Effect of methamphetamine on neurotensin concentrations in rat brain regions

High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immunoreactivity (NTLI) concentrations of the substantia nigra and striatum in rats after a single or multiple drug doses; smaller but significant increases of 30 to 50% were observed in the hypothalamus and hippocampus after multiple, but not single, METH administrations whereas no measurable changes were detected in the NTLI levels of the periaqueductal gray area or the amygdala. These METH-induced increases in NTLI concentrations were attenuated by coadministration of haloperidol in the substantia nigra, hypothalamus and hippocampus, indicating a possible involvement of dopamine receptors in these tissues. In the striatum haloperidol alone produced significant increases in NTLI levels; these increases were additive with those induced by METH treatment demonstrating that the neurotensin pathways associated with the striatum are regulated differently from that of the other brain areas examined. The implications of these findings to the relationship between dopamine and neurotensin transmitter systems are discussed.     

Neurotensin-dopamine interactions in the substantia nigra of the rat brain

Single or multiple doses of the potent dopamine releaser, methamphetamine (METH), increases the content of neurotensin (NT)-like immunoreactivity (NTLI) in the substantia nigra of the rat brain by 2- to 3-fold. Concurrent blockade of D-1 receptors with METH treatment completely antagonized the increase in nigral NTLI content induced by this drug. These results suggest that activation of D-1 receptors by endogenous dopamine results in an increase in the level of NTLI in the substantia nigra. The present study was performed to characterize further the mechanisms underlying dopaminergic regulation of nigral NT systems. Prior selective destruction of the nigrostriatal dopamine pathway completely prevented the increase in nigral NTLI content induced by treatment with METH, which suggests that the effects of METH on nigral NT systems are mediated by the nigrostriatal dopamine projections. However, unlike METH, treatment of rats with the direct-acting, D-1-selective agonist, SKF 38393, did not alter nigral NTLI content but when combined with stimulation of D-2 receptors, a significant increase in the level of NTLI occurred. Surprisingly, activation of only D-2 receptors caused a significant decrease in nigral NTLI content. These data suggest that although activation of D-2 receptors alone has an effect opposite to that of the D-1 subtype, in combination with D-1 stimulation they facilitate the effect of D-1 receptors on nigral NT systems. In addition to the effects of direct or indirect stimulation of dopamine activity on nigral NT levels, basally released dopamine also appeared to regulate the level of NTLI in the substantia nigra. Thus, interruption of tonic dopamine activity by reserpine-induced depletion of dopamine significantly reduced the level of NTLI in the substantia nigra. The role of D-1 receptors in this tonic dopaminergic regulation of nigral NT systems was evident when concurrent activation of D-1, but not D-2, receptors with reserpine treatment prevented or reversed the decrease in NTLI content caused by dopamine depletion. Additional evidence for the D-1-mediated tonic regulation of NT systems in the substantia nigra was that blockade of D-1 receptors with SCH 23390 decreased the nigral NTLI content but blockade of D-2 receptors with sulpiride had no effect.     

尼古丁对帕金森病大鼠纹状体脑胶质细胞源性神经营养因子和多巴胺含量的影响

背景流行病学研究显示,吸烟和帕金森病(Parkinson's disease,PD)存在负相关系,吸烟可能对PD具有保护作用.人们一直在探索尼古丁对PD的保护作用机制.目的研究尼古丁对PD大鼠纹状体脑胶质源性神经营养因子(glialcelltine derived neurotrophic factor,GDNF)和多巴胺含量的影响.设计随机对照研究.地点和对象实验地点华中科技大学同济医学院协和医院,80只大鼠被随机分为预防组50只和治疗组30只.干预本文第一作者将6-羟多巴胺(6-hydroxydopamine,6-OHDA)立体定向注射到大鼠右侧中脑腹侧被盖部和黑质致密部,建立大鼠模型.采用生化,免疫组织化学方法观察不同剂量尼古丁对PD大鼠的作用.主要观察指标检测纹状体GDNF表达及多巴胺含量的变化.结果造模前及造模后皮下注射尼古丁的PD大鼠,纹状体GDNF表达及多巴胺含量较PD组有明显改善(P＜0.05).结论尼古丁可减轻6-OHDA对黑质多巴胺能神经元的损伤,对PD大鼠具有保护作用.     

