食欲素信号系统在成瘾中的作用

成瘾是对成瘾物质的强迫性、持续性需求并缺乏控制能力的行为,它会导致大脑中枢奖赏回路的改变。下丘脑是调控自然奖赏的重要脑区,它能特异性地表达一种被称为食欲素(orexins/hypocretins)的神经肽。食欲素通过作用于食欲素受体调控睡眠、觉醒状态,同时,食欲素受体在药物成瘾和奖赏相关的行为中也有重要作用,投射到不同脑区的食欲素对不同药物导致的成瘾调节作用也不同,调控食欲素信号系统,将可能成为治疗成瘾的重要方法。本文重点总结了食欲素信号系统在不同药物成瘾过程中的作用的最新研究进展。     

下丘脑黑皮质素及中脑多巴胺系统对奖赏行为的调控

动机行为受生理需求相关神经环路的调控,包括管理摄食、能量代谢等内在动机行为的下丘脑黑皮质素(melanocortin, MC)系统和负责奖赏环路的中脑多巴胺(dopamine, DA)系统. MC系统中前阿黑皮素原(proopiomelanocortin,POMC)神经元与刺豚鼠相关蛋白(agouti-related protein,AgRP)神经元合成与分泌的递质及神经肽协同完成了对摄食等动机行为的调控,且DA系统通过调节奖赏环路参与摄食等动机行为的发生过程.此外,高强度的激活DA系统是成瘾性药物的共同特征,当DA系统激活与用药行为反复关联后,部分使用者进入药物成瘾状态,他们表现出强迫性的觅药动机.已有研究提示,药物成瘾的过程可能是药物导致动机行为调控中枢发生适应性改变的过程,这个变化反之促发了强迫性觅药行为的形成.本文将从下丘脑黑皮质素系统两种主要的神经元——POMC神经元和AgRP神经元——在对于摄食和用药相关的奖赏行为调控作用入手,分析它们与DA系统的相互作用模式,论述下丘脑黑皮质素系统的功能失调与药物成瘾的关系.     

食欲素神经肽在应激过程中的作用

食欲素因其在调节能量代谢、睡眠和唤醒等生理功能中的作用而备受关注.近年来研究逐渐发现,食欲素参与应激和奖赏过程的调节,特别是其在药物成瘾过程中的作用是目前的研究热点.主要介绍食欲素系统与应激相关系统之间的神经联系,阐述了其在应激相关的生理、神经内分泌与行为反应中的作用.并进一步介绍了食欲素系统在应激诱发药物成瘾复吸过程中的作用.食欲素对应激反应的调控作用具有相对特异性,受应激的种类、其他应激相关神经递质系统及食欲素神经元的投射通路等多种因素影响.     

食欲素系统与物质成瘾

成瘾是物质使用障碍的严重形式,是一种以奖励、动机、记忆等功能紊乱为特征的慢性脑部疾病,给个人和社会造成严重后果.食欲素是下丘脑食欲素能神经元分泌的一类神经肽,不仅参与多种神经系统的正常生理功能,也与多种神经系统疾病的发生有着密切关系.其中,食欲素在物质成瘾中的作用研究正逐步得到重视,现已证实食欲素在多种物质成瘾中发挥着...     

Orexin神经元调节应激反应的研究进展

orexin是下丘脑的一种重要神经肽,在摄食、睡眠和药物成瘾等生理心理过程中起着重要作用.近年来发现下丘脑Orexin能神经纤维密集地投向参与应激调控的脑区;orexin基因敲除的老鼠表现为防御反应迟钝;另外,侧脑室微量注射orexin可导致血浆中ACTH水平的上升并诱导出应激样呼吸-心血管反应和行为反应;因此,下丘脑及中枢orexin系统对应激的调控可能起关键作用.其可能机制为强烈刺激能活化下丘脑orexin神经元,诱导中枢神经系统orexin的释放,从而激活CRF通路及蓝斑-交感-肾上腺髓质系统,提高血浆皮质酮与去甲肾上腺素的水平,诱导应激反应,维持机体的稳定.     

