多巴胺转运体在精神兴奋剂依赖中的作用

精神兴奋剂是一类能够兴奋中枢和外周神经系统并容易产生依赖性的精神活性物质。大量研究表明,单胺类神经递质尤其是多巴胺在精神兴奋剂的行为效应和精神兴奋剂依赖过程中发挥重要作用,而多巴胺转运体控制着神经元内多巴胺的稳态和多巴胺神经通路的传递,因此多巴胺转运体在精神兴奋剂的奖赏和行为刺激效应中具有重要作用。     

多巴胺转运蛋白研究进展

多巴胺转运蛋白(dopaminetransporter，DAT)，位于中枢多巴胺能神经元末梢，是一种膜蛋白，属于Na+／Cl-依赖性转运体基因家族。其生理作用为将突触间隙内已发挥生理效应的多巴胺(DA)重新摄入突触前膜，以备再次利用，同时终止神经细胞间的信息传递。由于分子生物学技术的应用，对DAT的作用有了深一层的认识。DAT已成为调节DA神经系统功能的重要环节。近年来的研究表明，DA能神经毒素MPP+是通过DAT进入神经元的，且单光子发射计算机断层扫描（SPECT）显示早期帕金森病（PD）病人的DAT水平明显降低。因此，对DAT深入广泛的研…     

纹状体中神经元活动的多巴胺调节

纹状体参与机体各种不同的行为活动 ,这些活动主要依赖于完整的多巴胺能神经支配 ,最近的电生理研究表明多巴胺通过改变电压依赖性的通道传导和突触传递来调节靶细胞的活动。该文对多巴胺如何调节纹状体神经元的活动作简要综述     

多巴胺D3受体在中枢神经兴奋剂成瘾中的作用

中枢神经兴奋剂成瘾是一种慢性、易复发性脑疾病,主要表现为强迫性觅药、摄药行为和强烈的渴求心理[1].研究表明,从腹侧被盖区投射到伏核、大脑额叶皮层、嗅结节、杏仁核的中脑边缘多巴胺系统的形态和功能改变是产生中枢神经兴奋剂成瘾的重要神经基础.中枢神经兴奋剂通过抑制多巴胺重吸收或促进多巴胺释放增加突触间隙多巴胺浓度,高于生理水平的多巴胺作用于相应的多巴胺受体,从而产生神经适应性和成瘾行为[2].中脑边缘系统中的伏核壳区多巴胺释放增加是成瘾药物产生欣快和奖赏效应的关键位点[3-5].     

SKF97541抑制大鼠骶髓后联合核神经元

目的研究GABAB受体特异性激动剂SKF97541对骶髓后联合核(SDCN)神经元的作用。方法在大鼠骶段脊髓横切薄片上,利用全细胞膜片钳法记录骶髓后联合核神经元。电流钳记录模式下,观察SKF97541对神经元膜电位和动作电位发放的影响。电压钳模式下,观察谷氨酸能兴奋性突触后电流(EPSCs)对SKF97541处理的变化。结果SKF97541(0.5μmol.L-1)通过作用于GABAB受体,减少SDCN神经元动作电位发放,同时促进细胞膜超极化。SKF97541在电压钳模式下,减少谷氨酸介导的微小EPSCs的频率,但对振幅无影响,提示SKF97541通过作用于突触前GABAB受体抑制谷氨酸释放。突触前刺激引起的突触后电位,也被SKF97541抑制。结论在骶髓后联合核,SKF97541通过作用于突触后GABAB受体,直接抑制神经元的兴奋性和动作电位发放;并通过突触前GABAB受体,抑制谷氨酸的释放。以上结果提示SKF97541的抑制作用可能抑制骶髓后联合核神经元对伤害性信息的传递。     

