BACKGROUND & AIMS: :This review considers some of the novel therapies that are under development for the treatment of tobacco dependence, outlines their efficacy in clinical studies and explains their mechanisms of action in terms of contemporary theories for the psychobiology of the dependence. It focuses on three treatments with differing mechanisms of action that are at different stages of clinical development. The first is varenicline, a partial agonist at the alpha4beta2 nicotinic receptors, which are thought to play a central role in the addiction to nicotine. Preclinically, this drug mimics the effects of nicotine on dopamine (DA) release in the nucleus accumbens when given alone but attenuates this response to a subsequent nicotine challenge and reduces nicotine self administration. Very encouraging results have been seen in the five clinical studies that have been reported with this drug. The second compound, rimonabant, is a cannabinoid CB1 receptor antagonist. Preclinically, this compound reduces nicotine self administration, DA turnover in nucleus accumbens and attenuates reinstatement of nicotine-seeking behaviour. Clinically, the drug is well tolerated but its effects on smoking cessation are equivocal. However, it has the valuable additional property of inhibiting post-cessation weight gain. Nicotine 'vaccines' are the final group of treatments considered, which involves raising antibodies in the blood that limit the amount of nicotine that penetrates into the brain, thereby reducing the psychopharmacological responses to the drug. The vaccines also reduce DA turnover in nucleus accumbens and reinstatement of nicotine-seeking behaviour after nicotine readministration. The three vaccines discussed are well tolerated and show signs of good efficacy; however, the increase in antibody titre, evoked by the treatment, shows significant inter-individual variation and is generally short lived. Thus, although this approach may provide a valuable aid to smoking cessation, it seems unlikely that it can be used for primary prevention.

背景与目标： ：这篇综述考虑了一些正在治疗烟草依赖的新疗法，概述了它们在临床研究中的功效，并根据当代有关依赖心理生物学的理论解释了它们的作用机理。它着重于在临床发展的不同阶段具有不同作用机理的三种治疗方法。第一个是伐尼克兰，它是α4beta2烟碱受体的部分激动剂，据认为在尼古丁成瘾中起重要作用。临床前，这种药物模仿单独使用尼古丁对伏隔核中多巴胺（DA）释放的影响，但会减弱对随后尼古丁激发的反应并减少尼古丁的自我给药。在用这种药物报道的五项临床研究中已经看到了非常令人鼓舞的结果。第二种化合物，利莫那班，是一种大麻素CB1受体拮抗剂。临床上，该化合物减少尼古丁的自我给药，伏隔核中的DA转换并减弱尼古丁寻找行为的恢复。在临床上，该药物耐受性良好，但其对戒烟的作用却模棱两可。但是，它具有抑制戒烟后体重增加的有价值的附加特性。尼古丁“疫苗”是考虑的最后一类治疗方法，涉及提高血液中的抗体，限制进入大脑的尼古丁含量，从而减少对该药物的心理药理反应。这些疫苗还减少了尼古丁重新给药后伏隔核中的DA转换和恢复尼古丁寻找行为。讨论的三种疫苗具有良好的耐受性，并显示出良好的疗效。然而，治疗引起的抗体滴度增加表明个体间存在显着差异，并且通常寿命短。因此，尽管这种方法可以为戒烟提供宝贵的帮助，但似乎不太可能将其用于一级预防。

