黑质内注射GABA对帕金森病模型大鼠行为影响的研究

为观察中枢神经递质 GABA对帕金森病模型大鼠旋转行为的影响 ,采用单侧黑质致密部注射 6-羟基多巴胺 ( 6-OHDA)选择性损毁黑质多巴胺 ( DA)能神经元的方法建立帕金森病大鼠模型 ,并在损伤侧黑质网状部 ( SNr)埋置不锈钢套管。术后一周经腹腔注射阿朴吗啡诱发帕金森病模型大鼠向健侧旋转后 ,再经套管微量注射不同浓度的 GABA。结果显示 ,黑质内注射不同浓度的 GABA均可加重帕金森病模型大鼠的旋转行为 ,且旋转持续时间延长。     

慢病毒介导的新型Tet-On系统大鼠GDNF和TH双基因脑内转移对帕金森病大鼠模型的保护作用

目的探讨慢病毒介导的新型Tet-On系统大鼠胶质细胞源性神经营养因子(GDNF)基因和酪氨酸羟化酶(TH)双基因直接转移对帕金森病(PD)大鼠的保护作用。方法将携带TH、GDNF基因并含启动子为Palb的四环素应答元件的慢病毒(Lv-TH-GDNF)和四环素反式作用子rtTA2s-M2病毒共同注射到SD大鼠左侧纹状体,用强力霉素(DOX)诱导大鼠目的基因GDNF和TH的表达。1周后在大鼠的同侧纹状体注射6-羟基多巴胺(6-OHDA)损毁纹状体的DA能神经元。通过旋转行为、黑质TH免疫组化染色以及高效液相色谱-电化学方法(HPLC-ECD)检测纹状体DA含量评估其保护效应;通过RT-PCR、免疫印迹观察Lv-TH-GDNF在脑内的表达。实验与健康对照组、磷酸缓冲液(PBS)对照组进行比较。结果在6-OHDA损伤后4周,Lv-TH-GDNF+rt-TA2s-M2+DOX组大鼠阿扑吗啡诱发的旋转效应均明显低于PBS对照组(P<0.01),损毁侧的的黑质区TH阳性细胞表达强度、纹状体DA含量均明显高于PBS对照组(P<0.01),但二者均低于健康对照组(P<0.01)。RT-PCR、免疫印迹结果显示,与PBS对照组比较,Lv-TH-GDNF+rtTA2s-M2+DOX组大鼠纹状体TH、GDNF基因的表达明显增高(P<0.01)。结论慢病毒介导的新型Tet-On系统大鼠GDNF和TH双基因脑内直接转移,在强力霉素诱导下可减缓6-OHDA诱发的大鼠DA能神经元进行性变性,具有保护作用。     

大鼠黑质致密部注射6-羟基多巴胺制作帕金森病模型成模率的MRI分析

目的 从行为学及磁共振成像(MRI)表现上评价6-羟荩多巴胺(6-OHDA)单侧毁损大鼠黑质致密部建立偏侧帕金森病(PD)模型的方法.方法 70只SD大鼠随机分为3组:A组,30只,15μg/3μl黑质致密部(SNc)单点注射;B组,30只,30μg/6μISNc单点注射;C组10只6μl含0.2%抗坏血酸的生理盐水SNc单点注射.术后不同时期观察阿扑吗啡(APO)腹腔注射诱导的大鼠旋转行为.6周后各组随机选取部分成模与非成模大鼠在高场强MRI下活体检测,观察大鼠颅内毁损情况.结果 A、B组大鼠6-OHDA毁损黑质后,大部分成模大鼠在第3天可以检测到稳定的旋转(＞210 r/30min),其余成模大鼠在第14天可以检测到稳定的旋转.两组成模率相仿,成模率高达76.4%.第6周,MRI显示成模大鼠穿刺针道恰位于黑质部,而非成模大鼠穿刺针道偏离黑质部.结论 应用6-OHDA单侧毁损大鼠黑质致密部可以高效、简便、稳定地制作PD大鼠模删;MRI检测可以客观评价其成模质量.     