大脑皮质神经元及其网络的兴奋

大脑皮质中神经元的种类丰富多样,它们通过突触彼此连接,形成了能实现感觉、运动、学习、语言和决策等各种功能的神经网络。网络中信息的传递需要单个神经元及其交互神经网络的激活,即产生动作电位(AP)和网络电活动。AP首先在轴突产生,由轴突上各种离子通道和自身的生物物理特性所决定。交互神经网络的兴奋除了由各类神经元的兴奋性决定外,还被兴奋性和抑制性突触的递质释放模式所调控。传统观念认为,拥有"全或无"爆发特征的AP是信息传递的唯一方式,即数字信号编码模式。近期研究表明,阈下膜电位的波动也能调节由AP引发的突触传递,即模拟信号编码模式。在网络活动中,由谷氨酸能神经元提供的兴奋性信号和由γ-氨基丁酸(GABA)能神经元提供的抑制性信号往往是相辅相成的,从而达到兴奋和抑制的平衡。各类GABA能神经元所组成的抑制性微环路对平衡的维持十分重要,神经元间特异的突触传递模式可调控这些微环路的功能,如模拟信号传递模式和非同步化递质释放模式等。综上,本文阐述了大脑皮质中多种神经元及其网络的兴奋和调控机制。     

震颤麻痹的药物治疗进展

震颤麻痹又称帕金森病（PD），是锥体外系统的疾病，常见病状有震颤、肌肉僵直、运动障碍等。目前认为震颤麻痹是由于纹状体内缺乏多巴胺（DA），主要病变在黑质-纹状体多巴胺能神经通路上。黑质中有多巴胺能神经元，其上行纤维到达纹状体，末梢释放多巴胺为抑制性神经递质。同时黑质-纹状体通路中还有胆碱能神经元，其释放的递质为乙酰胆碱，是兴奋性递质，两种递质正常处时处于平衡状态。若多巴胺合成减少，胆碱能神经元功能相对亢进造成多巴胺能神经功能和胆碱能神经功能失衡，则产生帕金森病症状。PD是中老年人中常见的神经系统疾病，应用左旋多巴治疗，可取得显著疗效。     

单次可卡因注射对VTA区DA神经元兴奋性突触传递和内在兴奋性的影响

目的:研究单次可卡因注射24 h后VTA区多巴胺能(DA)神经元兴奋性突触传递强度和内在兴奋性的变化。方法:采用离体膜片钳技术,检测单次可卡因注射24 h后VTA区DA神经元自发性慢性内向流(slow inwardcurrents,SICs)、内在兴奋性以及兴奋性突触后电流(EPSCs)的变化。结果:DA神经元的SICs、内在兴奋性和EPSCs均有显著增强。结论:单次可卡因注射后VTA区DA神经元兴奋性突触传递强度和内在兴奋性呈现协同增强效应。     

木犀草素联合芦丁抗6-羟多巴胺诱导的帕金森病大鼠震颤及神经保护作用

目的探讨木犀草素和芦丁组合物(mixture of luteolinand rutin,MLR)对6-羟多巴胺(6-OHDA)诱导的帕金森病(parkinson's disease,PD)模型大鼠减轻震颤和保护神经元的作用及机制。方法运用6-OHDA两点注射法,损毁大鼠左侧中脑多巴胺能神经元,复制PD模型。2周后,将造模成功大鼠随机分为模型组、美多芭给药组(50 mg·kg-1)、MLR给药组(125、250、375 mg·kg-1),另取手术并注射生理盐水、经检测无旋转运动的大鼠为假手术组。在给药后第3周记录大鼠后肢肌电(EMG),观察肌肉震颤。行为学检查完毕后采用免疫组化法检测大鼠黑质酪氨酸羟化酶(TH)、多巴胺转运体(DAT)、胶质原纤维酸性蛋白(GFAP)阳性细胞数。结果 EMG检测结果显示,MLR各给药组可明显降低大鼠的震颤频率和幅度,中、高剂量组的作用优于美多芭组。免疫组化结果显示,MLR高剂量组TH免疫阳性神经元的数目约为模型组的499.14%,MLR高剂量组GFAP免疫阳性星形胶质细胞的数目比模型组降低了43.68%。结论MLR可剂量依赖性抑制PD模型大鼠震颤,减轻神经元受损程度,抑制星形胶质细胞激活和促炎因子释放,从而延缓DA能神经元进行性退变。     