胚胎神经上皮干细胞脑内移植治疗大鼠帕金森病

背景：研究表明胚胎干细胞移植可改善血管性痴呆大鼠的学习记忆功能,增强神经的可塑性,诱导自身定向迁移并分化为成熟神经元。目的：观察胚胎神经上皮干细胞脑内移植治疗帕金森病大鼠及移植细胞的迁徙情况。方法：将绿色荧光蛋白转基因鼠的胚胎神经上皮干细胞分别移植到帕金森病大鼠的黑质、纹状体和侧脑室内,移植后检测移植细胞的存活、迁徙与分化;利用高效液相色谱法检测实验动物脑内多巴胺神经递质的含量：对比实验动物旋转行为的改变,评估胚胎神经上皮干细胞移植对帕金森病大鼠的治疗作用。结果与结论：移植细胞存活良好且分化出了酪氨酸羟化酶阳性细胞,向黑质纹状体环路迁徙趋势明显;脑内多巴胺含量增加,动物旋转行为改善明显。表明移植到帕金森病大鼠脑内的神经上度干细胞多向黑质纹状体环路迁徙,且可增加脑内多巴胺神经递质的含量治疗帕金森病。     

CNS gene therapy applications of the Semliki Forest virus 1 vector are limited by neurotoxicity.

The Semliki Forest virus (SFV) 1 vector system is highly efficient at gene transduction in a broad range of host cells, including neurons. To determine the potential of SFV1-based vectors to mediate gene expression in substantia nigra neurons, we inoculated d1EGFP-expressing SFV virus-like particles stereotaxically into the mouse brain. This system selectively and extensively mediated gene expression in dopaminergic neurons of the substantia nigra. Continual reporter gene expression was evident in neuronal cell bodies for up to 3 weeks postinoculation and d1EGFP-positive neuronal processes were apparent for 12 weeks. There was no evidence of an apoptotic response to infection, but with time cell degeneration and an axonopathy, indicative of neuronal loss, were increasingly apparent. This system has potential for experimental studies requiring efficient transient gene transduction of mouse CNS neurons. The current SFV1 vector system is, however, limited in its potential for CNS gene therapy by neurotoxicity.     

颈动脉体球细胞移植对帕金森病大鼠神经递质和行为的影响

目的：探讨颈动脉体球细胞移植对帕金森病（PD）大鼠神经递质和行为的影响。方法：采用立体定位注射6－羟多巴胺（6－OHDA）制备偏侧PD大鼠模型，右侧纹状体内分别移植入自、异体颈动脉体和胚鼠中脑组织快，移植后2、4、8和12周进行阶梯实验和阿朴吗啡诱发大鼠的旋转实验，测定移植区多巴胺（DA）的含量改变。结果：与对照组比较，PD大鼠摄食行为和阿朴吗啡诱发的旋转行为明显改善达12周之久，DA水平升高显著（P＜0．01）且以自体颈动脉体移植组最佳。结论：脑内移植颈动脉体球细胞可明显改善PD大鼠的神经行为缺损，提高纹状体内DA含量，是一种有效治疗PD的方法。     

低频rTMS对帕金森大鼠纹状体DA及其代谢产物的影响

目的:探讨0.2 Hz 55%刺激强度下,单次刺激及连续刺激14 d后帕金森大鼠纹状体多巴胺及其代谢产物含量的变化。方法:应用6-羟基多巴损毁SD大鼠右侧黑质致密部制备模型,用高效液相色谱仪-电化学检测法检测重复经颅磁刺激作用前、第1次刺激后、连续14次刺激后纹状体多巴胺、3,4-二羟基苯乙酸及高香草酸含量的变化。结果:单次刺激减少3,4-二羟基苯乙酸的含量,连续14次刺激后多巴胺、3,4-二羟基苯乙酸、高香草酸含量增高。结论:单次经颅磁刺激抑制多巴胺代谢、连续14次刺激通过增加多巴胺生成或/和释放发挥生物学效应。     

小胶质细胞介导帕金森病小鼠的氧化应激损伤

背景：研究证实,小胶质细胞诱导型一氧化氮合酶可增加多巴胺能神经元对百草枯的摄取。造成百草枯对多巴胺能神经元的特异性杀伤作用。帕金森病的黑质纹状体存在小胶质细胞的激活,但其产生氧化应激作用机制尚不明确。目的：建立帕金森病小鼠模型,观察小胶质细胞介导的氧化应激损伤在帕金森病中的作用。方法：36只C57BL／6小鼠随机分为帕金森病模型组和对照组,每组18只。以腹腔注射百草枯10mg／kg为模型组,等体积生理盐水为对照组,分别观察小鼠行为活动改变。采用高效液相法测定两组小鼠黑质纹状体多巴胺的含量及免疫组织化学方法检测两组小鼠黑质部位酪氨酸羟化酶、mac-1蛋白表达,同时应用化学比色法测定两组小鼠黑质部位超氧化物歧化酶、还原性谷胱甘肽、谷胱甘肽过氧化物酶活性和丙二醛水平的变化。结果与结论：模型组小鼠自发行为活动较对照组减少（P〈0．05）。高效液相法检测模型组小鼠黑质纹状体多巴胺含量及酪氨酸羟化酶蛋白的表达均显著低于对照组（P〈0．05）,mac-1蛋白表达高于对照组（P〈0．05）。模型组超氧化物歧化酶、还原性谷胱甘肽、谷胱甘肽过氧化物酶活性较对照组均显著下降（P〈0．05）,丙二醛水平较对照组显著升高（P〈0．05）。提示中脑黑质部位小胶质细胞的激活致使氧化应激反应增强及抗氧化保护作用减弱可能是引起帕金森病发病的重要机制。     

Nonviral glial cell-derived neurotrophic factor gene transfer enhances survival of cultured dopaminergic neurons and improves their function after transplantation in a rat model of Parkinson's disease

Transplantation of dopaminergic fetal mesencephalic tissue into the striatum is currently being developed for treatment of patients with advanced Parkinson's disease. Ethical concerns regarding the use of human fetal tissue, and the limited availability as well as poor survival and differentiation of dopaminergic neurons after transplantation have reduced the extent and outcome of this approach so far. With the purpose of finding means to increase the yield of dopaminergic neurons in transplants, and to reduce the amount of fetal tissue needed for each transplanted patient, we transfected rat fetal ventral mesencephalic (VM) tissue grown as organotypic free-floating roller tube (FFRT) cultures with a vector encoding human glial cell-derived neurotrophic factor (hGDNF). For transfer of an episomal expression vector (pRep7-GDNF8) a nonviral, nonliposomal cationic transfection technique was applied and optimized. Recombinant hGDNF expression resulted in a higher number of TH-positive neurons in the cultures as measured 6 days after transfection. Ventral mesencephalic cultures expressing hGDNF were then grafted into the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. Grafting of genetically modified VM cultures resulted in earlier functional recovery compared with grafting nontransfected cultures. We conclude that organotypic free-floating roller tube cultures can be successfully transfected to produce hGDNF with effects on TH-expressing neurons in vitro and functional effects after grafting in a rat Parkinson's disease model.     

小胶质细胞介导帕金森病模型小鼠的炎症损伤

背景:研究表明帕金森病的黑质纹状体存在小胶质细胞的激活,但其释放炎症因子在帕金森病发病过程中的作用尚不明确。目的:观察小胶质细胞激活所释放的两种炎症因子整合素α及肿瘤坏死因子α在小鼠黑质部位的蛋白表达及酪氨酸羟化酶的蛋白表达。方法:将C57BL/6小鼠经腹腔注射百草枯(10mg/kg),设为帕金森病模型组,并设置对照组,观察两组小鼠行为活动。用高效液相法测定小鼠黑质纹状体多巴胺的含量。采用免疫组织化学法检测黑质部位酪氨酸羟化酶、整合素α及肿瘤坏死因子α蛋白表达。结果与结论:百草枯可造成帕金森病模型组小鼠运动减少,并伴有运动迟缓、震颤、探嗅、竖毛及尾巴硬类似于帕金森病样的行为表现,并且脑内黑质纹状体多巴胺含量降低(P<0.05),酪氨酸羟化酶蛋白表达降低(P<0.05),整合素α和肿瘤坏死因子α蛋白表达增加(P<0.05),肿瘤坏死因子α在模型组小鼠黑质纹状体有阳性表达,且主要分布在小胶质细胞上。结果表明小胶质细胞介导的炎症损伤参与了帕金森多巴胺能神经元的损害过程。     

Does neuronal expression of GDNF effectively protect dopaminergic neurons in a rat model of Parkinson's disease?

The transfer of the Glial cell line-derived neurotrophic factor (GDNF) gene to the central nervous system by a recombinant adenoviral vector (Ad) was studied. We constructed the adenovirus vector Ad-NSE-GDNF from which the E1, E3/E4 regions of Ad5 have been deleted and in which the GDNF gene was under the control of a neuron-specific enolase (NSE) promoter. The vector was injected into the striatum of a rat model of Parkinson's disease. We found that (i) the NSE promoter can restrict transgene expression in neurons; (ii) Ad-NSE-GDNF significantly protected dopaminergic (DA) neurons in the substantia nigra (SN) but did not reverse the impairments of amphetamine-induced rotational behavior in lesioned rats.     

Endogenous opioids in dopaminergic cell body regions modulate amphetamine-induced increases in extracellular dopamine levels in the terminal regions

Opioid antagonists attenuate behavioral effects of amphetamine and amphetamine-induced increases in extracellular dopamine levels in nucleus accumbens and striatum of rats but do not alter those effects of cocaine. This study was performed to determine 1) if the effect of opioid antagonists on the dopamine response to amphetamine is mediated in either the terminal or cell body region of the nigrostriatal and mesolimbic pathways, and 2) if the enkephalinase inhibitor thiorphan, which slows degradation of endogenous opioid peptides, increases the dopamine response to amphetamine but not to cocaine. Microdialysis probes were placed either into a dopaminergic terminal region or into both a terminal and cell body region of rats. Naloxone methiodide (1.0 microM), a lipophobic opioid antagonist, was administered into either the terminal or cell body region by reverse dialysis, whereas extracellular dopamine was collected in the terminal region. Increases in extracellular dopamine in nucleus accumbens and striatum caused by amphetamine (0.1-6.4 mg/kg, s.c.) were reduced significantly (28-39%) by naloxone methiodide administered into either substantia nigra or ventral tegmentum but not into terminal regions. Thiorphan (10 microM) administered into substantia nigra increased significantly the dopamine response to amphetamine in the ipsilateral striatum by as much as 42% but did not affect the dopamine response to cocaine (3.0-56 mg/kg, i.p.). These results suggest that amphetamine promotes release of endogenous opioids, which, through actions in the ventral tegmentum and substantia nigra, contribute to amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and striatum.     

Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins.

Adeno-associated virus (AAV) serotype 8 appears to be the strongest of the natural serotypes reported to date for gene transfer in liver and muscle. In this study, we evaluated AAV8 in the brain by several methods, including biophotonic imaging of green fluorescent protein (GFP). In the adult rat hippocampus, levels of GFP expressed were clearly greater with AAV8 than with AAV2 or AAV5 by Western blot and biophotonic imaging and slightly but significantly greater than AAV1 by Western blot. In the substantia nigra, the GFP expression conferred by AAV8 was toxic to dopamine neurons, although toxicity could be avoided with dose titration. At the low dose at which there was no GFP toxicity from the GFP vector, another AAV8 vector for a disease-related (P301L) form of the microtubule-associated protein tau caused a 78% loss of dopamine neurons and significant amphetamine-stimulated rotational behavior. The AAV8 tau vector-induced cell loss was greater than that from AAV2 or AAV5 tau vectors, demonstrating that the increased gene transfer was functional. While the toxicity observed with GFP expression warrants great caution, the efficient AAV8 is promising for animal models of neurodegenerative diseases and potentially as well for gene therapy of brain diseases.     

A proteomic approach in the study of an animal model of Parkinson's disease

BACKGROUND: The aetiology of Parkinson's disease (PD), an age-related disorder characterized by a progressive degeneration of dopaminergic neurons of the substantia nigra (SN) pars compacta, remains unclear. Current treatments, such as administration of L-DOPA, are only symptomatic and do not stop or delay the progressive loss of neurons. In fact, it has been suggested that the dopamine precursor L-DOPA, increases generation of reactive oxygen species (ROS) leading to further neuronal damage. A similar loss in nigrostriatal dopaminergic neurons is produced on intracerebral administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA). In an animal model of PD, termed 'the hemiparkinsonian rat', unilateral injection of 6-OHDA into the nigrostriatal pathway results in extensive loss of dopaminergic cells in the ipsolateral SN. In an attempt to identify some of the proteins that are involved in dopaminergic neuronal death, we used the proteomic methods to analyze this animal model of PD. METHODS: Five hemiparkinsonian rats were obtained by intranigral stereotaxic injection of 6-OHDA.The right 6-OHDA-lesioned substantia nigra and striatum tissues along with the left, unlesioned controlateral tissues, were excised and homogenized, using urea-based buffer, to extract the tissues protein. The separation of the protein mixtures and the visualization of the protein patterns obtained were performed using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Protein profiles of control and treated tissues were compare by the PDQuest 2D-gel analysis software (BIO-Rad laboratory). The protein spots showing differential expression were analysed by matrix assisted laser desorption/ionizing time of flight (MALDI-TOF) mass spectrometry. RESULTS: The brain protein extraction and solubilization protocol was validated obtaining a satisfactory protein profile. In comparison to the normal rats, hemiparkinsonian animals exhibited a different expression in alpha-enolase and beta-actin in substantia nigra and striatum, respectively. CONCLUSION: The proteomic study of 6-OHDA-induced lesions in the nigrostriatial pathway allowed us to identify two proteins, alpha-enolase and beta-actin, showing increased levels in the 6-OHDA-lesioned brain tissues compared to control. Previous studies described the same proteins as oxidized and proteins in Alzheimer's disease (AD) brain. Our preliminary data could mirror those results pointing out a common mechanism of neurodegenerative diseases.     

Neurotensin-induced dopamine release in vivo and in vitro from substantia nigra and nucleus caudate

We compared the dopamine (DA) releasing effects of neurotensin (NT) from cell bodies (substantia nigra) and nerve terminals (nucleus caudate). In rats implanted with push-pull cannula, NT induced DA release from substantia nigra and nucleus caudate. NT was more potent in releasing DA from the substantia nigra than from the nucleus caudate (EC50%, 1.1 microM in substantia nigra and 9.8 microM in nucleus caudate). In vitro, in superfused rabbit brain slices, NT enhanced the depolarization-evoked release of DA and exerted a direct releasing effect. The latter was greater in the substantia nigra, and the former in the nucleus caudate. The direct releasing effect of NT was not inhibited, but enhanced by nomifensine (3 microM). Sulpiride, a D2 DA receptor antagonist, failed to modify NT-induced DA release; in addition, NT did not affect the inhibition of DA and acetylcholine release produced by LY-171555, a D2 DA agonist. In both the substantia nigra and the nucleus caudate, desensitization to the releasing effect of NT was observed, either after 2.5, 5, or 10 min of exposure to the peptide. A synergistic interaction on DA release was observed between NT and potassium (K+), and between NT and electrical stimulation. Greater synergism was observed with high extracellular K+. Pretreatment of striatal slices with 15 mM K+ produced a 9-fold enhancement of NT-induced DA release. When K+ (25 mM, 2 min) was given together with NT there was a 2- to 3-fold increase in DA release compared to the release evoked by K+ in the absence of NT.(ABSTRACT TRUNCATED AT 250 WORDS)     

小胶质细胞介导帕金森病模型小鼠的炎症损伤术

背景：研究表明帕金森病的黑质纹状体存在小胶质细胞的激活,但其释放炎症因子在帕金森病发病过程中的作用尚不明确。目的：观察小胶质细胞激活所释放的两种炎症因子整合素a及肿瘤坏死因子a在小鼠黑质部位的蛋白表达及酪氨酸羟化酶的礞白表达。方法：将C57BL／6小鼠经腹腔注射百草枯（10mg／kg）,设为巾f{金森病模型组,并设置对照组,观察两组小鼠行为活动。用高效液相法测定小鼠黑质纹状体多巴胺的含量。采用免疫组织化学法检测黑质部位酪氰酸羟化酶、整合索a及肿瘤坏死因子a蛋白表达。结果与结论：百草枯可造成帕金森病模型组小鼠运动减少,并伴有运动迟缓、震颤、探嗅、峰毛及尾巴硬类似于帕金森病样的行为表现,并且脑内黑质纹状体多巴胺含量降低（P〈0．05）,酪氨酸羟化酶蛋白表达降低（P〈0．05）,整合索a和肿瘤坏死因子a蛋白表达增N（P〈O．05）,肿瘤坏死因子a在模型组小鼠黑质纹状体有阳性表达,且主要分布在小胶质细胞上。结果表明小胶质细胞介导的炎症损伤参与了帕金森多巴胺能神经元的损害过程。     

