运动奖赏效应及其神经生物学机制的研究进展

身体活动不足已经成为当今社会的公共卫生问题。深入理解运动的奖赏效应及其可能的神经生物学机制,将为改善身体活动不足提供科学有效的干预靶点。本文指出运动是一种典型的自然奖赏行为。大脑奖赏相关的腹侧背盖区-伏隔核的多巴胺能神经环路、前额叶皮质-伏隔核的谷氨酸能神经投射、红核-腹侧背盖区的谷氨酸能神经投射是调控运动奖赏效应的关键神经环路机制。此外,多巴胺、内源性大麻素系统和内源性阿片肽等多种神经分子参与了运动奖赏效应的调控。然而,大脑奖赏系统的过度激活将会导致运动成瘾。     

药物成瘾与抑郁症共病机制的研究进展

药物成瘾和抑郁症的共患率日益提高,已发展成为常见的精神共病状态,但这两种疾病之间的联系及潜在的机制仍不明确,开发针对药物成瘾共病抑郁症的有效治疗手段仍是一项重大挑战。大量的文献表明,药物成瘾和抑郁症存在着共同的发生脑区及分子机制。该文阐述了伏隔核、外侧缰核和中脑腹侧被盖区等脑区在这种共病中的重要性,还介绍了κ阿片受体、促肾上腺激素释放因子和脑源性神经营养因子等分子在这种共病中的作用及机制。这些发现为研究药物成瘾与抑郁症共病的机制提供了新的思路,并为药物成瘾共病抑郁症患者的治疗提供了新的靶点。     

多巴胺对吗啡成瘾大鼠海马区痛觉调制的研究进展

当今社会日益增长的吗啡等阿片类药物的非法滥用已经严重威胁到人类的健康。然而,迄今为止尚没有找到能够较为有效的防治阿片成瘾的方法。目前研究已知,阿片成瘾的形成所涉及的脑区及核团包括中脑腹侧被盖区(VTA)、伏隔核(NAc)、海马等,其成瘾涉及的神经递质系统包括多巴胺、5-羟色胺等。本文将就多巴胺及海马在痛觉调制及药物成瘾过程中的作用进行综述,为吗啡的成瘾与戒断的进一研究及治疗提供线索。     

miRNAs与药物成瘾

药物成瘾是一种慢性复发性脑病,主要表现为不可控制的对药物持续渴求和戒断后的高复吸。目前观点认为,成瘾是中脑腹侧被盖（ventral tegmental area,VTA）到伏隔核（nucleus accumbens,NAc）脑区多巴胺能奖赏通路中神经可塑性发生改变而导致的一种神经精神疾病。基因表达变化在神经可塑性中发挥着重要作用,但成瘾药物导致相关脑区结构和功能改变的机制还不甚清楚。微小RNAs（microRNAs,miRNAs）是一类非编码RNA,主要通过结合靶基因mRNA 3′非翻译区（3′untranslated region,3′UTR）,在转录后水平阻断其翻译成蛋白质或触发其不稳定而降解。越来越多的研究证实,miRNAs参与调节成瘾相关神经可塑性的变化。本文较系统地阐述miRNAs在药物成瘾中的作用研究进展,将为深入阐明药物成瘾的机制以及药物成瘾临床有效干预和诊治提供新思路。     

脑内多巴胺信号动态变化的检测方法及在成瘾研究中的应用

多巴胺是脑内重要的神经递质,中脑多巴胺系统在控制奖赏、动机、运动和情绪调节过程中起重要作用。脑内多巴胺功能紊乱与药物依赖、精神分裂症、抑郁症和帕金森氏病等神经精神障碍有关,动态测定脑内多巴胺变化对于了解多巴胺功能和揭示相关疾病病理机制具有重要意义。本文主要介绍了微透析、快速扫描循环伏安法和光纤光度法的基本原理和方法,并对比分析了这些技术在多巴胺动态检测应用中的优缺点。以药物成瘾研究为应用实例,利用微透析法发现伏隔核壳部是成瘾性药物产生奖赏效应的关键部位,快速扫描循环伏安法检测到与可卡因自身给药行为相关的三种多巴胺信号模式,而光纤光度法则揭示了酒精成瘾和复吸过程中伏隔核和中脑复侧被盖区多巴胺活动特征存在空间和时间上的多样性。这些发现为揭示药物成瘾的机制做出了重要贡献。     

