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。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Neuropharmacological studies of Schistosoma mansoni were conducted in vitro using visual observations of motor activity and measurements of worm length and extracellular electrical activity. The instrumentation and methodology described quantitatively measure extracellular electrical potentials associated with motor activity, and provide a highly sensitive, objective technique for studying effects of antischistosomal compounds and for evaluating schistosomes as a model for neuropharmacological investigation. The visual motor and electrical responses of schistosomes to various pharmacological agents support earlier claims for the presence of an excitatory tryptaminergic system and an inhibitory cholinergic system. The stimulation of motor activity by 5-hydroxytryptamine was blocked by the antagonists metergoline and cyproheptadine in a dose-dependent manner. The hypermotility induced by cholinergic blockade (atropine or mecamylamine) or 5-hydroxytryptamine release (p-chlorophenylethylamine) was abolished by these antagonists. The cholinomimetic agents, acetylcholine, carbachol and arecoline, and the cholinesterase inhibitors neostigmine and metrifonate, caused a flaccid paralysis of schistosomes. Carbachol-induced paralysis was reversed by both the nicotinic cholinergic blocker, mecamylamine, and the muscarinic cholinergic blocker, atropine. This reversal occurred in a dose-dependent manner. It is suggested that the cholinoceptive site in S. mansoni has unique pharmacological properties, distinctly different from those in mammals. Dopamine, apomorphine, epinephrine and norepinephrine had little effect on schistosome motility, but produced marked increases in worm length. The dopaminergic antagonist, haloperidol, completely blocked the dopamine response. A broad range of putative amino acid neurotransmitters failed to alter schistosome motor activity. The simple nervous system of the schistosome appears to have many unique pharmacological features which may make it a useful model for the study of drugs for human use, as well as providing an effective point for chemotherapeutic attack.

背景与目标： ：曼氏血吸虫的神经药理研究是在体外进行的，采用运动活动的目测观察和蠕虫长度及细胞外电活动的测量。描述的仪器和方法定量地测量了与运动活动相关的细胞外电位，并为研究抗血吸虫病化合物的作用和评估血吸虫病作为神经药理学研究的模型提供了一种高度灵敏，客观的技术。血吸虫对各种药理剂的视觉运动和电反应支持了较早的关于存在兴奋性色胺能系统和抑制性胆碱能系统的主张。 5-羟色胺对运动活性的刺激被拮抗剂美特古林和赛庚啶阻断，呈剂量依赖性。这些拮抗剂消除了胆碱能阻滞（阿托品或美加明）或5-羟色胺释放（对氯苯基乙胺）引起的运动过快。拟胆碱药，乙酰胆碱，卡巴胆碱和槟榔碱，以及胆碱酯酶抑制剂新斯的明和美甲芬酯，导致血吸虫的松弛性麻痹。烟碱型胆碱能阻滞剂美卡明胺和毒蕈碱型胆碱能阻滞剂阿托品逆转了卡巴胆碱引起的瘫痪。这种逆转以剂量依赖性方式发生。有人提出曼氏葡萄球菌的胆汁感受性位点具有独特的药理特性，与哺乳动物的明显不同。多巴胺，阿扑吗啡，肾上腺素和去甲肾上腺素对血吸虫的蠕动影响不大，但蠕虫长度却明显增加。多巴胺能拮抗剂氟哌啶醇完全阻断了多巴胺反应。广泛的推定氨基酸神经递质未能改变血吸虫的运动活性。血吸虫的简单神经系统似乎具有许多独特的药理特性，这可能使其成为研究人类使用药物的有用模型，并为化学疗法的发作提供有效的方法。

BACKGROUND & AIMS: :Perspectives on the P300 event-related brain potential (ERP) are reviewed by outlining the distinction between the P3a and P3b subcomponents. The critical factor for eliciting P3a is how target/standard discrimination difficulty rather than novelty modulates task processing. The neural loci of P3a and P3b generation are sketched and a theoretical model is developed. P3a originates from stimulus-driven disruption of frontal attention engagement during task processing. P3b originates when temporal-parietal mechanisms process the stimulus information for memory storage. The neuropharmacological implications of this view are then outlined by evaluating how acute and chronic use of ethanol, marijuana, and nicotine affect P3a and P3b. The findings suggest that the circuit underlying ERP generation is influenced in a different ways for acute intake and varies between chronic use levels across drugs. Theoretical implications are assessed.

背景与目标： ：通过概述P3a和P3b子组件之间的区别，回顾了P300事件相关脑电势（ERP）的观点。引起P3a的关键因素是目标/标准区分难度而不是新颖性如何调制任务处理。绘制了P3a和P3b生成的神经基因座，并建立了理论模型。 P3a源于任务处理过程中刺激驱动的正面注意力参与的破坏。 P3b始于时顶机制处理用于记忆存储的刺激信息。然后，通过评估乙醇，大麻和尼古丁的急性和慢性使用如何影响P3a和P3b，概述了这种观点的神经药理学含义。这些发现表明，ERP产生的基础回路以不同的方式影响急性摄入，并且在不同药物的长期使用水平之间有所不同。对理论意义进行了评估。

BACKGROUND & AIMS: :In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the 'brain-gut axis' and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT(2B), 5-HT(7) and putative 5-HT(1p) receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.

背景与目标： ：最近，功能性胃肠道疾病（如肠易激综合征（IBS））的观念已发生根本性转变。现在认为这种疾病是严重的疾病，其特征是胃肠功能的神经元调节受到干扰。内脏超敏性的概念，“脑肠轴”中神经元网络的表征以及几种新型5-HT介导的机制的鉴定都为这一转变做出了贡献。在这里，我们回顾这些新机制中一些更有希望的机制（例如，涉及5-HT转运蛋白和5-HT（2B），5-HT（7）和推定的5-HT（1p）受体的机制）如何导致一系列第二代疗法，可能会彻底改变功能性胃肠道疾病，特别是IBS的治疗。

BACKGROUND & AIMS: :The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the effects that drugs can have on the function and composition of the gut microbiome. Both microbiota-mediated alterations in drug metabolism and drug-mediated alterations in the gut microbiome can have beneficial or detrimental effects on the host. Greater insights into the mechanisms driving these reciprocal drug-gut microbiota interactions are needed to guide the development of microbiome-targeted dietary or pharmacological interventions, which may have the potential to enhance drug efficacy or reduce drug side effects. In this review, we explore the relationship between drugs and the gut microbiome, with a specific focus on potential mechanisms underpinning the drug-mediated alterations on the gut microbiome and the potential implications for psychoactive drugs. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc.

背景与目标： 药物的命运和活性通常不仅取决于宿主本身，还取决于胃肠道中存在的微生物。已知肠道微生物组直接或间接地影响药物代谢。现在有更多证据表明药物可以对肠道微生物组的功能和组成产生影响。微生物在药物代谢中介导的改变和肠道微生物组中药物介导的改变都可以对宿主产生有益或有害的影响。需要对驱动这些相互的肠道菌群相互作用的机制有更深入的了解，以指导针对微生物组的饮食或药理干预措施的发展，这些措施可能具有增强药物疗效或减少药物副作用的潜力。在这篇综述中，我们探讨了药物与肠道微生物组之间的关系，并特别关注了支撑肠道微生物组药物介导的改变的潜在机制以及对精神活性药物的潜在影响。链接的文章：本文是“何时药理学遇到微生物组：治疗学的新目标？”主题部分的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc。