cardiac mortality. METHODS: The subjects were 28 women and men with unipolar major depression who were taking antidepressant medications and who were in partial remission and free of cardiovascular or other serious disease, and 28 healthy control subjects matched for sex, age, and ethnicity. The two samples were compared for negative affective dispositions (anger expression, hostility, defensiveness, anxiety), spontaneous (closed-loop) baroreflex activity, heart rate, heart rate variability, systolic blood pressure, and heart rate-systolic blood pressure double product under resting conditions. RESULTS: Depressed patients showed a general disposition to anger suppression coupled with higher hostility and anxiety, and lower defensiveness. The patients showed higher general sympathetic activity (high levels of blood pressure, low-frequency heart rate variability) and lower parasympathetic-related activity (high heart rate and reduced high frequency heart rate variability) with affected cardiac metabolism estimated by the double product. Depressed patients had lower baroreflex sensitivity related to a higher gain of the afferent component of the baroreflex without respective gain adjustment of its efferent component (reflex gain 'de-afferentation'). It was coupled with a compensatory higher number of effective baroreflex reactions (reflex gating 're-afferentation'). Antidepressant agents and depressed mood had additional independent effects on baroreflex sensitivity through the efferent component of the cardiac baroreflex loop. CONCLUSIONS: The data indicate that different baroreflex components and mechanisms may be impaired in patients with depression and may contribute to their increased cardiac risk.     

Norepinephrine elicits both excitatory and responses from Purkinje cells in the in vitro rat cerebellar slice

Superfusion of Purkinje neurons in the in vitro rat cerebellar slice with norepinephrine caused increases and decreases of spontaneous Purkinje cell firing. Excitations were evoked by low concentrations of norepinephrine (0.5–10 μM) and by the β receptor agonist isoproterenol (0.1–5 μM). These excitations were reduced by timolol (1–2 μM), a β receptor antagonist. Perfusion with higher concentrations of norepinephrine (> 16 μM), caused a depression of Purkinje neuron spontaneous activity. This inhibitory response was blocked by the α receptor antagonist phentolamine. The α₁ selective agonist phenylephrine had no effect on spontaneous activity at concentrations up to 100 μM, but the α₂ selective agonist clonidine (1–50 μM) elicited decreases in firing rate. These responses appeared to be due to a direct action on Purkinje cells, because neither the excitation nor the depression of Purkinje neuron activity elicited by norepinephrine was substantially altered when tested in a medium which substantially blocked synaptic transmission within the slice. Under these in vitro conditions, norepinephrine appears to increase the firing rate of Purkinje neurons via an interaction with β adrenergic receptors, while norepinephrine induced depressions may be linked to α adrenergic receptor interactions; both receptors appear to be located directly on the Purkinje neurons.     

Cortical serotonin and norepinephrine denervation in parkinsonism: preferential loss of the beaded serotonin innervation

Parkinson's Disease (PD) is marked by prominent motor symptoms that reflect striatal dopamine insufficiency. However, non-motor symptoms, including depression, are common in PD. It has been suggested that these changes reflect pathological involvement of non-dopaminergic systems. We examined regional changes in serotonin (5-HT) and norepinephrine (NE) systems in mice treated with two different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment paradigms, at survival times of 3 or 16 weeks after the last MPTP injection. MPTP caused a decrease in striatal dopamine concentration, the magnitude of which depended on the treatment regimen and survival interval after MPTP treatment. There was significant involvement of other subcortical areas receiving a dopamine innervation, but no consistent changes in 5-HT or NE levels in subcortical sites. In contrast, we observed an enduring decrease in 5-HT and NE concentrations in both the somatosensory cortex and medial prefrontal cortex (PFC). Immunohistochemical studies also revealed a decrease in the density of PFC NE and 5-HT axons. The decrease in the cortical serotonergic innervation preferentially involved the thick beaded but not smooth fine 5-HT axons. Similar changes in the 5-HT innervation of post-mortem samples of the PFC from idiopathic PD cases were seen. Our findings point to a major loss of the 5-HT and NE innervations of the cortex in MPTP-induced parkinsonism, and suggest that loss of the beaded cortical 5-HT innervation is associated with a predisposition to the development of depression in PD.     