多巴胺作用机制及代谢

帕金森病(Parkinsondisease,PD)是一种多发于中老年人,以肌肉震颤、肌肉强直、运动活动启动困难、姿势反射丧失为特征的中枢神经系统疾病。首次就诊时的平均年龄是55岁,此年龄组人口约1%患有此病,其症状特点首先由JamesParkinson于1817年描述。PD主要病理生理学特点是黑质致密部(SNc)色素沉着神经元进行性死亡导致多巴胺(Dopamine,DA)代谢障碍,此种神经元已被鉴定为黑质DA神经元。脑的其他区域亦可累及,如蓝斑核,Meynert'基底核,甚至下丘脑。SNc多巴胺能神经元的死亡导致帕金森综合征,这一重大发现为药物治疗PD、调控DA突触传递提…     

Psychostimulants induce low-frequency oscillations in the firing activity of dopamine neurons.

The reinforcing properties of psychostimulants depend critically on their effects on dopamine (DA) neurons in the ventral tegmental area (VTA). Using in vivo single unit recording in rats and spectral analysis, this study presents evidence for a new, non-DA-mediated effect of psychostimulants on VTA DA neurons. Thus, as previously observed with D-amphetamine, all psychostimulants tested, including cocaine, methamphetamine, and methylphenidate, had two opposing effects on firing rate of DA neurons: a DA-mediated inhibition and a non-DA-mediated excitation. The latter effect was normally masked by the DA-mediated inhibition and was revealed when the inhibition was blocked by a DA antagonist. Using spectral analysis, this study further showed that during psychostimulant-induced excitation, DA cells exhibited not only an increase in firing rate and bursting but also a low-frequency rhythmic oscillation (0.5-1.5 Hz) in their firing activity. The oscillatory response was unique to psychostimulants since it was not observed with the GABA(A) agonist muscimol, which also increased DA cell firing, and not mimicked by the nonpsychostimulant DA agonist L-dopa. Results further suggest that the effect requires activation of adrenergic alpha1 receptors and depends on intact forebrain inputs to DA neurons. Further understanding of this novel effect may provide important insights into both the mechanism of action of psychostimulants and the neuronal circuitry that controls the activity of DA neurons in the brain.     

Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.     

Modulation of eating by central catecholamine systems

The focus of the present review is the modulation of eating by the endogenous catecholamines (CA) dopamine (DA) and norepinephrine (NE). Topics addressed include pharmacological and genomic manipulations of brain CA systems and subsequent changes in ingestive behavior. DA in particular is a key component of brain reinforcement systems and feeding-associated changes in DA may play a role in the reinforcing aspects of feeding. NE has been linked to both stimulation and suppression of eating and recent evidence has linked these effects to activation of distinct adrenoceptor subtypes. Recent evidence suggests that NE systems may interact with DA systems to augment the activational effects of psychostimulant drugs, such as cocaine or amphetamine, and DA/NE interactions may play a key role in the capacity of psychostimulants to suppress eating.     

Role of monoamine transporters in mediating psychostimulant effects

Monoamine transporters such as the dopamine (DA) transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2) are critical regulators of DA disposition within the brain. Alterations in DA disposition can lead to conditions such as drug addiction, Parkinson's disease, and schizophrenia, a fact that underscores the importance of understanding DAergic signaling. Psychostimulants alter DAergic signaling by influencing both DAT and VMAT-2, and although the effects of these drugs result in increased levels of synaptic DA, the mechanisms by which this occurs and the effects that these drugs exert on DAT and VMAT-2 vary. Many psychostimulants can be classified as releasers (ie, amphetamine analogs) or uptake blockers (ie, cocaine-like drugs) based on the mechanism of their acute effects on neurotransmitter flux through the DAT. Releasers and uptake blockers differentially modulate the activity and subcellular distribution of monoamine transporters, a phenomenon likely related to the neurotoxic potential of these drugs to DAergic neurons. This article will review some of the recent findings whereby releasers and uptake blockers alter DAT and VMAT-2 activity and how these alterations may be involved in neurotoxicity, thus providing insight on the neurodegeneration observed in Parkinson's disease.     