食欲素系统的生物学功能研究进展

食欲素是由下丘脑外侧区中特定的神经元分泌产生的一种神经多肽类物质,通过激活广泛分布于中枢神经系统的食欲素受体1与食欲素受体2来发挥生理功能。相关研究证实,食欲素系统参与调节摄食和睡眠-觉醒周期,并与学习认知和其他机体生理功能密切相关,对癌细胞的调控可表现出促增殖与促凋亡的双重作用。本文根据近年的研究成果,综述了食欲素及其受体的功能研究进展。     

脂肪酸受体4在食欲调控中的研究进展

食欲调控与人类健康密切相关。脂肪酸受体4(free fatty acid receptor 4,FFA4)具有重要的食欲调控功能,有望成为食欲调控药物的新靶点。中枢激活FFA4能够抑制神经肽Y(neuropeptide Y,NPY)神经元,缓解下丘脑炎症,提高中枢瘦素(leptin)和胰岛素(insulin)等抑食欲因子敏感性,从而发挥抑食欲作用。大量研究表明,FFA4在外周抑制食欲。一方面,FFA4与G_(i/o)蛋白偶联能够抑制腺苷酸环化酶途径,并抑制促食欲因子胃饥饿素(ghrelin)的表达,抑制食欲;另一方面,FFA4与G_(q11)蛋白激活下游的磷脂酰肌醇途径和PI3K/Akt途径,增加抑制食欲因子胰高血糖素样肽1(glucagon-like peptide 1,GLP-1)、胆囊收缩素(cholecystokinin,CCK)的分泌,抑制食欲。就FFA4对食欲调控作一综述,为以FFA4作为靶标开发食欲调控药物提供基础资料。     

前边缘皮质生长激素抑制素神经元在吗啡引起的行为学改变中的作用

药物成瘾是一种由药物滥用所引起的慢性、复发性的精神疾病,主要特征是不计后果的强迫性用药。药物成瘾涉及多个脑区的神经可塑性改变。前边缘皮质(prelimbic cortex, PrL)是背内侧前额叶皮质的主要区域,有大量的锥体神经元,其兴奋性神经投射可以促进可卡因觅药行为。PrL还存在少量GABA能中间神经元,对PrL的兴奋性神经元功能、信息整合和传递起到重要的调控作用,而这一部分神经元在药物成瘾过程中的作用并不清楚。小清蛋白(parvalbumin, PV)和生长激素抑制素(somatostatin, SST)神经元是前额叶皮质中分布广泛的两类主要的抑制性GABA能中间神经元。本研究利用PV-Cre和SSTCre的转基因小鼠,结合化学遗传学的方法探究PrL中间神经元在吗啡引起的行为学改变中的作用。结果显示,特异性抑制PrL脑区SST神经元可以显著增加小鼠的焦虑水平,但不影响小鼠的运动能力;抑制PrL脑区SST神经元降低小鼠吗啡诱导的活动性增强及条件位置偏爱;而抑制PrL脑区PV神经元则对小鼠的运动能力、焦虑水平及吗啡引起的行为学改变均没有显著影响。本研究通过对PrL脑区PV及SST中间神经元在吗啡诱导的行为学改变中作用的研究,为成瘾药物作用的细胞及神经基础提供了依据。     

单次注射人工合成大麻素降低大鼠中脑腹侧背盖区多巴胺能神经元兴奋性北大核心CSCD

大麻成瘾可能维持一生。中脑腹侧背盖区(ventral tegmental area,VTA)作为投射到意识及情绪相关皮层和边缘系统的多巴胺能神经元的主要来源,是奖赏系统的关键部位之一,与药物成瘾密切相关。目前,对于VTA多巴胺能神经元在药物成瘾过程中的作用研究,主要集中在药物成瘾过程中突触可塑性的变化。已有研究表明,大麻素慢性作用5天后,易化了低频电刺激诱导VTA多巴胺能神经元产生突触传递的长时程减弱(long-term depression,LTD)效应,而此过程中多巴胺能神经元兴奋性的变化情况还未见报道。实验中,作者采用离体脑片膜片钳技术,观察单次注射人工合成大麻素HU210对大鼠VTA区多巴胺能神经元兴奋性的影响。结果显示,HU210作用后,神经元基强度增大,平均放电频率降低,其细胞膜电生理特性也发生了改变,表明单次注射人工合成大麻素HU210,降低了VTA多巴胺能神经元的兴奋性,提示神经元内在兴奋性的可塑性改变可能在药物成瘾中发挥作用。     