腹侧被盖区多巴胺神经元全脑神经环路示踪

摘要 目的：研究小鼠中脑腹侧被盖区（VTA）多巴胺能神经元接受的全脑输入性上游投射及其输出性下游投射,解析其全脑上下游神经环路连接。方法：用立体定位仪将辅助病毒AAV-EF1a-DIO-GT和AAV-EF1a-DIO-G的混合液（1：1）注射到DAT-cre转基因小鼠的VTA脑区,2周后将重组狂犬病毒（RV）EnVA-RV-mCherry微注射到VTA脑区,1周后RV病毒完成逆向跨突触感染并充分表达荧光蛋白,全脑冰冻切片,用全自动扫描荧光显微镜全脑拍片。用立体定位仪将顺行示踪病毒AAV-EF1a-DIO-GFP微注射到DAT-cre转基因小鼠的VTA脑区,2周后待病毒及荧光蛋白充分表达后,全脑冰冻切片,VTA区脑片用TH抗体行免疫荧光染色,全自动扫描荧光显微镜全脑拍片。结果：狂犬病毒逆向跨单级突触示踪结果显示,全脑许多脑区核团神经元表达RV病毒携带的红色荧光蛋白,主要包括前脑皮层、纹状体、伏隔核、下丘脑视前区、外侧下丘脑、下丘脑室旁核、杏仁核、腹侧被盖区、黑质、中缝背核、臂旁核、缰核。顺行示踪病毒结果显示,表达绿色荧光蛋白的纤维投射主要集中在内侧前额叶皮层、纹状体、伏隔核、背外侧隔核、杏仁核、外侧下丘脑几个脑区。结论：VTA多巴胺能神经元的上游输入性投射广泛的分布于全脑,包括前脑皮层、基底神经节区、下丘脑区、边缘系统、中脑的许多核团都向其发出纤维投射。VTA多巴胺神经元的下游输出性投射主要集中在基底神经节的伏隔核和纹状体,内侧前额叶皮层及下丘脑也有一定投射。     

甲基苯丙胺成瘾的表观遗传学机制

苯丙胺类兴奋剂是全世界第二大滥用程度的药物,甲基苯丙胺作为苯胺类兴奋剂中的主要药物,是中国滥用的“头号毒品”。而现有的研究对甲基苯丙胺成瘾机制尚不清晰,且临床上对药物成瘾的治疗依然存在无药可医的局面。因此,发现新的成瘾机制和治疗策略尤为迫切。甲基苯丙胺成瘾与额前叶皮质（mPFC）、中脑腹侧被盖区（VTA）和伏隔核（NAc）中的多巴胺（DA）、谷氨酸（Glu）、去甲肾上腺素（NE）和血清素（SNRIS）等神经递质的异常释放有关。研究表明,这些神经递质受到表观遗传机制中组蛋白乙酰化、甲基化、泛素化和非编码RNA等调节,某些基因的表达在甲基苯丙胺的诱导过程中增强或被抑制,导致甲基苯丙胺依赖性产生。本文将针对表观遗传学对甲基苯丙胺成瘾机制的影响进行着重论述,以期推进临床开发甲基苯丙胺戒断药物的研究。     

Orexin-A通路对胃运动的调控研究

目的:探讨下丘脑外侧核(LHA)-伏隔核(NAcc)orexin-A神经和功能通路构成及该通路对胃运动的影响及潜在机制。方法:将健康成年雄性Wistar大鼠随机分为逆行追踪组和胃运动组:逆行追踪组大鼠采用逆行追踪技术结合免疫荧光组织化学染色法,观察下丘脑外侧核-伏隔核间是否存在orexin-A神经通路;胃运动组大鼠通过在体胃运动研究,观察伏隔核内微量注射不同浓度orexin-A对大鼠胃运动幅度和频率的影响,以及电刺激下丘脑外侧核后,大鼠胃运动的变化及机制。结果:荧光逆行追踪结合荧光免疫组织化学染色结果显示:下丘脑外侧核内有荧光金和orexin-A双重标记的神经元。胃运动研究结果显示:伏隔核内微量注射orexin-A,大鼠胃运动幅度和频率显著增加,并呈现显著剂量依赖关系(P0.05),伏隔核预先微量注射SB-334867,可反转该效应(P0.05)。电刺激下丘脑外侧核,大鼠胃运动幅度和频率显著增强(P0.05)。同样,伏隔核内微量注射SB-334867,再电刺激下丘脑外侧核,电刺激导致的胃运动增强效应显著减弱(P0.05)。结论:下丘脑外侧核-伏隔核存在orexin-A神经和功能通路,该通路可能通过orexin-A受体介导参与胃动力和能量代谢调控。     

食物成瘾的研究进展

食物成瘾是指个体长期无法理性控制对某特定食物的摄入量或时间而对该食物具有依赖的一种现象。近年来,食物成瘾已被认为是升高发达国家肥胖、2型糖尿病等代谢性疾病发病率的危险因素。文章综述了食物成瘾的概念、诊断标准、产生机制、与代谢性疾病的关联、预防及治疗措施,旨在为食物成瘾的进一步研究提供科学依据。     