天舒胶囊对电刺激硬脑膜诱导偏头痛模型大鼠神经递质的影响

目的 研究天舒胶囊对电刺激大鼠上矢状窦区硬脑膜诱导偏头痛模型的影响,并探讨其作用机制。方法 雄性SD大鼠,脑部电极植入术后,ig给予天舒胶囊(1.08、0.36、0.18 g/kg),阳性药对照组ig琥珀酸舒马普坦片(9.72 mg/kg),除对照及假手术组外,行电压10 V、频率3 Hz、脉宽0.25 ms、时间1 h电刺激,对照组不予手术,并于刺激0、30、60 min进行眼眶采血,采血后取脑组织。采用放射免疫法检测血浆和脑组织中降钙素基因相关肽(CGRP)、P物质和去甲肾上腺素(NE)水平。结果 假手术组与对照组比较大鼠脑组织中CGRP、P物质和NE水平均无显著性差异;与假手术组相比,模型组大鼠脑组织中CGRP明显升高、P物质和NE水平明显降低(P<0.05),提示模型成功。与模型组相比,天舒胶囊可以显著提高大鼠血浆和脑中NE水平(P<0.05),降低CGRP水平(P<0.05),阳性药舒马普坦可以明显降低血浆中CGRP水平(P<0.05)。结论 天舒胶囊对电刺激上矢状窦区硬脑膜大鼠脑部损伤具有显著改善作用,其作用机制之一为调节神经递质释放。     

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.     

Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions

Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user’s genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT_2A or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.     

一测多评法同时测定附子中5种水溶性成分的含量

目的:建立一测多评的方法测定附子中5种水溶性成分含量的方法。方法:以盐酸多巴胺为参照物,采用Diamonsil C18色谱柱(4.6 mm×250 mm,5μm),流动相甲醇-0.2%磷酸水,梯度洗脱,柱温30℃,流速1.0 m L·min~(-1),检测波长260,280 nm,对附子中5种水溶性成分进行含量测定并计算其相对校正因子,采用外标法与一测多评法分别测定10批附子药材中的含量,以验证一测多评法在附子水溶性成分含量测定中的准确性与可行性。结果:建立用于测定附子中5种水溶性成分含量的一测多评方法,并对10批附子药材进行测定,其计算值与测定值的差异较小(RSD5%)。结论:一测多评法用于测定附子中5种水溶性成分的含量方法简单、有效,结果准确无误,可为后续的一测多评法的研究提供参考价值。     

加强扬刺百会穴对抑郁症患者体内单胺类神经递质代谢影响的研究

目的 探讨加强扬刺百会穴治疗抑郁症患者的疗效,及其对患者体内单胺类神经递质代谢影响的作用机制.方法 选取符合纳入标准的抑郁症患者40例,其汉密尔顿焦虑量表（HAMI）评分均大于20分,采用加强扬刺法针刺百会穴治疗.于治疗前后分别检测患者血浆中单胺类递质5-羟色胺（5-HT）及去甲肾上腺素（NE）的含量变化,并与40名健康志愿者进行对比.结果 治疗前后40名抑郁症患者体内5-HT及NE的含量均有统计学意义（P＜0.05）.治疗前二者的含量显著低于健康志愿者（P＜0.05）;治疗后与健康志愿者无统计学意义（P＞0.05）.结论 加强扬刺百会穴可缓解抑郁症患者的各种症状,调节患者血浆中单胺类神经递质的代谢水平.     

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent,Norepinephrine-Independent Processes

The alpha2 adrenergic receptor (α₂-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α₂-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX₁R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR₁) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX₁R–dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX₁R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.     

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of α₁-, β₁-, and β₂-adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.