BACKGROUND & AIMS: :Neuropharmacology had several major past successes, but the last few decades did not witness any leap forward in the drug treatment of brain disorders. Moreover, current drugs used in neurology and psychiatry alleviate the symptoms, while hardly curing any cause of disease, basically because the etiology of most neuro-psychic syndromes is but poorly known. This review argues that this largely derives from the unbalanced prevalence in neuroscience of the analytic reductionist approach, focused on the cellular and molecular level, while the understanding of integrated brain activities remains flimsier. The decline of drug discovery output in the last decades, quite obvious in neuropharmacology, coincided with the advent of the single target-focused search of potent ligands selective for a well-defined protein, deemed critical in a given pathology. However, all the widespread neuro-psychic troubles are multi-mechanistic and polygenic, their complex etiology making unsuited the single-target drug discovery. An evolving approach, based on systems biology considers that a disease expresses a disturbance of the network of interactions underlying organismic functions, rather than alteration of single molecular components. Accordingly, systems pharmacology seeks to restore a disturbed network via multi-targeted drugs. This review notices that neuropharmacology in fact relies on drugs which are multi-target, this feature having occurred just because those drugs were selected by phenotypic screening in vivo, or emerged from serendipitous clinical observations. The novel systems pharmacology aims, however, to devise ab initio multi-target drugs that will appropriately act on multiple molecular entities. Though this is a task much more complex than the single-target strategy, major informatics resources and computational tools for the systemic approach of drug discovery are already set forth and their rapid progress forecasts promising outcomes for neuropharmacology.

背景与目标： ：Neuropharmacology在过去取得了几项重大成就，但最近几十年来在脑部疾病的药物治疗方面并未取得任何飞跃。而且，目前用于神经病学和精神病学的药物减轻了症状，同时几乎不能治愈任何疾病原因，这主要是因为大多数神经精神病学综合征的病因学知之甚少。这篇评论认为，这在很大程度上是由于分析还原论方法在神经科学中的不平衡流行所致，其集中在细胞和分子水平上，而对整合的大脑活动的理解仍然更加薄弱。在过去的几十年中，在神经药理学领域，药物发现产量的下降非常明显，这与对一种确定的蛋白质有选择性的有效配体的单一靶标集中搜索的出现相吻合，这被认为在给定的病理学中至关重要。但是，所有广泛存在的神经心理问题都是多机制的和多基因的，其复杂的病因使其不适用于单靶标药物的发现。一种基于系统生物学的不断发展的方法认为，疾病是对生物功能基础相互作用网络的一种干扰，而不是单个分子成分的改变。因此，系统药理学试图通过多靶点药物恢复受干扰的网络。该评论注意到神经药理学实际上依赖于多靶点药物，出现这种特征仅仅是因为这些药物是通过体内表型筛选选择的，或者是从偶然的临床观察中出现的。然而，该新颖的系统药理学旨在设计从头开始的多靶标药物，其将适当地作用于多个分子实体。尽管这是一项比单目标策略复杂得多的任务，但已经为药物发现的系统方法提出了主要的信息学资源和计算工具，并且它们的快速进展预示了神经药理学的前景。

BACKGROUND & AIMS: Applying the basic principles, therapy guides to our hypothetical cases can be constructed. The 60 year old man with postoperative abdominal perineal resection with hypertension and parkinsonism may well need a transurethral resection of the prostate; however, other options include decreasing his anticholinergic-type medications, such as antiparkinsonism medications, changing his hypertensive therapy from beta blockers such as propranolol and metoprolol to alpha blockers such as methyldopa and prazosin. Bethanacol would seldom be helpful alone, but with an alpha blocker could help if not contraindicated by the presence of vascular disease. The second example, a 45 year old woman with stress incontinence, may be assisted with improved storage by an anticholinergic agent, an alpha enhancer, a mucosal enhancer, and if pertinent, switching hypertensive therapy from an alpha blocker to a beta blocker. The last example, a T10 paraplegic with a spastic, hyperreflexic bladder, can have improved storage with anticholinergics, decreased sphincter tone with alpha blockers, as well as decreased sphincter tone with alpha blockers, as well as decreased spasms through suppression of hyperactive spinal cord activity with baclofen.