四种细胞因子在中华蟾蜍脑中的分布

采用免疫组织化学SABC法,研究白介素-1α、干扰素-γ、神经生长因子-β和肿瘤坏死因子-α在成体中华蟾蜍脑中的表达和分布特点。结果发现,白介素-1α阳性细胞数量很多,分布于脑的各个区域。白介素-1α多在细胞的胞体中,而原始海马锥体细胞,中脑的背前侧被盖核和腹后侧被盖核中的细胞可见阳性的突起。干扰素-γ阳性细胞数量较多,分布在端脑的原始海马和隔区,丘脑腹外侧核,下丘脑的视前区、视交叉上核和腹侧漏斗核,中脑被盖的背前侧被盖核、腹前侧被盖核、背后侧被盖核和腹后侧被盖核中,小脑的Purkinje细胞层和延髓的网状核,其中原始海马,背前侧被盖核和背后侧被盖核,视交叉上核,Purkinje细胞层和网状核中的细胞中可见阳性突起。神经生长因子-β阳性细胞数量较少,主要存在于下丘脑的视前区和视交叉上核,中脑被盖的腹前侧被盖核,小脑的Purkinje细胞层和延髓的网状核中,其中视前区、Purkinje细胞层和网状核中细胞可见阳性突起。肿瘤坏死因子-α阳性细胞数量最少,分布范围仅限于中脑被盖背前侧区和延髓的网状核及中缝核,但细胞具有阳性突起。因此,白介素-1α和干扰素-γ在成体动物脑中分布较为广泛,可能是神经细胞生命活动所必需的;而神经生长因子-β和肿瘤坏死因子-α在成体动物脑中分布范围狭窄,其作用可能仅限于脑中的某些特殊区域。     

Food Reward-Induced Neurotransmitter Changes in Cognitive Brain Regions

Recent evidence indicates that mechanisms involved in reward and mechanisms involved in learning interact, in that reward includes learning processes and learning includes reward processes. In spite of such interactions, reward and learning represent distinct functions. In the present study, as part of an examination of the differences in learning and reward mechanisms, it was assumed that food principally affects reward mechanisms. After a brief period of fasting, we assayed the release of three neurotransmitters and their associated metabolites in eight brain areas associated with learning and memory as a response to feeding. Using microdialysis for the assay, we found changes in the hippocampus, cortex, amygdala, and the thalamic nucleus, (considered cognitive areas), in addition to those in the nucleus accumbens and ventral tegmental area (considered reward areas). Extracellular dopamine levels increased in the nucleus accumbens, ventral tegmental area, amygdala, and thalamic nucleus, while they decreased in the hippocampus and prefrontal cortex. Dopamine metabolites increased in all areas tested (except the dorsal hippocampus); changes in norepinephrine varied with decreases in the accumbens, dorsal hippocampus, amygdala, and thalamic nucleus, and increases in the prefrontal cortex; serotonin levels decreased in all the areas tested; although its metabolite 5HIAA increased in two regions (the medial temporal cortex, and thalamic nucleus). Our assays indicate that in reward activities such as feeding, in addition to areas usually associated with reward such as the mesolimbic dopamine system, other areas associated with cognition also participate. Results also indicate that several transmitter systems play a part, with several neurotransmitters and several receptors involved in the response to food in a number of brain structures, and the changes in transmitter levels may be affected by metabolism and transport in addition to changes in release in a regionally heterogeneous manner. Food reward represents a complex pattern of changes in the brain that involve cognitive processes. Although food reward elements overlap with other reward systems sharing some neurotransmitter compounds, it significantly differs indicating a specific reward to process for food consumption. Like in other rewards, both learning and cognitive areas play a significant part in food reward. Special issue dedicated to Dr. Moussa Youdim.     

Central mechanisms of roles of taste in reward and eating

Taste is unique among sensory systems in its innate association with mechanisms of reward and aversion in addition to its recognition of quality, e.g., sucrose is sweet and preferable, and quinine is bitter and aversive. Taste information is sent to the reward system and feeding center via the prefrontal cortices such as the mediodorsal and ventrolateral prefrontal cortices in rodents and the orbitofrontal cortex in primates. The amygdala, which receives taste inputs, also influences reward and feeding. In terms of neuroactive substances, palatability is closely related to benzodiazepine derivatives and beta-endorphin, both of which facilitate consumption of food and fluid. The reward system contains the ventral tegmental area, nucleus accumbens and ventral pallidum and finally sends information to the lateral hypothalamic area, the feeding center. The dopaminergic system originating from the ventral tegmental area mediates the motivation to consume palatable food. The actual ingestive behavior is promoted by the orexigenic neuropeptides from the hypothalamus. Even palatable food can become aversive and avoided as a consequence of a postingestional unpleasant experience such as malaise. The neural mechanisms of this conditioned taste aversion will also be elucidated.     