可卡因环境相关奖赏记忆提取激活伏隔核中央核和杏仁核基底外侧核神经元

奖赏刺激和伴药环境之间的强烈关联记忆,使得成瘾者在戒除药物数月或数年后暴露于类似环境即可诱发复吸。研究成瘾记忆的神经生物学基础有重要意义。本研究以可卡因条件位置偏爱(conditioned place preference,CPP)实验为行为学模型模拟分析药物与环境之间关联的建立。c-Fos、Zif268是常用的反映神经元活动增加的即早基因标记物。本文旨在通过采用免疫组织荧光染色方法,对可卡因环境相关的奖赏记忆提取后小鼠各脑区c-Fos、Zif268表达进行定量,比较分析它们的表达差异,以此来观察环境相关奖赏记忆提取时不同脑区神经元的激活情况。C57BL/6小鼠分为三组:生理盐水提取组、可卡因环境相关奖赏记忆提取组以及可卡因未提取组。后两组均接受CPP训练(一侧为伴可卡因侧,另一侧为伴生理盐水侧),训练结束后可卡因环境相关奖赏记忆提取组提取相关记忆,可卡因未提取组不提取。生理盐水提取组在放入CPP箱两侧前均腹腔注射生理盐水。结果显示,在药物成瘾相关脑区伏隔核核部,可卡因环境相关奖赏记忆提取组c-Fos、Zif268蛋白表达量显著高于生理盐水提取组。可卡因环境相关奖赏记忆提取组杏仁核基底外侧核Zif268蛋白表达量显著高于生理盐水提取组。在中脑边缘多巴胺系统的其他相关脑区如前额叶皮层、海马等,各组间c-Fos、Zif268蛋白表达量并未观察到明显的差异。以上结果表明伏隔核中央核和杏仁核基底外侧核在可卡因环境相关奖赏记忆提取过程中被激活,这提示伏隔核中央核和杏仁核基底外侧核脑区内激活的神经元是可卡因环境相关奖赏记忆的重要神经基础,为进一步解析药物成瘾记忆机制打下了基础。     

Lesions of orexin neurons block conditioned place preference for sexual behavior in male rats

The hypothalamic neuropeptide orexin (hypocretin) mediates reward related to drugs of abuse and food intake. However, a role for orexin in sexual reward has yet to be investigated. Orexin neurons are activated by sexual behavior, but endogenous orexin does not appear to be essential for sexual performance and motivation in male rats. Therefore, the goal of the current study was to test the hypothesis that orexin is critically involved in processing of sexual reward in male rats. First, it was demonstrated following exposure to conditioned contextual cues associated with sexual behavior in a conditioned place preference paradigm that cFos expression is induced in orexin neurons, indicating activation of orexin neurons by cues predicting sexual reward. Next, orexin-cell specific lesions were utilized to determine the functional role of orexin in sexual reward processing. Hypothalami of adult male rats were infused with orexin-B-conjugated saporin, resulting in greater than 80% loss of orexin neurons in the perifornical-dorsomedial and lateral hypothalamus. Orexin lesions did not affect expression of sexual behavior, but prevented formation of conditioned place preference for a sexual behavior paired chamber. In contrast, intact sham-treated males or males with partial lesions developed a conditioned place preference for mating. Orexin lesioned males maintained the ability to form a conditioned place aversion to lithium chloride-induced visceral illness, indicating that orexin lesions did not disrupt associative contextual memory. Overall, these findings suggest that orexin is not essential for sexual performance or motivation, but is critical for reward processing and conditioned cue-induced seeking of sexual behavior.     

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine

Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.     

Cell immunoblot assay study demonstrating the release of PACAP from individual anterior pituitary cells of rats and the effect of PACAP on LH release

Orexin A (or hypocretin 1)-immunoreactive neurons in the rat lateral hypothalamus project to several areas of the medulla oblongata that are closely associated with cardiovascular regulation. The present study was undertaken to further strengthen the hypothesis that orexin A accelerates cardiovascular response by activating sympathoexcitatory neurons in the rat rostral ventrolateral medulla (RVLM). First, immunohistochemical studies revealed the presence of orexin A-immunoreactive fibers in the RVLM. Double labeling the sections with orexin A- and tyrosine hydroxylase (TH)-antisera further showed that orexin A-immunoreactive fibers are in close proximity with TH-immunoreactive neurons, some of which may be barosensitive, bulbospinal neurons in the RVLM. Second, microinjection of orexin A (6.35, 12.7 and 38.1 microM) into the RVLM, which was verified later by histological examination, caused a significant increase of mean arterial pressure (MAP) and a moderate increase of heart rate (HR) in awake rats. L-glutamate (33.3 mM) injected into the same sites, caused a larger increase in MAP, but a decrease in HR; whereas, saline injection was without significant effect. Results from this study suggest that orexin A, which may be released from the nerve fibers originating from the neurons in the lateral hypothalamus, acting on RVLM neurons in the medulla, increases sympathetic outflow targeted to the heart and blood vessels in awake animals.     