背景与目标： 运用基本原理，可以为我们的假设病例构建治疗指南。患有高血压和帕金森氏症的术后会阴腹部会阴切除术的60岁男性很可能需要经尿道前列腺电切术。但是，其他选择包括减少他的抗胆碱能型药物（例如抗帕金森病药物），将他的高血压治疗从β受体阻滞剂（如心得安和美托洛尔）改为α受体阻滞剂（如甲基多巴和哌唑嗪）。单独使用Bethanacol很少会有所帮助，但是如果没有血管疾病的禁忌，使用α受体阻滞剂可能会有所帮助。第二个例子是一名患有压力性尿失禁的45岁女性，可以通过抗胆碱能药，α增强剂，粘膜增强剂来改善储存，并在适当的情况下将高血压治疗从α阻滞剂转换为β阻滞剂。最后一个例子是截瘫的T10痉挛性，高反射性膀胱炎，使用抗胆碱能药物可改善储存，使用α受体阻滞剂可降低括约肌张力，使用α受体阻滞剂可降低括约肌张力，并通过抑制过度活跃的脊髓活动来减少痉挛用巴氯芬。

BACKGROUND & AIMS: :Single mammalian neurons can be isolated with adherent functional synaptic terminals using an enzyme-free, mechanical dissociation procedure. This allows investigations of the effects of presynaptic modulators of synaptic transmission with unprecedented ease and accuracy. Furthermore, single presynaptic terminals and boutons can be visualized using fluorescent markers and can also be focally stimulated with electrical pulses. In this article, the isolated-nerve-adherent-synaptic-bouton preparation and some examples of its general properties and uses are discussed.

背景与目标： ：单个哺乳动物神经元可以使用无酶，机械解离程序与附着的功能性突触末端分离。这允许以前所未有的简便性和准确性研究突触传递前突触调节剂的作用。此外，单个突触前的末端和钮扣可以使用荧光标记物进行可视化，也可以通过电脉冲进行局部刺激。在本文中，讨论了离体神经粘附突触bouton制剂及其一般性质和用途的一些实例。

BACKGROUND & AIMS: :This issue of the British Journal of Pharmacology is dedicated to reviews of the major animal models used in neuropharmacology to examine drugs for both neurological and psychiatric conditions. Almost all major conditions are reviewed. In general, regulatory authorities require evidence for the efficacy of novel compounds in appropriate animal models. However, the failure of many compounds in clinical trials following clear demonstration of efficacy in animal models has called into question both the value of the models and the discovery process in general. These matters are expertly reviewed in this issue and proposals for better models outlined. In this editorial, we further suggest that more attention be made to incorporate pharmacokinetic knowledge into the studies (quantitative pharmacology). We also suggest that more attention be made to ensure that full methodological details are published and recommend that journals should be more amenable to publishing negative data. Finally, we propose that new approaches must be used in drug discovery so that preclinical studies become more reflective of the clinical situation, and studies using animal models mimic the anticipated design of studies to be performed in humans, as closely as possible.

背景与目标： ：本期《英国药理学杂志》（British Journal of Pharmacology）致力于研究神经药理学中用于检查神经和精神疾病的药物的主要动物模型。几乎所有主要条件都经过审查。通常，监管机构要求在适当的动物模型中提供有关新化合物功效的证据。然而，在清楚地证明了动物模型中的功效之后，许多化合物在临床试验中的失败使人们对模型的价值和一般的发现过程都产生了疑问。本期将对这些问题进行专家审查，并概述更好的模型的建议。在这篇社论中，我们进一步建议将更多的药代动力学知识纳入研究（定量药理学）。我们还建议更加注意确保发布完整的方法学详细信息，并建议期刊应更适合发布负面数据。最后，我们建议在药物开发中必须使用新方法，以使临床前研究更能反映临床情况，并且使用动物模型进行的研究尽可能模仿拟在人体中进行的预期研究设计。

BACKGROUND & AIMS: :The place conditioning paradigm has proven successful in identifying the neural mechanisms of drug reinforcement. Two classes of drugs, opiates and psychomotor stimulants, have received the most study, and in each case an important role for DA neurons of the mesolimbic system has been established. Moreover, both receptor subtypes, D1 and D2, appear to be involved. Despite this progress, the substrates of drug reward are not completely understood. First, a role for DA has not been established for all stimulants: DA receptor blockade failed to affect conditioned place preferences produced by the stimulants methylphenidate, nomifensine, or bupropion. Second, preliminary evidence suggests that intact serotonergic transmission is important in morphine place conditioning, but a similar consistent finding has not been observed with amphetamine place conditioning. Further study may reveal an interesting dissociation of serotonin's role in the rewarding effects of psychomotor stimulants and opiates. Finally, the role of the opiate receptor subtype kappa is not known; also, the significance of the several anatomical sites that support opiate place conditioning remains unclear.