左旋千金藤碱对大鼠旋转模型的作用

大鼠脑内单侧黑质注射6羟基多巴胺(6OHDA)后,受损侧纹状体DA及其代谢物二羟苯乙酸和高香草酸含量分别下降88.4%,81.0%和60.1%。5HT与对侧相比略有增加(+13%),5羟吲哚醋酸无显著差异,提示6OHDA选择性地损毁了单侧黑质—纹状体DA神经通路。皮下注射阿朴吗啡(APO)后能诱发损伤大鼠向健侧方向旋转。阿朴啡类生物碱(1-STP)(10mg/kg)能拮抗APO的上述旋转作用,增大剂量(15mg/kg)作用增强,呈剂量—效应依赖关系。结果提示1-STP具有突触后DA受体阻滞作用。     

毛钩藤碱对6-羟基多巴胺诱导的帕金森病模型大鼠神经保护作用及机制研究

目的 探讨毛钩藤碱对帕金森病(Parkinson′s disease, PD)模型大鼠的神经保护作用及机制。方法 采用右侧中脑黑质致密部注射6-羟基多巴胺(6-hydroxydopamine, 6-OHDA)制备大鼠PD模型,将建模成功的PD大鼠随机分为模型组、美多芭组、毛钩藤碱低剂量和高剂量组,同时设置正常对照组,每组12只。给予相应药物灌胃干预,每天1次,连续1个月。采用旋转试验、转棒试验和Morris水迷宫试验检测大鼠行为学变化;HE染色法观察大鼠右侧中脑黑质病理学变化;高效液相色谱法(HPLC)检测大鼠右侧纹状体中多巴胺(dopamine, DA)水平;免疫组化法检测大鼠右侧中脑黑质中多巴胺能神经元标志物酪氨酸羟化酶(tyrosine hydroxylase, TH)表达;ELISA法检测大鼠右侧中脑黑质IL-6、IL-1β和TNF-α水平;Western blot检测大鼠右侧中脑黑质中NF-κB p65、NF-κB抑制因子α(IκBα)、p-IκBα等蛋白表达水平。结果 毛钩藤碱能显著改善PD大鼠行为学障碍及中脑黑质损伤,升高纹状体DA含量及中脑黑质中TH阳性神经元数量和Iκ...     

依达拉奉对6-OHDA诱导的帕金森病大鼠黑质纹状体神经元的保护作用

目的探讨依达拉奉对6-羟基多巴胺(6-OHDA)诱导的帕金森病(PD)大鼠模型的神经保护作用及其作用机制。方法用6-OHDA制备SD大鼠PD模型,观察依达拉奉对PD模型大鼠行为学改变、酪氨酸羟化酶(TH)阳性细胞数和超氧化物歧化酶(SOD)、羟自由基(.OH)的影响。结果依达拉奉呈剂量依赖性减少阿朴吗啡(APO)诱发的大鼠PD模型旋转次数(P<0.01);依达拉奉(3mg/kg×14d,×28d)可阻止模型大鼠TH阳性细胞的减少,增加大鼠黑质纹状体SOD含量(P<0.05),降低.OH含量。结论依达拉奉增加大鼠黑质纹状体SOD含量,降低.OH含量,对6-OHDA诱导的PD动物模型具有神经保护作用。     

左旋千金藤立定和DA受体激动剂对6-OHDA损毁大鼠旋转行为和基底核神经元放电的作用部位(英文)

目的:确定l-SPD在基底神经核的作用部位。方法:6-OHDA损毁大鼠单侧黑质致密区(SNC),核团内微注或微电泳给予l-SPD或DA激动剂,作旋转实验和神经元放电记录。结果:1)大鼠纹状体损毁侧DA免疫反应物减少。2)新纹状体或黑质网质区(SNR)内微注DA激动剂Apo(D_1/D_2),SK＆F38393(D_1)或SPD引起大鼠强烈旋转,而微注Ly171555(D_2)于SNR或DA激动剂和l-SPD于苍白球(GP)均不引起旋转。卡英酸进一步损毁GP或脚间核(EP),DA激动剂或l-SPD诱发大鼠旋转显著下降。3)微电泳Apo或SPD引起SNR神经元放电,但对GP神经元无效。结论:l-SPD诱发大鼠旋转和神经元放电由D_1受体介导,基底核新纹状体和SNR是其作用部位,而不是GP。通过SNR的直接环路在旋转行为中起重要作用。     

