应激诱发复吸行为的生物学机制研究进展

复吸是药物依赖的主要特征,也是治疗的首要问题.应激可以诱发复吸.应激诱发复吸的神经生物学机制不同于启动药物诱发复吸的机制.启动药物诱发复吸涉及中脑边缘多巴胺通路的激活;而应激诱发复吸主要涉及脑去甲肾上腺素和促肾上腺皮质激素释放因子,终纹床核是两者相互作用的关键部位.去甲肾上腺素外侧被盖核和终纹床核是应激诱发复吸的重要脑区.不同应激源可能通过相关机制诱发复吸.     

复吸诱发因素的作用机制

复吸问题是目前药瘾治疗过程中的最大难题 ,已知诱发复吸的三种最常见的因素分别为 :成瘾药物本身、药物相关情景和应激。本文即从这三方面着手 ,综述了各因素诱发复吸的理论假设、中枢作用机制和神经生物学基础。     

复吸诱发因素的作用机制

复吸问题是目前药瘾治疗过程中的最大难题，已知诱发复吸的三种最常见的因素分别为：成瘾药品物本身、药物相关情景和应激。本即从这三方面着手，综述了各因素诱发复吸的理论假设、中枢作用机制和神经生物学基础。     

缺血性脑损伤大鼠对应激反应性的实验研究

目的探讨缺血性脑损伤大鼠对轻度束缚应激的反应性。方法通过阻断大脑中动脉（MCAO）建立缺血性脑损伤大鼠模型，术后第5周开始行2周束缚应激，应激结束后处死大鼠，脑组织HE染色明确缺血灶，免疫组化法检测大鼠脑内Fos和促肾上腺皮质激素释放因子（CRF）蛋白表达水平。结果单纯MCAO组（M）和MCAO＋应激组（MR）大鼠可见明确缺血灶，损伤侧大脑半球萎缩和脑室扩大，光镜观察缺血区大量核固缩，坏死灶周边神经胶质细胞增生；MR组大鼠下丘脑室旁核、杏仁核中央亚核及终纹床核Fos和CRF阳性神经元明显多于其他组，差异有统计学意义（P〈0．05）。结论缺血性脑损伤后大鼠脑内Fos和CRF蛋白表达对应激的反应性增强，CRF通过前反馈机制持续激活下丘脑-垂体-肾上腺轴并导致抑郁可能是脑卒中后抑郁发生的主要机制之一。     

下丘脑室旁核神经元亚群在应激反应中的作用与机制

下丘脑室旁核由多种类型神经元构成,是启动并调节应激反应的关键核团之一。在应激源的作用下,下丘脑室旁核神经元释放多种激素至垂体门脉系统或神经垂体,启动应激反应,并在生殖稳态、电解质平衡以及血压调节中发挥关键作用。本文综述了下丘脑室旁核的不同神经元亚群在应激中的作用与研究进展,旨在为应激的机制研究和药物研发提供新的思路。     

神经类固醇在抑郁症病理机制中的研究进展

有关抑郁症的病因和病理机制,国内外学者进行了大量研究,主要涉及5一羟色胺(5-HT)能系统和去甲肾上腺素能系统.     

瑞波西汀治疗抑郁症的临床应用

瑞波西汀是临床上用于治疗抑郁症的药物,其主要作用机理是去甲肾上腺素再摄取抑制剂。根据瑞波西汀的作用机制以及抑郁症的发病机制,本文针对目前临床应用该药的技巧及注意事项予以总结。     

药物成瘾脑深部电刺激术研究进展

药物成瘾是严重的全球性医学和社会问题,其治疗分为脱毒和防止复吸两个阶段,后者是治疗成功的关键。以立体定向伏隔核毁损术为代表的外科手术方法,在戒断后预防复吸中显示出较好疗效,但因其具有破坏性,临床应用受到限制。随着脑深部电刺激术在运动障碍性疾病中的成功应用,该疗法预防戒断后复吸的动物实验和临床研究逐步深入。在药物成瘾相关神经核团中伏隔核仍是目前研究最多、预防复吸疗效最好的手术靶点。同时,以伏隔核为基础的多靶点联合刺激目前也在研究中。尽管目前治疗机制尚不明确,脑深部电刺激术可能成为难治性药物成瘾的尝试性治疗方法。刺激参数设置、获得客观治疗反馈、医学伦理学争议等尚待进一步大样本、长期的临床研究。     

《缰核——一些难治性疾病治疗的新靶标》出版发行

<正>由韩济生院士作序、王绍教授主编的《缰核——一些难治性疾病治疗的新靶标》一书已由科学出版社于2011年4月出版。缰核在中枢神经系统中处于调控多巴胺、5-羟色胺、去甲肾上腺素递质释放的关键地位。该书介绍了缰核的发生和结构特点,特别是缰核的左右不对称性及其发生机制;缰核神经元的痛觉属性与痛觉调制;对心血管功能的调节;与呼吸功能、生殖功能、睡眠、免疫功能的紧密关系;缰核与认知、奖赏、稳态调节的关系等研究的新近发展;更有临床实用意义的是,缰核与应激性高血压、     