背景与目标： ：场所调节范例已被证明可以成功地识别药物增强的神经机制。研究最多的两类药物是阿片类药物和精神运动兴奋剂，在每种情况下，均已确立了中脑边缘系统DA神经元的重要作用。而且，两个受体亚型D1和D2似乎都参与了。尽管取得了这一进展，但尚未完全了解药物奖励的底物。首先，并不是所有兴奋剂都具有DA的作用：DA受体阻滞不能影响兴奋剂哌醋甲酯，诺米芬或安非他酮产生的条件性位置偏爱。第二，初步证据表明完整的血清素能传递在吗啡位置调节中很重要，但是在苯丙胺位置调节中未观察到类似的一致发现。进一步的研究可能揭示5-羟色胺在精神运动兴奋剂和鸦片制剂的奖励作用中的作用有一个有趣的分解。最后，阿片受体亚型κ的作用尚不清楚。同样，支持鸦片位置调节的几个解剖部位的意义仍然不清楚。

BACKGROUND & AIMS: :Venlafaxine (Effexor) is an effective antidepressant and has also been approved for the treatment of generalized anxiety disorder. Venlafaxine was initially characterized as an inhibitor of both serotonin (5HT) and norepinephrine (NE) uptake and was therefore termed a "dual uptake inhibitor." This chapter reviews data from both in vitro and in vivo studies regarding its effects on 5HT and NE neurotransmission. In addition, the effects of venlafaxine on other systems that may play a role in its therapeutic efficacy effects are described. The data indicate that venlafaxine is a relatively weak inhibitor of NE transport in vitro. In vivo studies indicate that venlafaxine selectively inhibits 5HT uptake at low therapeutic doses and inhibits both 5HT and NE uptake at higher therapeutic doses. This chapter concludes with a discussion of the effects of venlafaxine on various aspects of physiology.

背景与目标： ：Venlafaxine（Effexor）是一种有效的抗抑郁药，也已被批准用于治疗广泛性焦虑症。最初将文拉法辛表征为5-羟色胺（5HT）和去甲肾上腺素（NE）摄取的抑制剂，因此被称为“双重摄取抑制剂”。本章回顾了有关其对5HT和NE神经传递的影响的体内和体外研究数据。另外，描述了文拉法辛对可能在其治疗功效中起作用的其他系统的作用。数据表明文拉法辛是体外NE转运的相对较弱的抑制剂。体内研究表明，文拉法辛在低治疗剂量下选择性抑制5HT摄取，在高治疗剂量下同时抑制5HT和NE摄取。本章最后讨论了文拉法辛对生理学各个方面的影响。

BACKGROUND & AIMS: In this article we will review available evidence concerning the effects of forebrain catecholaminergic and cholinergic activity on verbal perseveration. The anatomy and physiology of these two major neuropharmacological systems make it likely that they influence speech and language functioning directly as well as the cognitive systems that have an indirect impact on speech and language functions. Both catecholaminergic and cholinergic agents have been shown to influence executive cognitive functions (ECFs) such as "resistance to interference" and "attentional switching" as well as mnemonic encoding and retrieval processes. The ECF effects are most likely mediated by prefrontal cortex; mnemonic processes are mediated by both prefrontal and temporal lobes. Although no full-scale clinical trials on the effects of pharmacological agents on verbal perseveration have been conducted as yet, existing preclinical trials suggest that both presynaptic and postsynaptic dopaminergic agents can reduce perseverative responding by increasing inhibitory control processes. Cholinesterase inhibitors and other cholinergic agents can reduce perseverative responding by reducing verbal intrusions.