慢病毒介导新型Tet-On系统调控大鼠GDNF和TH双基因表达对帕金森病大鼠的实验研究

目的观察改良Tet-On系统修饰慢病毒(Lv-TH-GDNF)目的基因的表达调控及纹状体内直接转移对帕金森病(PD)大鼠的作用。方法 1用Lv-TH-GDNF与rt TA2s-M2病毒感染He La细胞,免疫印迹法检测强力霉素(Dox)对TH、GDNF基因表达的调控。2用Lv-TH-GDNF与rt TA2sM2病毒共同注射到PD大鼠患侧纹状体,Dox诱导目的基因表达。通过观察阿扑吗啡(APO)诱导旋转行为、黑质多巴胺能神经元数量、患侧纹状体DA、DOPAC含量评估Lv-THGDNF治疗效应;通过移植侧纹状体内TH与GDNF蛋白量评估外源基因在体内的表达。结果 1在体外He La细胞实验,仅Dox阳性组见TH、GDNF蛋白条带。2在动物体内实验,病毒移植4周后,与PBS对照组相比,仅病毒+Dox组大鼠旋转行为明显改善(P<0.01),损伤侧黑质致密部TH阳性细胞数、纹状体DA、DOPAC含量及TH和GDNF蛋白量明显增高(P<0.01)。结论新型Tet-On系统修饰的Lv-THGDNF目的基因表达受四环素类抗生素调控,在体外实验未见基础活动,且纹状体内直接转移对PD大鼠有一定治疗作用。     

左旋千金藤立定诱导6-羟基多巴胺损毁大鼠的纹状体Fos、前脑啡肽mRNA、前强啡肽mRNA表达与旋转行为的关系(英文)

目的:研究左旋千金藤立定(SPD)调节6-羟基多巴胺(6-OHDA)损毁大鼠纹状体的Fos、前脑腓肽(PENK)和前强啡肽(PDYN)mRNA表达水平与旋转行为的关系.方法:用免疫细胞化学法观察Fos表达,用地高辛非同位素法标记的寡核苷酸探针检测纹状体PENK和PDYN mRNA,进行图像处理作半定量分析.结果:(1)SPD给予1,3,7 d后,损毁大鼠旋转行为仍维持在高水平;(2)SPD诱导双侧纹状体Fos显著表达,尤以损侧为甚.SPD重复应用使双侧纹状体的Fos诱导表达下降,尤以健侧为显著;(3)与健侧相比,损毁侧纹状体的PENK mRNA表达水平增加非常显著.SPD重复应用7 d,使这种增加的PENK mRNA水平明显下降.同时,SPD也使健侧PENK mRNA水平降低.然而,6-OHDA损毁和SPD处理对双侧纹状体的PDYN mRNA水平无明显影响.结论:SPD激发6-OHDA损毁大鼠旋转行为维持在高水平,与损侧纹状体的Fos表达和PENK mRNA水平下降是同步的.但是,6-OHDA损毁和SPD均未显示出对PDYN mRNA表达的影响.     

培高利特对帕金森病大鼠保护作用的实验研究

目的　探讨多巴胺受体激动剂培高利特 (pergolide)对帕金森病 (PD)模型大鼠的抗氧化作用及其机制。方法　Wistar大鼠随机分为 4组 (对照组和 3个实验组 ) ,实验组预先于腹腔内分别注射培高利特 (1 0mg·kg-1)、选择性D2 受体拮抗剂氨黄酰基苯甲酰胺化合物 (Sulpiride ,2 5mg·kg-1)及培高利特 +Sulpiride。各组预处理均 1次 /天 ,连续 7d后 ,每组大鼠各取 6只分离纹状体 ,测定抗氧化物SOD及GSH活性。各组所剩大鼠则通过立体定位注射 6 羟基多巴胺 (6 OHDA)制作PD模型 ,两周后比较各组阿朴吗啡诱导的旋转行为 ,并取损伤侧纹状体测定多巴胺 (DA)及其代谢产物多巴克 (DOPAC)、高香草酸 (HVA)的含量。结果　大鼠预先连续注射培高利特 7天 ,可明显增强纹状体SOD及GSH的活性 (P <0 0 5 ) ,并对抗 6 OHDA损伤后纹状体DA及其代谢产物含量的下降 (P <0 0 1) ,降低阿朴吗啡诱导的旋转行为 (P <0 0 5 )。而同时应用Sulpiride可抑制培高利特的促纹状体抗氧化作用 ,并消除其对DA能神经元的保护效应。结论　培高利特可通过增加纹状体抗氧化能力 ,对纹状体DA能神经元提供保护作用 ,其机制可能主要与刺激DAD2 受体有关。     

