孤束核微注射5-羟色胺系统药物对大鼠睡眠-觉醒的影响及机制

目的:探讨孤束核(NST)微注射5-羟色胺(5-HT)系统药物对大鼠睡眠-觉醒的影响及其机制.方法:选用雄性SD大鼠,分7组,孤束核分别微注射5-羟基色氨酸(5-HTP)、非特异性5-HT受体阻断剂麦角新碱(MS)、5-羟色胺1A受体(5-HT1AR)激动剂8-OH-DPAT、5-HT1AR拮抗剂spiperone、cAMP、cAMP依赖的蛋白激酶A(PKA)拮抗剂H89和生理盐水(NS)后,采用光电脑电机记录脑电和肌电;采用免疫组化ABC法检测NST处5-HT1AR及5-HT表达情况.结果:与处理前相比,NS组和MS组大鼠睡眠-觉醒各期差异均无统计学意义,5-HTP组、8-OH-DPAT组和H89组给药后均显示觉醒期(W)缩短,异相睡眠(PS)延长(P<0.05或P<0.01),8-OH-DPAT组和H89组慢波睡眠(SWS)延长(P<0.01或P<0.05);spiperone组和cAMP组W延长(P<0.01或P<0.05),SWS缩短(P<0.01或P<0.05),spiperone组PS缩短(P<0.05).免疫组化结果显示,与NS组相比,5-HTP组的5-H T1AR阳性细胞数较多,5-HT能神经纤维末梢5-HT表达增强,MS组则结果相反.结论:作为睡眠诱发区,孤束核很可能是通过5一羟色胺作用于5-HT1AR,使cAMP生成减少,PKA磷酸化减少而发挥使觉醒减少、睡眠增加的生物学效应.     

经前期综合征肝气郁证大鼠血清对海马神经元5-HT1AR信号转导通路的影响

目的:研究经前期综合征(PMS)肝气郁证大鼠血清对大鼠原代海马神经元的5-羟色胺1A受体(5-HT1AR)信号转导通路相关基因5-羟色胺转运蛋白(SERT)、单胺氧化酶(MAO)-A、MAO-B表达的影响。方法:采用慢性束缚应激法复制PMS肝气郁证大鼠模型;高效液相色谱(HPLC)法检测血清中5-HT的含量;运用RT-PCR半定量和Westernblot法检测正常、模型、经前舒干预大鼠的血清对海马神经元中5-HT1AR、SERT、MAO-A、MAO-B表达的影响。结果:加入模型大鼠血清的大鼠海马原代神经细胞中MAO-A表达较正常大鼠显著升高(P<0.05),5-HT1AR、SERT表达显著降低(P<0.05),MAO-B表达无显著性差异。而加入经前舒干预大鼠血清后,5-HT1AR、SERT、MAO-A表达均趋于正常。结论:PMS肝气郁证的发生与海马神经元中MAO-A、SERT、5-HT1AR表达异常相关,可能是PMS肝气郁证发病的微观机制。     

脑室内注射5-羟色胺受体激动剂对正常清醒大鼠排尿反射的影响

目的 探讨脑室内注射5-羟色胺(5-HT)受体激动剂对正常清醒大鼠排尿反射的影响.方法 SD大鼠30只随机分为5组,将PE-50聚乙烯导管分别插入大鼠膀胱顶部及右侧脑室进行膀胱测压与药物注入.在脑室内分别注入5-HT、5-HTlA受体激动剂8-OH-DPAT、5-HT2受体激动剂1-甲基-5-HT、5-HT3受体激动剂...     

白术-木香药对对脾虚腹泻型肠易激综合征大鼠肠道菌群与短链脂肪酸代谢的调节作用

目的 探讨白术-木香药对对脾虚腹泻型肠易激综合征（IBS-D）大鼠肠道菌群与短链脂肪酸（SCFAs）代谢的调节作用。方法 使用番泻叶灌胃联合束缚刺激构建大鼠脾虚IBS-D模型。将造模成功的大鼠分为模型组、阳性对照组（匹维溴铵1.5 mg/kg）和白术-木香药对低、中、高剂量组（0.7、1.4、2.8 g/kg）,每组6只;另取6只健康大鼠作为空白对照组。空白对照组与模型组大鼠灌胃生理盐水,其余各组灌胃相应药液,每天1次,连续14 d。观察大鼠一般状况,并检测粪便含水量;检测大鼠肠道敏感性[以腹壁撤退反射（AWR）阈值评价]和肠道推进率;检测大鼠血清中5-羟色胺（5-HT）、P物质（SP）水平;观察大鼠结肠组织病理变化,检测大鼠结肠组织中5-HT3受体（5-HT3R）、5-HT4受体（5-HT4R）、5-HT转运体（SERT）蛋白表达水平。取空白对照组、模型组和白术-木香药对高剂量组大鼠粪便样本进行16S rRNA测序分析,并检测粪便中乙酸、丙酸、丁酸的含量。结果 与模型组比较,白术-木香药对中、高剂量组大鼠给药7、14 d后的体重,粪便含水量,AWR阈值,结肠组织中5-HT4R、SER...     

5-HT受体激动剂和拮抗剂及其在功能性胃肠病中的应用

5-羟色胺（5-hydroxytryptamine，5-HT）又称血清素（serotonin），是重要的神经递质，人体内95％的5-HT在胃肠道的肠嗜铬细胞（enterochromaffin cells，EC）及肠神经元中合成，5-HT通过与其受体相互作用，在胃肠道动力、感觉和分泌中发挥重要作用。5-HT受体超家族可分为7种亚型（5-HT1-7受体）和更多的亚亚型。胃肠道内至少有5种受体，     

5-羟色胺与创伤后应激障碍的研究进展

创伤后应激障碍(posttraumatic stress disorder,PTSD)是当机体遭受威胁生命或者强烈精神创伤后发生的疾病。近年来研究发现,5-羟色胺(5-HT)可能通过5-羟色胺转运体 (SERT)、5-HT受体(主要包括5-HT 1A 、5-HT1B、5-HT2A和5- HT2C受体),以及多巴胺、去甲肾上腺素等神经递质相互作用,参与PTSD的发生,该文就此进行综述。     

5-羟色胺（5-HT）1A受体配体的研究进展

5-羟色胺（5-HT）是重要的神经递质，5-HT受体（5-HTR）在认知、情感等众多神经活动中发挥着重要作用，是重要的药物靶标。5-HT1A受体（5-HT1AR）是众多5-HTR亚型中研究最为广泛和深入的一类受体，研究5-HT1A受体配体（5-HT1ARL）对于临床上治疗焦虑、抑郁、疼痛等疾病都具有重要的价值。该文主要从5-HT1ARL结构类型的角度综述5-HT1ARL的最新研究进展，并简要介绍定向多靶标配体的研究成果，展望5-HT1ARL药物的开发前景。     

茶色素对吗啡成瘾小鼠脑内去甲肾上腺素、多巴胺、5-羟色胺和β-内啡肽的影响

目的:探索茶色素对吗啡依赖小鼠脑内去甲肾上腺素(NE)、多巴胺(DA)、5-羟色胺(5-HT)和β-内啡肽(β-EP)的影响。方法:建立吗啡依赖模型,采用催促戒断治疗实验测定小鼠跳跃反应次数。运用高效液相法测定下丘脑,脑干和大脑皮质内NE、DA、5-HT含量,采用放射免疫法测定大脑皮质内β-EP含量。结果:茶色素12.5,25,50,100 mg.kg-1组均显著降低吗啡依赖小鼠的跳跃次数。降低吗啡依赖小鼠下丘脑中NE和DA的含量。降低吗啡依赖小鼠大脑皮质内β-EP含量。但对下丘脑,脑干和大脑皮质内的5-HT含量没有明显影响。结论:茶色素能降低吗啡依赖小鼠的跳跃次数,其机制可能与茶色素降低吗啡依赖小鼠下丘脑中NE和DA及大脑皮质β-EP含量相关。     