Regulation of psychomotor functions by dopamine: integration of various approaches

(1)The basal ganglia circuitry mediates a wide rage of brain functions such as motor control, behavioral planning, and reward prediction. Dopamine (DA) transmission plays an essential role in the regulation of these brain functions. DA action not only regulates the firing activity of target neurons but also is involved in the pattern formation of their firing. The striatopallidal neurons containing dopamine D(2) receptor plays a dual role in motor coordination dependent on DA transmission. (2)Activation of presynaptic D(2)-like receptors on GABAergic terminals onto striatal cholinergic interneurons selectively blocks N-type Ca(2+) channels, thereby inhibiting GABA release. In addition, contribution of N-type channels and D(2)-like receptor-mediated presynaptic inhibition decreases in parallel with development, implying some relationship between basal ganglia-related function or dysfunction and age. (3)As an approach to determine dopamine neuronal activity, we monitored neuronal activities by measuring cytosolic Ca(2+) concentration in VTA dopamine neurons. The present study indicates that VTA dopamine neurons are the direct targets of orexin-A and psychostimulants, and the [Ca(2+)](i) signaling is thought to play a significant role in the regulation of dopamine neuronal activity. (4)The excitability of neostriatal neurons is regulated by a balance of glutamatergic and dopaminergic inputs. Glutamate has been shown to modulate dopaminergic signaling. Studies on the regulation of DARPP-32 phosphorylation by glutamate provide a molecular basis for both the synergistic and antagonistic effects of glutamate on dopaminergic signaling. (5) Impairment of function of stem/progenitor cells may be implicated in the pathogenesis of schizophrenia. To test this hypothesis, several experiments are currently ongoing in our laboratory, and the preliminary results obtained are described here.     

GABAB receptor-mediated modulation of the firing pattern of ventral tegmental area dopamine neurons in vivo

Previous work demonstrates the fundamental role of the firing pattern, specifically the burst firing mode of midbrain dopamine (DA) neurons in the regulation of DA release. Spontaneous burst firing has been shown to be dependent upon NMDA receptor activation of the DA cells. In addition to NMDA receptors, previous studies have reported that also GABA(B) receptors modulate the firing pattern of DA neurons in the substantia nigra. In the present electrophysiological study the role of GABA(B) receptors in the modulation of the firing pattern of DA neurons in the ventral tegmental area (VTA) in anaesthetised Sprague-Dawley rats was analysed. Systemic administration of the selective and potent GABA(B) receptor agonist baclofen dose-dependently reduced firing rate and burst firing in VTA DA neurons. An increase in the regularity of DA cell firing was also observed. All these effects were effectively antagonized by administration of the selective GABA(B) antagonist CGP 35348 (100 mg/kg or 200 mg/kg, i.v.). Administration of CGP 35348 (400 mg/kg, i.v.) per se was associated with a long-lasting increase in burst firing activity. The effects of systemic administration of baclofen, alone or in combination with CGP 35348, on the firing rate were largely mimicked by local microiontophoretic application of the drugs onto the DA neurons.Our findings indicate that central GABA(B) receptors may contribute to control of the burst firing mode of VTA DA neurons. Physiologically, activation of GABA(B) receptors may subserve a dampening function on VTA DA cell excitability which may counterbalance NMDA receptor-mediated excitation.     

Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress.

Preclinical studies have shown that stress and glucocorticoids increase mesolimbic dopamine (DA) and thereby facilitate psychostimulant self-administration. The relationship between stress-induced cortisol and mesolimbic DA responses to psychostimulants has not been studied in humans. To test the hypotheses that glucocorticoid responses to psychological stress are correlated with DA and subjective responses to psychostimulants in humans, 25 healthy adults (18-29 years) completed the Trier Social Stress Test (TSST) and two positron emission tomography (PET) scans with high-specific [11C]raclopride. The first scan was preceded by intravenous saline and the second by amphetamine (AMPH). Findings showed that stress-induced cortisol levels were positively associated with AMPH-induced DA release in the ventral striatum and other striatal regions. Subjects with higher cortisol responses to stress also reported more positive subjective drug effects with AMPH than subjects with lower responses. The results are consistent with preclinical findings showing an interrelationship between glucocorticoids and mesolimbic DA dynamics, which may influence psychostimulant self-administration in humans.     

Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence

The development of novel pharmacological agents for the treatment of psychostimulant use disorders is an important research imperative. One potential target system that has been largely overlooked is the serotonin (5-HT) neurotransmitter system. Preclinical studies indicate that 5-HT may be important in modulating the reinforcing properties of various drugs of abuse. While the potential sites of action of 5-HT within the brain are extensive, the natural starting point to examine the mechanisms by which 5-HT may be useful in treatment of psychostimulant use disorders is the interaction between 5-HT and dopamine (DA), a primary mediator of the "rewarding" effects of psychostimulants. Two key modulators of DA output are the serotonin (5-HT)2A receptor (5-HT2A R) and the 5-HT2C R. These receptors are known to control the neurochemical and behavioral effects of psychostimulants, and in particular, the in vivo effects of cocaine. Preclinical studies indicate that 5-HT2A R antagonists and/or 5-HT2C R agonists may effectively reduce craving and/or relapse, and likewise, enhance abstinence, while 5-HT2C R agonists may also effectively reduce cocaine intake in active cocaine users. At present, the progression of studies to probe the effectiveness of 5-HT2A R and 5-HT2C R ligands in the clinical setting is hindered by a lack of available selective 5-HT2A R antagonists or 5-HT2C R agonists for use in human cocaine abusers. However, a number of selective 5-HT2 R ligands currently under development, or in early clinical trials for psychiatric and/or neurological disorders, may soon be available for translational studies to explore their effectiveness in modulating drug use and dependence.     

Inhibitory Inputs from Rostromedial Tegmental Neurons Regulate Spontaneous Activity of Midbrain Dopamine Cells and Their Responses to Drugs of Abuse

The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activation.     

Psychomotor-stimulant sensitization: a unitary phenomenon?

Repeated intermittent treatment with psychomotor stimulants or opiates sensitizes animals to the locomotor activating effects of these drugs. Whereas such sensitization may have important implications for the understanding of addiction, mental illness, and the cellular basis of memory, its mechanisms remain only partially understood. Psychomotor-stimulant sensitization can result in relatively permanent changes in the response of the mesolimbic dopamine system to these agents and to a variety of stressors, but the process does not depend upon simple activation of dopaminergic neurons. Psychomotor sensitization can be produced by direct (apomorphine, bromocriptine) and indirect (amphetamine, cocaine) dopamine agonists that inhibit the firing of dopaminergic neurons and thus reduce impulse-dependent dopamine release. Moreover, some treatments that cause dopaminergic activation and dopamine (DA)-dependent locomotion fail to cause robust psychomotor sensitization. While nucleus accumbens injections of amphetamine cause DA release and enhanced locomotion, they do not sensitize the animals to subsequent systemic amphetamine. On the other hand, ventral tegmental injections of amphetamine inhibit the DA system and DA-dependent locomotion but none the less sensitize the animal to subsequent systemic amphetamine treatment. While some drugs (cocaine, amphetamine, morphine, heroin) cross-sensitize animals to each other, other drugs (bromocriptine, quinpirole) sensitize animals to themselves and each other but not to cocaine or heroin. While some cases of sensitization involve Pavlovian association of environmental cues with the drug state, others seem largely independent of such conditioning. Thus it appears that there is more than one phenomenon and more than one mechanism of psychomotor sensitization.