鼠胚神经干细胞移植对帕金森模型大鼠的治疗作用

背景:干细胞移植是治疗帕金森的有潜力的方法之一。目的:观察神经干细胞纹状体移植对帕金森模型大鼠旋转行为及脑内多巴胺含量的影响。方法:采用6-羟基多巴胺定点注射毁损黑质纹状体的方法构建帕金森大鼠模型;向造模成功的大鼠纹状体内分别移植1×106(共计20μL)的第3代胚鼠神经干细胞或等量生理盐水。结果与结论:神经干细胞移植后,帕金森大鼠的旋转行为明显改善。干细胞移植后3周,免疫组化检测发现移植干细胞的帕金森大鼠脑黑质部位酪氨酸羟化酶阳性细胞数增多,纹状体内可见酪氨酸羟化酶阳性细胞;荧光显微镜下观察发现Hoechst33324d标记神经干细胞在移植针道附近最为密集,并向远隔部位迁徙。干细胞移植后8周,高效液相色谱检测显示移植干细胞的帕金森大鼠纹状体内多巴胺含量明显增高(P<0.01)。说明神经干细胞脑内移植能够减轻6-羟基多巴胺引起的大鼠中脑黑质多巴胺能神经元的损伤,改善大鼠的旋转行为。     

Effects of catecholamine depleting drugs and d-amphetamine on self-stimulation of the substantia nigra and locus coeruleus.

6-Hydroxydopamine treatments which preferentially depleted either norepinephrine or dopamine were used to define the importance of these transmitter systems in the behavioral alterations produced by catecholamine synthesis inhibitors and d-amphetamine on self-stimulation of the locus coeruleus and substantia nigra. After chronic reduction of brain dopamine, an acute depression of self-stimulation of both the locus coeruleus and substantia nigra occurred. Preferential depletion of norepinephrine with 6-hydroxydopamine did not result in a significant decrease in self-stimulation of locus coeruleus or substantia nigra. However, a dose of alpha-methyltyrosine wihch had no effect in control rats or in rats with brain norepinephrine depleted caused a significant reduction in responding at both electrode placements in animals depleted of brain dopamine. Administration of U-14,624 affected neither substantia nigra nor locus coeruleus self-stimulation, even though it produced an additional 70% depletion of norepinephrine. When d-amphetamine sulfate was given to 6-hydroxydopamine-treated rats, the facilitation of self-stimulation produced by this compound was significantly attenuated in rats with prior depletion of brain dopamine. Depletion of brain norepinephrine did not affect the actions of d-amphetamine on self-stimulation. In other experiments, the actions of d-amphetamine to increase self-stimulation of animals pretreated with reserpine was found to be antagonized by alpha-methyltyrosine but not by U-14,624. Results suggest that drugs can alter self-stimulation of a site in brain anatomically associated with noradrenergic neural pathways and self-stimulation of a site primarily associated with dopaminergic pathways in a similar manner. These data also provided evidence for the involvement of dopamine fibers in the pharmacological actions of d-amphetamine, reserpine and alpha-methyltyrosine.     

Tachykinins in the rat substantia nigra: effects of selective dopamine receptor antagonists

The effects of sustained blockade of dopamine receptors by selective dopamine antagonists on the tachykinin (substance P and neurokinin A) content in the substantia nigra were examined. The treatment of rats for 14 days with D-1/D-2 dopamine receptor antagonist haloperidol (2 mg/kg) or selective D-2 antagonist sulpiride (100 mg/kg) produced a similar and significant decrease in nigral substance P and neurokinin A-like immunoreactivity content, about 32-36% and 27-28% of control respectively. In contrast, administration of SCH 23390 (1 mg/kg), a selective and potent D-1 dopamine receptor antagonist, failed to affect the levels of substance P and neurokinin A in the substantia nigra and did not change the sulpiride-induced reduction of the nigral tachykinin peptides. These results indicate that the D-1 dopamine receptors are not involved in the modulation of nigral substance P and neurokinin A content and suggest that the blockade of the D-2 dopamine receptor subtype exerts the same regulation of the tachykinin gene expression, in spite of the existence of three mRNAs encoding substance P and neurokinin A.