玉屏风散对抽动模型大鼠的影响

目的：多发性抽动症（tourette syndrome,TS）是一种慢性神经精神障碍性疾病,临床表现为不自主的、反复的肌肉抽动引发的运动性抽动和发生性抽动,中医药治疗抽动症有明显优势。本文探讨玉屏风散对脂多糖（Lipopolysaccharides,LPS）联合1-（2,5-dimethoxy-4-iodo pheny l）-2-aminopropane（DOI）致大鼠抽动症（TS）的改善作用及其机制。方法：TS模型用ip DOI与LPS联合诱导的方法,分为5组：空白组、模型组、硫必利（15 mg·kg-1）组,玉屏风散高、低剂量（6.5、3.25 g·kg-1）组。末次给药24 h后做行为学检测。采用ELISA检测大脑纹状体、血清炎症因子白介素-6（interleukin-6,IL-6）、白介素-1β（interleukin-1β,IL-1β）、肿瘤坏死因子a（tumor necrosis factor-α,TNF-α）。采用Western Blot 技术检测纹状体TLR/NF-κB信号蛋白表达水平。采用免疫组化技术检测纹状体P-NF-κB P65蛋白表达。结果：玉屏风散能显著改善DOI联合LPS致抽动症大鼠的行为学征象,减少抽动症大鼠血清、纹状体炎症因子水平,抑制抽动症大鼠纹状体TLR/NF-κB信号激活。结论：玉屏风散能显著缓解DOI联合LPS诱导的大鼠抽动症,其机制与抑制纹状体TLR/NF-κB信号激活相关。     

以5-羟色胺2A受体为靶点的抗抑郁药研究进展

抑郁症的发病机制非常复杂，至今尚未完全阐明。大量临床及临床前研究表明，5-羟色胺(5-HT)能神经功能障碍可能是导致抑郁症的关键因素之一。在5-HT神经系统中，除5-羟色胺转运体(SERT)外，有多种5-HT受体亚型与抑郁症有关，尤以5-HT_1A及5-HT_2A受体与抑郁症关系最为密切。5-HT_2A受体在大脑中广泛分布，是调节情绪的重要物质基础，对情绪、感知的调控具有重要作用。5-HT_2A受体可以直接或间接调节单胺类递质释放，调节脑中单胺类递质水平，参与抑郁症发病过程。5-HT_2A受体拮抗剂可以增强5-羟色胺再摄取抑制剂等抗抑郁药对难治性抑郁症的治疗效果并减少性功能障碍及睡眠障碍等不良反应。目前有不少以5-HT_2A受体为靶点的抗抑郁药应用于临床，也有大量化合物处于临床及临床前研究。该文对5-HT_2A受体与抑郁症的关系及以5-HT_2A受体为靶点的抗抑郁药研究进展进行简要综述，以期为新型抗抑郁药物的研发提供参考。     

Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette syndrome: clues from an in vivo neurochemistry study with PET.

Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-R's), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DA(rel)) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DA rel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D(2)-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA rel and 5-HT2A BP, when compared with TS-OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DA rel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT2AR in individuals with TS who had increased DA rel, suggest a condition of increased phasic DA rel modulated by low 5-HT in concomitant OCD.     