New perspectives on cocaine addiction: recent findings from animal research

Research with laboratory animals has provided several insights into the nature of cocaine abuse and addiction. First, the nature of drug addiction has been reevaluated and the emphasis has shifted from physical dependence to compulsive drug-taking behavior. Second, animal studies suggest that cocaine is at least as addictive as heroin and possibly even more addictive. Third, cocaine is potentially more dangerous than heroin as evidenced by the higher fatality rate seen in laboratory animals given unlimited access to these drugs. Fourth, the neural basis of cocaine reinforcement has been identified and involves an enhancement of dopaminergic neurotransmission in the ventral tegmental dopamine system. Other addictive drugs (e.g., opiates) may also derive at least part of their reinforcing impact by pharmacologically activating this reward system. Fifth, although the biological consequences of repeated cocaine self-administration on central nervous system functioning are poorly understood, preliminary findings suggest that intravenous cocaine self-administration may decrease neural functioning in this brain reward system. This has important clinical implications because diminished functioning of an important brain reward system may significantly contribute to relapse into cocaine addiction. These and other findings from experimentation with laboratory animals suggest new considerations for the etiology and treatment of drug addiction.     

Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats

Findings from our laboratory and others have demonstrated that the hormone insulin has chronic effects within the CNS to regulate energy homeostasis and to decrease brain reward function. In this study, we compared the acute action of insulin to decrease intake of a palatable food in two different behavioral tasks-progressive ratios sucrose self-administration and micro opioid-stimulated sucrose feeding-when administered into several insulin-receptive sites of the CNS. We tested insulin efficacy within the medial hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, the nucleus accumbens, and the ventral tegmental area. Administration of insulin at a dose that has no chronic effect on body weight (5 mU) into the ARC significantly suppressed sucrose self-administration (75+/-5% of paired control). However, although the mu opioid DAMGO, [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin acetate salt, stimulated sucrose intake at all four CNS sites, the ventral tegmental area was the only sensitive site for a direct effect of insulin to antagonize acute (60 min) micro opioid-stimulated sucrose feeding: sucrose intake was 53+/-8% of DAMGO-induced feeding, when insulin was coadministered with DAMGO. These findings demonstrate that free feeding of sucrose, and motivated work for sucrose, can be modulated within unique sites of the CNS reward circuitry. Further, they support the interpretation that adiposity signals, such as insulin, can decrease different aspects of ingestion of a palatable food, such as sucrose, in an anatomically specific manner.     

Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.     

Reciprocal opioid-opioid interactions between the ventral tegmental area and nucleus accumbens regions in mediating mu agonist-induced feeding in rats

Feeding elicited by the mu-selective agonist, [D-Ala2, M-Phe4, Gly-ol5]-encephalin administered into the nucleus accumbens is blocked by accumbal pre-treatment with mu, delta1, delta2 and kappa, but not mu1 opioid antagonists. Correspondingly, mu-agonist-induced feeding elicited from the ventral tegmental area is blocked by ventral tegmental area pre-treatment with mu and kappa, but not delta opioid antagonists. A bi-directional opioid-opioid feeding interaction has been firmly established such that mu-agonist-induced feeding elicited from the ventral tegmental area is blocked by accumbal naltrexone, and that accumbal mu-agonist-induced feeding is blocked by naltrexone pre-treatment in the ventral tegmental area. To determine which opioid receptor subtypes mediate the regional bi-directional opioid-opioid feeding interactions between these two sites, the present study examined the dose-dependent ability of either general (naltrexone), mu (beta-funaltrexamine), kappa (nor-binaltorphamine) or delta (naltrindole) opioid antagonists administered into one site to block mu-agonist-induced feeding elicited from the other site. General, mu and kappa, but not delta opioid receptor antagonist pre-treatment in the ventral tegmental area dose-dependently reduced mu-agonist-induced feeding elicited from the nucleus accumbens. General, mu and delta, and to a lesser degree kappa, opioid receptor antagonist pre-treatment in the nucleus accumbens dose-dependently reduced mu-agonist-induced feeding elicited from the ventral tegmental area. Thus, multiple, but different opioid receptor subtypes are involved in mediating opioid-opioid feeding interactions between the nucleus accumbens and ventral tegmental area regions.     

Synaptic plasticity in drug reward circuitry

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.     

Receptors in the Ventral Tegmental Area Mediating Nicotine-Induced Dopamine Release in the Nucleus Accumbens

Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D₁: SCH 23390, D₂: eticlopride), and NMDA glutamatergic (MK 801) and GABA_B (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABA_B (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D₁ (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.