Reserpine-induced rigidity in rats: drug effects on muscle tone from corpus striatum and nucleus accumbens

A study of the pathophysiological mechanisms of reserpine rigidity with the aid of a mechanographic method for the quantification of muscle tone. Apomorphine was used as a test substance to reduce reserpine rigidity by stimulation of dopamine receptors. Some experiments were made with additional drug treatment in an attempt to ascertain the dopaminergic specificity of the test. Apomorphine injected bilaterally to the corpus striatum has been shown to counteract the rigidity [6]. Microinjections of reserpine to corpus striatum induced rigidity with dominance in the hindleg ipsilateral to the side of injection. This rigidity was reduced by subcutaneous apomorphine. The effect of subcutaneous apomorphine on the rigidity was blocked by prior microinjection of trifluoperazine to the corpus striatum. Injections to nucleus accumbens were ineffective in all these respects. It is concluded that reserpine induces rigidity mainly by interference with the dopamine transmission in the corpus striatum.     

Reserpine-induced rigidity in rats: drug effects on muscle tome from corpus striatum and nucleus accumbens

A study of the pathophysiological mechanisms of reserpine rigidity with the aid of a mechanographic method for the quantification of muscle tone. Apomorphine was used as a test substance to reduce reserpine rigidity by stimulation of dopamine receptors. Some experiments were made with additional drug treatment in an attempt to ascertain the dopaminergic specificity of the test. Apomorphine injected bilaterally to the corpus striatum has been shown to counteract the rigidity [6]. Microinjections of reserpine to corpus striatum induced rigidity with dominance in the hindleg ipsilateral to the side of injection. This rigidity was reduced by subcotaneous apomorphine. The effect of subcutaneous apomorphine on the rigity was blocked by prior microinjection of trifluoperazine to the corpus striatum. Injections to nucleus accumbens were ineffective in all these respects. It is concluded that reserpine induces rigidity mainly by interference with the dopamine transmission in the corpus striatum.     

Rats with unilateral median forebrain bundle, but not striatal or nigral, lesions by the neurotoxins MPP+ or rotenone display differential sensitivity to amphetamine and apomorphine

Rotenone and 1-methyl-4-phenyl pyridinium (MPP+) are two mitochondrial neurotoxins known to produce Parkinson's disease (PD) in experimental animals. In the present study, we compared drug-induced rotational asymmetry in rats lesioned using these neurotoxins at three distinct basal ganglia sites, the striatum, substantia nigra pars compacta (SNpc) and median forebrain bundle (MFB). The levels of dopamine (DA) in the ipsilateral striata of these hemiparkinsonian animals were assayed employing an HPLC-electrochemical procedure 2 days after the final rotational study. Rats infused with rotenone or MPP+ into the SNpc, but not into the striatum or MFB, exhibited contralateral rotations immediately after recovery from anesthesia. Irrespective of the lesion site or the toxin used, all the animals exhibited ipsilateral rotations when challenged with D-amphetamine. Apomorphine administration caused contralateral circling behavior in MFB-lesioned animals, but ipsilateral rotations in rats that received rotenone or MPP+ in the striatum or SNpc. Stereotaxic administration of rotenone into the MFB, SNpc or striatum caused a significant loss of DA in the ipsilateral striatum to varying degrees (96%, 62% and 30%, respectively, as compared to the contralateral side). However, unilateral MPP+ administration into the MFB, SNpc or striatum caused respectively about 98%, 74% and 59% loss of striatal DA. Behavioural observations and the neurochemical results indicate that, among the three anatomically distinct loci-lesioned, MFB-lesioned animals mimicked behavioral aberrations similar to nigral lesions caused by 6-hydroxydopamine, a classical parkinsonian neurotoxin. Moreover, the results point out that while both d-amphetamine and apomorphine-induced rotations could be considered as valuable behavioral indices to test novel drugs against PD, yet apomorphine-induced contralateral bias proves to be a more reliable indicator of specific destruction in the nigrostriatal pathway and development of post-synaptic DA receptor supersensitivity.     

Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining

Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson''s disease (PD) in agreement with animal studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses vs single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or 10 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies was assessed at different time points after methamphetamine by tyrosine hydroxylase immunohistochemistry and silver staining. The 3 × 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 × 5 and 1 × 30. Some degenerating axons could be followed from the striatum to the substantia nigra pars compacta (SNpc). All protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by amino-cupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect medium spiny neurons. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days after treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3 days after treatment. Locomotor activity and motor coordination were robustly decreased 1–3 days after treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum.     

Attenuation by Nardostachys jatamansi of 6-hydroxydopamine-induced parkinsonism in rats: behavioral, neurochemical, and immunohistochemical studies

Parkinson's disease (PD) is one of the commonest neurodegenerative diseases, and oxidative stress has been evidenced to play a vital role in its causation. In the present study, we evaluated whether ethanolic extract of Nardostachys jatamansi roots (ENj), an antioxidant and enhancer of biogenic amines, can slow the neuronal injury in a 6-OHDA-rat model of Parkinson's. Rats were treated with 200, 400, and 600 mg/kg body weight of ENj for 3 weeks. On day 21, 2 microl of 6-OHDA (12 microg in 0.01% in ascorbic acid-saline) was infused into the right striatum, while the sham-operated group received 2 microl of vehicle. Three weeks after the 6-OHDA injection, the rats were tested for neurobehavioural activity and were sacrificed after 6 weeks for the estimation of lipid peroxidation, reduced glutathione content, the activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, quantification of catecholamines, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. The increase in drug-induced rotations and deficits in locomotor activity and muscular coordination due to 6-OHDA injections were significantly and dose-dependently restored by ENj. Lesioning was followed by an increased lipid peroxidation and significant depletion of reduced glutathione content in the substantia nigra, which was prevented with ENj pretreatment. The activities of glutathione-dependent enzymes, catalase and superoxide dismutase in striatum, which were reduced significantly by lesioning, were dose-dependently restored by ENj. A significant decrease in the level of dopamine and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, and both were significantly recovered following ENj treatment. All of these results were exhibited by an increased density of tyrosine hydroxylase immunoreactive (TH-IR) fibers in the ipsilateral striatum of the lesioned rats following treatment with ENj; 6-OHDA injection had induced almost a complete loss of TH-IR fibers. This study indicates that the extract of Jatamansi might be helpful in attenuating Parkinsonism.     

Turning behavior of mice with unilateral 6-hydroxydopamine lesions in the striatum: effects of apomorphine, L-DOPA, amanthadine, amphetamine and other psychomotor stimulants

A simple and rapid technique of destroying the dopaminergic nerve terminals in the corpus striatum of the mouse has been developed. After unilateral injections of 6-hydroxydopamine into the striatum, mice exhibited marked ipsilateral reductions in forebrain dopamine concentrations and turned preferentially toward the side of the lesion (ipsilateral turning). Several psychomotor stimulants ((+)- and (?)-amphetamine, amantadine, caffeine, amfonelic acid, pipradrol and methylphenidate) increased the ipsilateral turning; morphine and clonidine were without effect. Apomorphine and l-DOPA, in doses too low to produce motor stimulation, caused contralateral turning. Turning evoked by (+)-amphetamine, but not by apomorphine, was blocked by α-methyltyrosine. Turning behavior as performed in these experiments is a simple but very sensitive index of central dopaminergic receptor stimulation.     