L-5-HTP facilitates the electrically stimulated flexor reflex in pithed rats: evidence for 5-HT2-receptor mediation

Different serotonin (5-HT) receptor agonists were tested on the electrically stimulated flexor reflex in pithed rats. The 5-HT2 receptor agonist, (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) [+/-)DOI), the mixed 5-HT1/5-HT2 receptor agonist, quipazine, and the 5-HT precursor, l-5-HTP, showed agonistic activity upon intravenous injection while 5-HT was without effect. A combination of the peripheral decarboxylase inhibitor, Ro 4-4602 (benzerazide), the specific 5-HT-uptake inhibitor, citalopram, and l-5-HTP induced a prolonged (greater than 3 h) increase of the flexor reflex in pithed rats. Different compounds were tested for an inhibitory effect against this l-5-HTP-induced flexor reflex. The 5-HT2 antagonists (ketanserin, methergoline and methiothepin) were potent antagonists. (-)Alprenolol (5-HT1A and 5-HT1B receptor antagonist) and the 5-HT3-receptor antagonist, ICS 205-930, were without an antagonistic effect. The inhibitory potencies in the reflex model (l-5-HTP, citalopram and Ro 4-4602) were significantly correlated (r = 0.83, P less than 0.01, r2 = 0.69) with the potencies to inhibit l-5-HTP-induced head twitches and quipazine-induced head twitches (r = 0.81, P less than 0.01, r2 = 0.66). There was less correlation (r = 0.75, P less than 0.01, r2 = 0.56) with the affinities for 5-HT2 receptors in vitro. There was no significant correlation between inhibitory potencies in the reflex model and affinities for dopamine (DA) D-2 receptors or alpha 1-adrenoceptors (r2 = 0.13 and 0.14, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function

Variability in expression of the 5-HT transporter (5-HTT) gene in the human population has been associated with a range of behavioural phenotypes. The underlying mechanisms are unclear but may involve changes in 5-HT receptor levels and/or signalling. The present study used a novel 5-HTT overexpressing transgenic mouse to test the hypothesis that variability in 5-HTT expression may alter 5-HT(2A) receptor function. In wildtype mice, the 5-HT(2) receptor agonist DOI increased regional brain mRNA expression of two immediate early genes (c-fos and Arc), and induced head twitches, and both effects were abolished by pre-treatment with the 5-HT(2A) receptor antagonist MDL 100907. In 5-HTT overexpressing mice, DOI induced a greater increase in both c-fos and Arc mRNA expression in cortical brain regions, and more head twitches, compared to wildtype mice. Autoradiographic and in situ hybridisation experiments showed that 5-HT(2A) receptor binding sites and 5-HT(2A) receptor mRNA did not differ between transgenic and wildtype mice. Finally, the transgenic mice had lower regional brain 5-HT levels compared to wildtype mice. This depletion of 5-HT may underpin the increase in 5-HT(2A) receptor function because in wildtype mice 5-HT depletion using the 5-HT synthesis inhibitor, p-chlorophenylalanine, enhanced the head twitch response to DOI. These data demonstrate that elevated 5-HTT expression is accompanied by increased 5-HT(2A) receptor function, an effect possibly mediated by decreased availability of synaptic 5-HT. Variation in levels of 5-HTT expression may therefore be a source of variability in 5-HT(2A) receptor function, which may be an important modifier of 5-HTT-linked phenotypes.     

Effects of MDMA on Extracellular Dopamine and Serotonin Levels in Mice Lacking Dopamine and/or Serotonin Transporters

3,4-Methylendioxymethamphetamine (MDMA) has both stimulatory and hallucinogenic properties which make its psychoactive effects unique and different from those of typical psychostimulant and hallucinogenic agents. The present study investigated the effects of MDMA on extracellular dopamine (DA(ex)) and serotonin (5-HT(ex)) levels in the striatum and prefrontal cortex (PFC) using in vivo microdialysis techniques in mice lacking DA transporters (DAT) and/or 5-HT transporters (SERT). subcutaneous injection of MDMA (3, 10 mg/kg) significantly increased striatal DA(ex) in wild-type mice, SERT knockout mice, and DAT knockout mice, but not in DAT/SERT double-knockout mice. The MDMA-induced increase in striatal DA(ex) in SERT knockout mice was significantly less than in wildtype mice. In the PFC, MDMA dose-dependently increased DA(ex) levels in wildtype, DAT knockout, SERT knockout and DAT/SERT double-knockout mice to a similar extent. In contrast, MDMA markedly increased 5-HT(ex) in wildtype and DAT knockout mice and slightly increased 5-HT(ex) in SERT-KO and DAT/SERT double-knockout mice. The results confirm that MDMA acts at both DAT and SERT and increases DA(ex) and 5-HT(ex).     