Dynamic interactions between orexin and dynorphin may delay onset of functional orexin effects: a modeling study

Orexin (also known as hypocretin) neurons play a key role in regulating sleep-wake behavior, but the links between orexin neuron electrophysiology and function have not been explored. Orexin neurons are wake-active, and spiking activity in orexin neurons may anticipate transitions to wakefulness by several seconds. However, it is suggested that while the orexin system is necessary to maintain sustained wake bouts, orexin has little effect on brief wake bouts. In vitro experiments investigating the actions of orexin and dynorphin, a colocalized neuropeptide, on orexin neurons indicate that the dynamics of desensitization to dynorphin may represent a mechanism for modulating local network activity and resolving the apparent discrepancy between the onset of firing in orexin neurons and the onset of functional orexin effects. To investigate the role of dynorphin on orexin neuron activity, a Hodgkin-Huxley-type model orexin neuron was developed in which baseline electrophysiology, orexin/dynorphin action, and dynorphin desensitization were closely tied to experimental data. In this model framework, model orexin neuron responses to orexin/dynorphin action were calibrated by simulating the physiologic effects of static orexin and dynorphin bath application on orexin neurons. Then behavior in a small network of model orexin neurons was simulated with pure orexin, pure dynorphin, or combined orexin and dynorphin coupling based on the mechanisms established in the static case. It was found that the dynamics of desensitization to dynorphin can mediate a clear shift from a network in which firing is suppressed by dynorphin-mediated inhibition to a network of neurons with high firing rates sustained by orexin-mediated excitation. The findings suggest that dynamic interactions between orexin and dynorphin at transitions from sleep to wake may delay onset of functional orexin effects.     

Orexin A and its role in the regulation of the hypothalamo-pituitary axes in the rat

Orexin A (OxA), a recently discovered neuropeptide, is synthesized mainly by neurons located in the posterolateral hypothalamus and is a 33 amino acid peptide with N-terminal pyroglutamyl residue and two inter-chain disulfide bonds. It is a potent agonist for both the orexin-1 (OxR1) and orexin-2 (OxR2) receptors. Orexin A and its receptors are widely distributed in the central nervous system (CNS) and peripheral organs suggesting the pleiotropic functions of this peptide. Orexin A is involved in food intake and energy expenditure in many species, but also plays an important role in the regulation of the hypothalamo-pituitary axes. The role of orexin A in the regulation of the hypothalamo-pituitary-adrenal, -thyroid, -somatotropic, and -gonadal axes has been inadequately investigated. Orexinergic fibres project to the septal-preoptic and arcuate nucleus-median eminence regions--two areas of the brain directly involved in the synthesis and release of gonadotropin-releasing hormone (GnRH). Contentious opinions concerning the influence of orexin A over the hypothalamo-gonadotropic axis have been reported in both in vivo and in vitro studies. Further studies are necessary to clarify relationships between orexin A and the hypothalamo-pituitary hormones involved in reproduction.     

Multiple reward signals in the brain

The fundamental biological importance of rewards has created an increasing interest in the neuronal processing of reward information. The suggestion that the mechanisms underlying drug addiction might involve natural reward systems has also stimulated interest. This article focuses on recent neurophysiological studies in primates that have revealed that neurons in a limited number of brain structures carry specific signals about past and future rewards. This research provides the first step towards an understanding of how rewards influence behaviour before they are received and how the brain might use reward information to control learning and goal-directed behaviour.     

Effects of dehydration on renal aminopeptidase activities in adult male and female rats

Orexin A injected into the lateral hypothalamus (LH) stimulates feeding and activates neurons in brain sites regulating feeding and arousal. The feeding effects of orexin A have been demonstrated during the light cycle, a time when rats are normally resting, and the effect of orexin A on activity after injection into the LH has not been previously measured. Thus, it is unclear whether LH orexin A-induced feeding is secondary to enhanced arousal. To address this, LH-cannulated rats habituated to a running wheel were injected with either orexin A (1000 pmol) or vehicle during light and dark cycles. Food intake and running wheel rotations were measured for 2 h. Spontaneous physical activity (SPA) was also measured during the dark cycle. During the light cycle, orexin A in the LH stimulated feeding in the presence and absence of a running wheel and increased number of running wheel rotations in the presence and absence of food. During the dark cycle, orexin A in the LH induced SPA (+/- presence of food), but had no effect on feeding. These data show that LH orexin A stimulation of feeding is not always coincident with increased activity, suggesting that feeding induced by LH-injected orexin A is not consequent to enhanced arousal.     

Distribution and quantification of immunoreactive orexin A in rat tissues.

A sensitive and specific radioimmunoassay for orexin A was developed. Orexin A immunoreactivity was found to be confined to the central nervous system (CNS) with the highest concentrations in the hypothalamus, inferior and superior colliculi and brainstem. Within the hypothalamus, the highest levels were found in the lateral and posterior hypothalamus. These regions had a greater orexin A content in females compared to males. The orexin A content of hypothalamic regions did not change with fasting and no difference was noted in hypothalami of rats fed a high fat diet. The hypothalamic orexin A content was not different in obese Zucker rats compared to lean controls. Thus, orexin A has a wide distribution in the CNS, but appetite regulation may not be its main function.