7-Hydroxy-N,N'-di-n-propyl-2-aminotetraline,a preferential dopamine D3 agonist,induces c-fos mRNA expression in the rat cerebellum

The effects of a preferential dopamine D3 receptor agonist 7-hydroxy-N,N'-di-n-propyl-2-aminotetralin (7-OH-DPAT) on c-fos mRNA expression in the rat cerebellum were studied by Northern blot analysis. 7-OH-DPAT (0.003-10 mg/kg, s.c.) markedly increased c-fos mRNA expression in the cerebellum, while its effects in the striatum, nucleus accumbens, and frontal cortex were negligible. The effect of 7-OH-DPAT on cerebellar c-fos mRNA expression was dose-dependent and statistically significant at doses of 0.3 mg/kg or more. A preferential dopamine D2 agonist, bromocriptine (0.01-3 mg/kg, s.c.), failed to increase c-fos mRNA expression in the cerebellum. The effect of 7-OH-DPAT was blocked by two dopamine D2-type-receptor antagonists, haloperidol and perospirone, but not the D1-type-receptor antagonist SCH23390. Furthermore, dopaminergic denervation by 6-hydroxydopamine did not inhibit but rather potentiated the 7-OH-DPAT-induced c-fos mRNA expression in the cerebellum. These findings suggest that 7-OH-DPAT increases c-fos mRNA expression in the rat cerebellum, probably through postsynaptic dopamine D3 receptor activation.     

Development of supersensitivity of apomorphine-induced increases in acetylcholine levels and stereotype after chronic fluphenazine treatment

Dopamine agonists administered systemically produce an increase in striatal levels of acetylcholine (ACh). Possible development of postsynaptic dopamine receptor supersensitivity after neuroleptic treatment was studied by measurement of apomorphine (APO)-induced increase in ACh levels in the striatum and olfactory tubercle. Apomorphine-induced Stereotypic behaviour was also measured. Rats received a single subcutaneous injection of either sesame seed oil vehicle or fluphenazine (FLU) decanoate (10mg kg^?1), a long-acting neuroleptic preparation. After 14 days, rats received APO intraperitoneally, in various doses (0.03–1.0 mg kg^?1). Fifteen minutes later, brain tissue was rapidly fixed by microwave irradiation, dissected, and ACh levels determined by means of gas chromatography. Acetylcholine levels were 75nmol g^?1 in olfactory tubercle and 70 nmol g^?1 in striatum. Apomorphine treatment resulted in dose-dependent increases of ACh level in both regions. Apomorphine-induced increases were greater in rats pretreated with FLU than in controls. Using 0.1 mg kg^?1 APO, the higher striatal ACh-elevating effect found 14 days after FLU treatment was also present 21 days, but not 27 days after FLU treatment. At 21 days after subcutaneous injection, 0.25 mg kg^?1 APO induced significantly greater Stereotypic behaviour in FLU-treated rats than in controls. Thus. FLU treatment led to an apparent temporary supersensitivity of APO-induced increases in ACh levels and stereotypic behaviour.     

Dopamine autoreceptor mediation of the effects of apomorphine on serotonin neurons

The effects of direct apomorphine (APO) infusion to the dorsal raphe and the substantia nigra on serotonergic neurons were examined in male rats. The results showed that APO infusion to the dorsal raphe failed to produce a significant effect on serotonin (5-HT) neurons in the dorsal raphe or 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the corresponding projection site, the striatum. Conversely, direct APO infusion to the substantia nigra mimicked the effects of systemic APO, namely, elevated 5-HT fluorescence in the dorsal raphe and increased 5-HT and 5-HIAA concentrations in the striatum. Serotonin neurons in the median raphe and its projection site, the hippocampus, were unaffected. Furthermore, horseradish peroxidase injection to the dorsal raphe resulted in specific cell labelling in the substantia nigra and fiber labelling in the ventral tegmental area. Together with previous findings that the serotonergic actions of systemic APO were antagonized by haloperidol or intraventricular 6-hydroxydopamine pretreatment; and the selective dopamine (DA) autoreceptor agonist 3-3-hydroxyphenyl-N-n-propyl-piperidine mimicked the effects of APO on 5-HT neurons, these results suggest that the observed effects of APO on the mesostriatal serotonergic system are probably mediated through DA autoreceptors in the substantia nigra and possibly by a direct nigroraphe pathway.