MDMA的神经毒性及SERT mRNA的表达

目的 :探讨MDMA的神经毒性及SERTmRNA的表达。方法 :设立对照组和实验组 ,实验组给予MDMA(2 0mg·kg- 1 ,每日 2次 ,ip ,连续 4d) ,对照组给予等体积生理盐水。采用高效液相色谱法测定不同脑区的DA和 5 -HT含量 ,原位杂交方法检测SERTmRNA的表达。结果 :给予MDMA后 ,大鼠额叶皮层、海马和纹状体的 5 -HT下降 (P <0 0 0 1) ,SERTmRNA的表达明显减少 (P <0 0 0 1)。结论 :MDMA对中枢 5 -HT系统有明显的神经毒性 ,导致SERTmRNA表达下调。     

Brain serotonin metabolism with relation to the head twitches elicited by lithium in combination with reserpine in mice.

Lithium alone, which scarcely induced head twitches, did not affect brain 5-hydroxytryptamine (5-HT) levels but increased 5-hydroxyindoleacetic acid (5-HIAA) levels. However, the combined use of lithium chloride (2 mEq/kg x 5, SC) and reserpine (5 mg/kg, SC) administered hourly markedly elicited the head twitches, together with the pronounced decrease of 5-HT levels and increase of 5-HIAA levels as similarly seen by reserpine alone. Pretreatment with p-chlorophenylalanine (PCPA) strongly potentiated the twitches elicited by the combined administration of lithium and reserpine, along with inducing the significant decrease of 5-HT levels and no change of 5-HIAA levels as compared with those levels in the PCPA-treated mice. The results imply that lithium produces the head twitches in the presence of reserpine, and an increase of 5-HIAA or a decrease of 5-HT levels do not necessarily interfere with the incidence of the twitches, and that the receptor sensitivity to 5-HT is strongly involved in the incidence of the head twitches.     

Functional interactions between 5-HT2A and presynaptic 5-HT1A receptor-based responses in mice genetically deficient in the serotonin 5-HT transporter (SERT)

Background and purpose:

Despite decreased presynaptic 5-HT_1A and altered 5-HT_2A receptor function in genetically-deficient serotonin (5-HT) transporter (SERT) mice, the 5-HT_1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100635) still induced head twitches in these mice, a well-established 5-HT_2A receptor-mediated response.

Experimental approach:

Interactions between 5-HT_1A and 5-HT_2A receptors were assessed using the head-twitch response following 5-HT_1A and 5-HT_2A receptor agonists and antagonists in SERT wild-type (+/+), heterozygous (+/−), and knockout (−/−) mice. The role of brain 5-HT availability in WAY 100635 induced head twitches was also examined.

Key results:

WAY 100635 induced head twitches in a SERT gene-dose dependent manner, inducing 5-fold more head twitches in SERT −/− versus SERT +/+ mice. In SERT −/− mice, inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA) markedly depleted tissue 5-HT in all five brain areas examined and abolished WAY 100635 induced head twitches. Further, the selective 5-HT reuptake inhibitor fluvoxamine increased WAY 100635 induced head twitches in SERT +/+ and +/− mice. Head twitches following the 5-HT_2A receptor agonist (+/−)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) were robust in SERT +/+ and +/− mice but much reduced in SERT −/− mice. DOI-induced head twitches were decreased by the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in SERT +/+ and +/− mice. All drug-induced head twitches were blocked by the 5-HT_2A receptor antagonist a-Phenyl-1-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939).