背景与目标： 在本文中，我们将回顾有关前脑儿茶酚胺能和胆碱能活性对言语持久性影响的现有证据。这两个主要的神经药理学系统的解剖学和生理学使得它们有可能直接影响言语和语言的功能，以及对言语和语言功能产生间接影响的认知系统。儿茶酚胺能和胆碱能药物均已显示出影响执行认知功能（ECF），例如“抗干扰性”和“注意转换”以及助记符编码和检索过程。 ECF的作用很可能是由额叶前皮层介导的。助记过程由前额叶和颞叶介导。尽管尚未进行有关药理作用对言语持久性影响的全面临床试验，但现有的临床前试验表明，突触前和突触后多巴胺能药物均可通过增加抑制控制过程来降低持久性反应。胆碱酯酶抑制剂和其他胆碱能药物可通过减少言语侵扰来降低持久性反应。

BACKGROUND & AIMS: :We describe a functional profiling strategy to identify and characterize subtypes of neurons present in a peripheral ganglion, which should be extendable to neurons in the CNS. In this study, dissociated dorsal-root ganglion neurons from mice were exposed to various pharmacological agents (challenge compounds), while at the same time the individual responses of >100 neurons were simultaneously monitored by calcium imaging. Each challenge compound elicited responses in only a subset of dorsal-root ganglion neurons. Two general types of challenge compounds were used: agonists of receptors (ionotropic and metabotropic) that alter cytoplasmic calcium concentration (receptor-agonist challenges) and compounds that affect voltage-gated ion channels (membrane-potential challenges). Notably, among the latter are K-channel antagonists, which elicited unexpectedly diverse types of calcium responses in different cells (i.e., phenotypes). We used various challenge compounds to identify several putative neuronal subtypes on the basis of their shared and/or divergent functional, phenotypic profiles. Our results indicate that multiple receptor-agonist and membrane-potential challenges may be applied to a neuronal population to identify, characterize, and discriminate among neuronal subtypes. This experimental approach can uncover constellations of plasma membrane macromolecules that are functionally coupled to confer a specific phenotypic profile on each neuronal subtype. This experimental platform has the potential to bridge a gap between systems and molecular neuroscience with a cellular-focused neuropharmacology, ultimately leading to the identification and functional characterization of all neuronal subtypes at a given locus in the nervous system.

背景与目标： ：我们描述了一种功能分析策略，以识别和表征周围神经节中存在的神经元亚型，该亚型应可扩展至中枢神经系统中的神经元。在这项研究中，将来自小鼠的离解的背根神经节神经元暴露于各种药理剂（挑战化合物），同时通过钙成像同时监测> 100个神经元的单个反应。每个挑战化合物仅在背根神经节神经元的一个子集中引起反应。使用了两种一般类型的挑战化合物：改变细胞质钙浓度的受体激动剂（离子型和代谢型）（影响受体激动剂的挑战）和影响电压门控离子通道的化合物（膜电位挑战）。值得注意的是，后者是K通道拮抗剂，它在不同细胞中引起意想不到的不同类型的钙反应（即表型）。我们使用了各种挑战性化合物，以根据其共有和/或不同的功能性，表型特征来鉴定几种推定的神经元亚型。我们的结果表明，多种受体激动剂和膜电位挑战可应用于神经元群体，以识别，表征和区分神经元亚型。这种实验方法可以揭示质膜大分子的星座，这些星座在功能上耦合以赋予每种神经元亚型特定的表型特征。该实验平台具有弥合以细胞为中心的神经药理学的系统与分子神经科学之间的鸿沟的潜力，最终导致了神经系统中给定基因座上所有神经元亚型的鉴定和功能表征。

BACKGROUND & AIMS: :Central nervous system (CNS) drug development has been plagued by a failure to translate effective therapies from the lab to the clinic. There are many potential reasons for this, including poor understanding of brain pharmacokinetic (PK) and pharmacodynamic (PD) factors, preclinical study flaws, clinical trial design issues, the complexity and variability of human brain diseases, as well as species differences. To address some of these problems, we have developed a platform for CNS drug discovery comprising: drug screening of primary adult human brain cells; human brain tissue microarray analysis of drug targets; and high-content phenotypic screening methods. In this opinion, I summarise the theoretical basis and the practical development and use of this platform in CNS drug discovery.

背景与目标： ：中枢神经系统（CNS）药物开发一直困扰着未能将有效的治疗方法从实验室转换到临床的过程。造成这种情况的原因很多，其中包括对大脑药代动力学（PK）和药效学（PD）因素的了解不足，临床前研究存在缺陷，临床试验设计问题，人脑疾病的复杂性和变异性以及物种差异。为了解决其中一些问题，我们开发了CNS药物发现平台，该平台包括：对成人原代人脑细胞进行药物筛选；药物靶标的人脑组织微阵列分析；和高含量的表型筛选方法。根据这一观点，我总结了该平台在中枢神经系统药物发现中的理论基础以及该平台的实际开发和使用。

BACKGROUND & AIMS: :Buspirone is a clinically effective anxiolytic with a unique structure and pharmacology which distinguishes it from the benzodiazepines. It has been termed anxioselective because it lacks anticonvulsant, sedative, or muscle-relaxant properties. Preclinical evidence suggests it lacks potential for abuse or physical dependence and interacts minimally with CNS depressants such as alcohol. Rather than working through traditional benzodiazepine mechanisms, buspirone affects diverse aspects of the brain's neurochemical circuitry. For example, it exerts potent influences on the nigrostriatal and mesolimbic dopamine systems, the dorsal raphe serotonergic system, and the locus coeruleus noradrenergic system. Although without direct receptor interaction, potentiation of cholinergically mediated behavior and involvement with GABAergic neurotransmission have also been demonstrated.

背景与目标： ：丁螺环酮是一种临床有效的抗焦虑药，具有独特的结构和药理作用，使其与苯二氮卓类药物区别开来。由于缺乏抗惊厥，镇静或松弛肌肉的特性，因此被称为抗焦虑药。临床前证据表明，它缺乏滥用或身体依赖性的潜力，并且与中枢神经系统抑制剂（如酒精）的相互作用极小。丁螺环酮不会通过传统的苯二氮卓类机制起作用，而是会影响大脑神经化学回路的各个方面。例如，它对黑质纹状体和中脑边缘的多巴胺系统，背沟纹血清素能系统和蓝斑顽固性去甲肾上腺素能系统产生有效影响。尽管没有直接的受体相互作用，但胆碱介导的行为的增强和与GABA能神经传递的参与也已得到证实。

BACKGROUND & AIMS: :Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.

背景与目标： ：抗胆碱能药和促运动药是肠易激综合征（IBS）患者的主要治疗手段，尽管它们的疗效有限且副作用严重。这些药物的临床局限性是它们与各种受体的相对广泛和非特异性药理相互作用的结果。肠道生理学的最新进展已导致鉴定可能在IBS发病机理中起关键作用的各种受体靶标。寻求安全有效的IBS治疗的药物化学家正在开发针对许多这些特定受体的化合物。最新一代的抗胆碱能药，例如扎米芬那，达利福星和YM-905，可提供对毒蕈碱3型受体的选择性拮抗作用。 Tegaserod是一种选择性5-HT4部分激动剂，已在多项临床试验中进行了测试，可有效减轻腹痛，腹胀和便秘的症状。 Ezlopitant和nepadudant分别是1型和2型神经激肽受体的选择性拮抗剂，在减少肠道蠕动和疼痛方面显示出希望。 Loperamide是一种mu（mu）阿片类受体激动剂，对于腹泻为主要肠综合征的IBS腹泻患者（IBS-D）是安全有效的。 Fedotozine是一种κ（阿片）阿片受体激动剂，已在各种临床试验中用作内脏镇痛剂，但结果相矛盾。 Alosetron是5-HT3受体拮抗剂，已在IBS-D患者中显示出疗效，但上市后随访中发现的缺血性结肠炎事件导致其退出市场。靶向胆囊收缩素的化合物。 A，N-甲基-D-天门冬氨酸，α2-肾上腺素和促肾上腺皮质激素释放因子受体也进行了审查。

BACKGROUND & AIMS: :Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

背景与目标： ：体内技术的结果，尤其是自由移动大鼠的脑内微透析，提供了对儿茶酚胺能药物治疗ADHD的功效和安全性负责的潜在机制的见解。所审查的药物来自不同的药理学类别：精神刺激释放剂，例如d-苯异丙胺；心理刺激性再摄取抑制剂，例如dl-苏式-哌醋甲酯（dl-MPH）和非刺激性再摄取抑制剂，例如阿莫西汀。目前在治疗多动症方面效果最好的精神刺激药在体内对啮齿动物脑中的神经外儿茶酚胺浓度表现出以下特征：1）它们增强去甲肾上腺素和多巴胺在中枢神经系统中的外排和功能。 2）它们产生的多巴胺外排的增加不限于皮质区域。 3）它们起效迅速，对药物作用没有上限。 d-苯丙胺具有独立于神经元放电速率的机制，取代神经内的儿茶酚胺储存，延迟其再摄取并抑制单胺氧化酶的分解代谢。 dl-MPH具有神秘的神经外作用，它依赖于神经元的放电速率并由再摄取转运蛋白介导，但自相矛盾的是，其作用与d-苯异丙胺差不多。在安全方面，这些强大的儿茶酚胺作用也使精神兴奋剂容易受到虐待。由于功效和安全性来自相同的药理机制，因此尚不可能分离这两个成分。但是，每天一次的精神兴奋药制剂和前药赖斯氨苯丙胺的开发，改善了患者的依从性，并大大缩小了其转移/滥用的范围。这篇综述将讨论批准的儿茶酚胺能药物治疗多动症的体内药理作用及其对临床疗效和滥用的影响。

BACKGROUND & AIMS: :Several lines of evidence indicate that rats emit ultrasonic vocalizations (USVs) in response to a wide range of stimuli that are capable of producing either euphoric (positive) or dysphoric (negative) emotional states. On these bases, recordings of USVs are extensively used in preclinical studies of affect, motivation, and social behavior. Rat USVs are sensitive to the effects of certain classes of psychoactive drugs, suggesting that emission of rat USVs can have relevance not only to neurobiology, but also to neuropharmacology and psychopharmacology. This review summarizes three types of rat USVs, namely 40-kHz USVs emitted by pups, 22-kHz USVs and 50-kHz USVs emitted by young and adult animals, and relevance of these vocalizations to neuropharmacological studies. Attention will be focused on the issues of how rat USVs can be used to evaluate the pharmacological properties of different classes of drugs, and how rat USVs can be combined with other behavioral models used in neuropharmacology. The strengths and limitations of experimental paradigms based on the evaluation of rat USVs will also be discussed.

背景与目标： ：有几条证据表明，大鼠会发出超声波发声（USV），以响应能够产生欣快（积极）或烦躁（消极）情绪状态的各种刺激。在这些基础上，USV的录音被广泛用于情感，动机和社会行为的临床前研究。大鼠USV对某些类型的精神活性药物敏感，这表明大鼠USV的排放不仅与神经生物学有关，而且与神经药理学和心理药理学有关。这篇综述总结了三种大鼠USV，即幼犬发出的40 kHz USV，幼年和成年动物发出的22 kHz USV和50 kHz USV，以及这些发声与神经药理学研究的相关性。注意将集中在如何将大鼠USV用于评估不同类别药物的药理特性以及如何将大鼠USV与神经药理学中使用的其他行为模型结合的问题。也将讨论基于大鼠USV评估的实验范式的优势和局限性。

BACKGROUND & AIMS: The efficacy and reliability of using intranasal oxytocin (OT) to clinically enhance social functions remains undependable. We discuss the potential benefit of concurrent administration of OT and naloxone (NAL) to robustly modulate social behavior. We further suggest that combinatorial neuropharmacology approaches should exploit the interactions between OT and serotonin to regulate social functions.

背景与目标： 使用鼻内催产素（OT）来临床增强社会功能的功效和可靠性仍然不确定。我们讨论了同时使用OT和纳洛酮（NAL）来稳健地调节社会行为的潜在益处。我们进一步建议，组合神经药理学方法应利用OT和血清素之间的相互作用来调节社会功能。