《缰核——一些难治性疾病治疗的新靶标》出版发行

<正>由韩济生院士作序、王绍教授主编的《缰核——一些难治性疾病治疗的新靶标》一书已由科学出版社于2011年4月出版。缰核在中枢神经系统中处于调控多巴胺、5-羟色胺、去甲肾上腺素递质释放的关键地位。该书介绍了缰核的发生和结构特点,特别是缰核的左右不对称性及其发生机制;缰核神经元的痛觉属性与痛觉调制;对心血管功能的调节;与呼吸功能、生殖功能、睡眠、免疫功能的紧密关系;缰核与认知、奖赏、稳态调节的关系等研究的新近发展;更有临床实用意义的是,缰核与应激性高血压、     

Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking

Relapse is a major characteristic of drug addiction, and remains the primary problem in treating drug abuse. Without an understanding of the factors that determine renewed drug-seeking, the urge to use drugs, and the persistent craving for them, it is unlikely that health care professionals can provide effective treatment. Using an animal model of relapse, the author and her team are studying factors that induce reinstatement of drug-taking behaviour after short and long periods of abstinence, and they are exploring the neurobiological basis of these effects. In their experiments, rats are trained to self-administer drugs intravenously by pressing 1 of 2 levers. During a subsequent period, the drug is no longer available, but the rats are free to try to obtain the drug (a period of "extinction training"). After extinction of responding, the investigators test for the ability of various events to reinitiate drug-seeking. On this background of renewed drug-seeking or relapse, the investigators search for pharmacological and neurochemical manipulations that might block or attenuate such behaviour. They have found that the 2 most effective events for reinstating responding after both short and long drug-free periods are re-exposure to the drug itself and exposure to a brief period of stress. The critical neurochemical pathways mediating drug-induced relapse are not identical to those mediating stress-induced relapse. Relapse induced by "priming" injections of heroin or cocaine involves activation of the mesolimbic dopaminergic pathways, whereas relapse induced by stress involves actions of corticotropin-releasing factor (CRF) in the brain, and of brain noradrenergic (NE) systems. In addition, evidence shows that CRF and NE may interact at the level of the bed nucleus of the stria terminalis in stress-induced relapse. By contrast, relapse induced by "priming" injections of drugs is relatively unaffected by manipulation of CRF and NE systems of the brain.     

The role of the bed nucleus of the stria terminalis in stress-induced inhibition of pulsatile luteinising hormone secretion in the female rat

The bed nucleus of the stria terminalis (BNST) occupies a central position in the neural circuitry regulating the hypothalamic-pituitary-adrenocortical axis response to stress. The potential role of the BNST in stress-induced suppression of the gondotrophin-releasing hormone (GnRH) pulse generator, the central regulator of the reproductive system, was assessed by examining the effects of micro-infusion of corticotrophin-releasing factor (CRF) or its antagonist into the BNST on pulsatile luteinising hormone (LH) secretion or stress-induced inhibition of LH pulses, respectively. Ovariectomised oestrogen-treated rats were implanted chronically with bilateral cannulae in the dorsolateral BNST and i.v. catheters. CRF (25, 50 or 100 pmol in 200 nl of artificial cerebrospinal fluid) administered bilaterally into the BNST resulted in a dose-dependent decrease in LH pulse frequency, and induced Fos expression in glutamic acid decarboxylase immunostained neurones in the medial preoptic area. These results suggest that the activation of hypothalamic GABAergic neurones in response to intra-BNST administration of CRF may be involved in the suppression of LH pulses. Furthermore, administration of CRF antagonist (280 pmol astressin-B, three times at 20-min intervals) into the BNST effectively blocked the suppression of pulsatile LH secretion in response to restraint (1 h) but not hypoglycaemic (0.25 U insulin/kg, i.v.) stress. These data suggest that CRF innervation of the dorsolateral BNST plays a key, but differential, role in stress-induced suppression of the GnRH pulse generator.     

Involvement of CRF2 receptor in the brain regions in restraint-induced anorexia

We have reported that corticotropin-releasing factor (CRF) receptor subtypes, CRF1 and CRF2, are involved in stress-induced anorexia. To clarify in which brain regions the CRF receptor is involved in mediating stress-induced anorexia, we examined the effect of microinjecting CRF1-selective or CRF2-selective antagonist into the lateral septum or the bed nucleus of the stria terminalis (BNST), which are implicated in regulating stress response. The results demonstrated that injecting antisauvagine-30 into the lateral septum or the BNST significantly attenuated restraint-induced anorexia, whereas injecting antalarmin into these regions did not affect anorexia. These results suggest that the CRF2 receptor in the lateral septum and the BNST is involved in the stress-induced inhibitory mechanism of feeding behavior.     

A.E. Bennett Research Award. Anatomic basis for differential regulation of the rostrolateral peri-locus coeruleus region by limbic afferents.

BACKGROUND: Neurochemical and electrophysiological studies indicate that the locus coeruleus (LC)-norepinephrine system is activated by physiological and external stressors. This activation is mediated in part by corticotropin-releasing factor (CRF), the hypothalamic neurohormone that initiates the endocrine response to stress. We have previously shown that the central nucleus of the amygdala (CNA) provides CRF afferents to noradrenergic processes in the peri-LC area that may serve to integrate emotional and cognitive responses to stress. The bed nucleus of the stria terminalis (BNST) shares many anatomical and neurochemical characteristics with the CNA, including a high density of CRF-immunoreactive cells and fibers; however, recent studies have suggested that the CNA and the BNST may differentially regulate responses to conditioned and unconditioned fear, respectively, suggesting divergent neuroanatomical circuits underlying these processes. METHODS: In the present study, neuroanatomical substrates subserving regulation of the LC by the BNST were examined. Anterograde tract-tracing was combined with immunoelectron microscopy to test the hypotheses that BNST efferents target noradrenergic neurons of the LC and that these efferents exhibit immunolabeling for CRF. RESULTS: Ultrastructural analysis of sections that were dually labeled for the anterograde tracer biotinylated dextran amine (BDA) injected into the BNST and tyrosine hydroxylase (TH)-immunoreactivity demonstrated that BDA-labeled axon terminals formed synaptic specializations (primarily inhibitory) with TH-labeled dendrites and dendrites that lacked TH immunoreactivity. In contrast to CNA efferents that exhibited substantial immunolabeling for CRF, far fewer BDA-labeled terminals from the BNST in the rostrolateral peri-LC contained CRF. CONCLUSIONS: The present results indicate that the BNST may provide distinct neurochemical regulation of the peri-LC as compared to other limbic afferents such as the CNA. These data are interesting in light of behavioral studies showing that the CNA and BNST may be differentially involved in fear versus anxiety, respectively.     

Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: Implications for balancing stress and affect

Activation of corticotrophin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) is necessary for establishing the classic endocrine response to stress, while activation of forebrain CRF neurons mediates affective components of the stress response. Previous studies have reported that mRNA for CRF2 receptor (CRFR2) is expressed in the bed nucleus of the stria terminalis (BNST) as well as hypothalamic nuclei, but little is known about the localization and cellular distribution of CRFR2 in these regions. Using immunofluorescence with confocal microscopy, as well as electron microscopy, we demonstrate that in the BNST CRFR2-immunoreactive fibers represent moderate to strong labeling on axons terminals. Dual-immunofluorescence demonstrated that CRFR2-fibers co-localize oxytocin (OT), but not arginine-vasopressin (AVP), and make perisomatic contacts with CRF neurons. Dual-immunofluorescence and single cell RT-PCR demonstrate that in the hypothalamus, CRFR2 immunoreactivity and mRNA are found in OT, but not in CRF or AVP-neurons. Furthermore, CRF neurons of the PVN and BNST express mRNA for the oxytocin receptor, while the majority of OT/CRFR2 neurons in the hypothalamus do not. Finally, using adenoviral-based anterograde tracing of PVN neurons, we show that OT/CRFR2-immunoreactive fibers observed in the BNST originate in the PVN. Our results strongly suggest that CRFR2 located on oxytocinergic neurons and axon terminals might regulate the release of this neuropeptide and hence might be a crucial part of potential feedback loop between the hypothalamic oxytocin system and the forebrain CRF system that could significantly impact affective and social behaviors, in particular during times of stress.     

Evidence that the bed nucleus of the stria terminalis contributes to the modulation of hypophysiotropic corticotropin-releasing factor cell responses to systemic interleukin-1beta

Systemic infection activates the hypothalamic-pituitary-adrenal (HPA) axis, and brainstem catecholamine cells have been shown to contribute to this response. However, recent work also suggests an important role for the central amygdala (CeA). Because direct connections between the CeA and the hypothalamic apex of the HPA axis are minimal, the present study investigated whether the bed nucleus of the stria terminalis (BNST) might act as a relay between them. This was done by using an animal model of acute systemic infection involving intravascular delivery of the proinflammatory cytokine interleukin-1beta (IL-1beta, 1 microg/kg). Unilateral ibotenic acid lesions encompassing the ventral BNST significantly reduced both IL-1beta-induced increases in Fos immunoreactivity in corticotropin-releasing factor (CRF) cells of the hypothalamic paraventricular nucleus (PVN) and corresponding increases in adrenocorticotropic hormone (ACTH) secretion. Similar lesions had no effect on CRF cell responses to physical restraint, suggesting that the effects of BNST lesions were not due to a nonspecific effect on stress responses. In further studies, we examined the functional connections between PVN, BNST, and CeA by combining retrograde tracing with mapping of IL-1beta-induced increases in Fos in BNST and CeA cells. In the case of the BNST, these studies showed that systemic IL-1beta administration recruits ventral BNST cells that project directly to the PVN. In the case of the CeA, the results obtained were consistent with an arrangement whereby lateral CeA cells recruited by systemic IL-1beta could regulate the activity of medial CeA cells projecting directly to the BNST. In conclusion, the present findings are consistent with the hypothesis that the BNST acts as a relay between the CeA and PVN, thereby contributing to CeA modulation of hypophysiotropic CRF cell responses to systemic administration of IL-1beta.     

Modulation of glutamatergic synaptic transmission in the bed nucleus of the stria terminalis

Glutamate, catecholamine and neuropeptide signaling within the bed nucleus of the stria terminalis (BNST) have all been identified as key participants in anxiety-like behaviors and behaviors related to withdrawal from exposure to substances of abuse. The BNST is thought to serve as a key relay between limbic cognitive centers and reward, stress and anxiety nuclei. Human studies and animal models have demonstrated that stressors and drugs of abuse can result in long term behavioral modifications that can culminate in psychological diseases such as addiction and post-traumatic stress disorder. The ability of catecholamines and neuropeptides to influence synaptic glutamatergic transmission (stemming from cognitive centers) within the BNST may have profound consequences over these behaviors. In this review we highlight studies examining synaptic plasticity and modulation of excitatory transmission within the BNST, emphasizing how such modulation may result in alterations in anxiety and reward related behavior.     

Resting‐state functional connectivity of the bed nucleus of the stria terminalis in post‐traumatic stress disorder and its dissociative subtype

The bed nucleus of the stria terminals (BNST) is a subcortical structure involved in anticipatory and sustained reactivity to threat and is thus essential to the understanding of anxiety and stress responses. Although chronic stress and anxiety represent a hallmark of post‐traumatic stress disorder (PTSD), to date, few studies have examined the functional connectivity of the BNST in PTSD. Here, we used resting state functional Magnetic Resonance Imaging (fMRI) to investigate the functional connectivity of the BNST in PTSD (n = 70), its dissociative subtype (PTSD + DS) (n = 41), and healthy controls (n = 50). In comparison to controls, PTSD showed increased functional connectivity of the BNST with regions of the reward system (ventral and dorsal striatum), possibly underlying stress‐induced reward‐seeking behaviors in PTSD. By contrast, comparing PTSD + DS to controls, we observed increased functional connectivity of the BNST with the claustrum, a brain region implicated in consciousness and a primary site of kappa‐opioid receptors, which are critical to the dynorphin‐mediated dysphoric stress response. Moreover, PTSD + DS showed increased functional connectivity of the BNST with brain regions involved in attention and salience detection (anterior insula and caudate nucleus) as compared to PTSD and controls. Finally, BNST functional connectivity positively correlated with default‐mode network regions as a function of state identity dissociation, suggesting a role of BNST networks in the disruption of self‐relevant processing characterizing the dissociative subtype. These findings represent an important first step in elucidating the role of the BNST in aberrant functional networks underlying PTSD and its dissociative subtype.     

Intrinsic neuronal plasticity in the juxtacapsular nucleus of the bed nuclei of the stria terminalis (jcBNST)

The juxtacapsular nucleus of the anterior division of the BNST (jcBNST) receives robust glutamatergic projections from the basolateral nucleus of the amygdala (BLA), the postpiriform transition area, and the insular cortex as well as dopamine (DA) inputs from the midbrain. In turn the jcBNST sends GABAergic projections to the medial division of the central nucleus of the amygdala (CEAm) as well as other brain regions. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the juxtacapsular nucleus of BNST (jcBNST) in response to high-frequency stimulation (HFS) of the stria terminalis that was impaired during protracted withdrawal from alcohol, cocaine, and heroin and in rats chronically treated with corticotropin-releasing factor (CRF) intracerebroventricularly. Here we show that DAergic neurotransmission is required for the induction of LTP-IE of jcBNST neurons through dopamine (DA) D1 receptors. Thus, activation of the central CRF stress system and altered DAergic neurotransmission during protracted withdrawal from alcohol and drugs of abuse may contribute to the disruption of LTP-IE in the jcBNST. Impairment of this form of intrinsic neuronal plasticity in the jcBNST could result in inadequate neuronal integration and reduced inhibition of the CEA, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. These results provide a novel neurobiological target for vulnerability to alcohol and drug dependence.