Conclusions and implications:

These data show that indirect activation of 5-HT_2A receptors via blockade of presynaptic 5-HT_1A receptors potentiated head-twitch responses, suggesting functional interactions between these receptors, interactions affected by altered 5-HT availability. Our findings strongly support the correlation of WAY 100635 induced head twitches with increased 5-HT availability, induced genetically or pharmacologically.     

人参、银杏叶提取物对β-淀粉样蛋白_(1-40)毒性损伤大鼠全脑神经递质的影响

目的探讨给予人参、银杏叶提取物(脑维康)前后,β-淀粉样蛋白(β-amyloid peptide,Aβ)1-40毒性损伤大鼠全脑乙酰胆碱、单胺类递质及其代谢产物水平的变化和可能机制。方法以双侧海马CA1区注射Aβ1-40(每侧4 g.L-1)大鼠为模型,给药组大鼠每天灌胃给予脑维康(15.5、31、62mg.kg-1)4 wk。以改进的柱前、柱后双酶柱结合高效液相电化学方法检测大鼠全脑乙酰胆碱含量,以高效液相电化学方法检测大鼠全脑单胺类神经递质及其代谢产物的含量。结果双侧海马注射Aβ1-404 wk后,大鼠全脑乙酰胆碱、5-羟色胺含量明显降低(P<0.05~0.01),多巴胺、去甲肾上腺素表现下降趋势。给药4 wk后,脑维康各给药组大鼠全脑乙酰胆碱含量较模型组大鼠升高(P<0.05~0.01),多巴胺、5-羟色胺水平无变化,高香草酸、5-羟吲哚乙酸水平呈下降趋势,其中脑维康15.5 mg.kg-1组高香草酸含量下降(P<0.05)。结论脑维康可升高Aβ1-40毒性损伤大鼠脑内的乙酰胆碱水平,对单胺类递质代谢有一定的调节作用。该药改善大鼠学习记忆损伤的机制可能与其保护脑内胆碱能和单胺能系统或干预神经递质的合成、摄取和降解等作用有关。     

Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit

Systemic administration of the 5-HT(2A/2C) agonist DOI [(1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride] in rabbits elicits head bobs and body shakes, which are mediated by 5-HT(2A) and 5-HT(2C) receptors, respectively. This study was designed to determine whether the receptors mediating these behaviors are primarily located in the brain or in the periphery. Systemic administration of the peripheral 5-HT(2A/2C) antagonist xylamidine 30 min before systemic DOI challenge attenuated DOI-elicited body shakes by 50% without an effect on head bobs, suggesting a central origin for head bobs and a partial peripheral and a partial central origin for body shakes. Central administration of DOI into the lateral ventricle (ICV) elicited head bobs but not body shakes, demonstrating that the receptors mediating head bobs are centrally located. Pretreatment with ICV xylamidine blocked head bobs elicited by ICV DOI, indicating that the lack of inhibition, when systemically administered, is due to xylamidine's failure to reach central receptors. ICV pretreatment with the 5-HT(2A) receptor antagonist ketanserin inhibited ICV DOI-elicited head bobs establishing that 5-HT(2A) receptors activation elicits head bobs. In conclusion, 5-HT(2A) receptors mediating head movements are located in the brain whereas 5-HT(2C) receptors mediating the body movements appear to be located at different central sites as well as in the periphery.     

Lu AA21004, a novel multimodal antidepressant,produces regionally selective increases of multiple neurotransmitters—A rat microdialysis and electrophysiology study

The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT_1A, 5-HT_1B, 5-HT₃, and 5-HT₇ receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT₃ and 5-HT₇ receptor antagonism, 5-HT_1B receptor partial agonism, 5-HT_1A receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT₃, 5-HT_1B and 5-HT_1A receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations.