Rapid desensitization of dopamine release induced by neurotensin and neurotensin fragments

Neurotensin (NT), a tridecapeptide, induced a concentration-dependent release of dopamine (DA) from the striatum. In addition, NT8-13 and Nacetyl-NT8-13, the carboxy-terminal-containing hexapeptides, were much more effective as DA releasers than the amino-terminal, NT1-6 peptide. The potency and efficacy of NT in inducing DA release was markedly enhanced by increases in the extracellular concentration of potassium (K+). Similar to electrical stimulation and to elevated extracellular K+, NT-induced DA release was inhibited by 70% in the presence of 0.13 mM calcium. Desensitization to NT was observed after a first exposure to NT for 2.5 to 10 min, despite a 20- to 85-min washout period between exposures, with NT-free medium. The loss of response was not due to degradation or inactivation of the peptide, nor it was due to activation of DA autoreceptors or the DA transporter. NT-induced desensitization was not associated to a loss of responsiveness to DA release elicited by electrical stimulation or by high K+. In addition, desensitization occurred even if NT-induced DA release was markedly enhanced by high extracellular K+ (10 and 15 mM). Inhibition of NT-induced DA release by low calcium (on the first exposure) did not prevent the development of desensitization. Similar to the parent peptide, desensitization was observed with the active carboxy-terminal NT fragments. However, a first exposure to NT1-6 did not induce desensitization to NT8-13. These results are compatible with the view that NT-induced DA release and the development of desensitization are mediated through an action of NT on NT receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fast two-layer two-photon imaging of neuronal cell populations using an electrically tunable lens

Functional two-photon Ca(2+)-imaging is a versatile tool to study the dynamics of neuronal populations in brain slices and living animals. However, population imaging is typically restricted to a single two-dimensional image plane. By introducing an electrically tunable lens into the excitation path of a two-photon microscope we were able to realize fast axial focus shifts within 15 ms. The maximum axial scan range was 0.7 mm employing a 40x NA0.8 water immersion objective, plenty for typically required ranges of 0.2-0.3 mm. By combining the axial scanning method with 2D acousto-optic frame scanning and random-access scanning, we measured neuronal population activity of about 40 neurons across two imaging planes separated by 40 μm and achieved scan rates up to 20-30 Hz. The method presented is easily applicable and allows upgrading of existing two-photon microscopes for fast 3D scanning.     

A radioimmunoassay for neurotensin in human plasma

A specific radioimmunoassay for neurotensin in plasma has been developed with a sensitivity of 2 pmol/l of plasma. The antiserum was directed towards the amino terminal region of neurotensin and did not cross-react with other gastrointestinal peptides. Non-specific interference was eliminated and the sensitivity increased by extracting the plasma samples with ethanol prior to assay. Within- and between-assay coefficients of variation were 7.8% and 12% respectively. The mean plasma concentration of neurotensin in 30 fasting subjects was 29 ± 4 pmol/l. A mixed meal increased plasma neurotensin from 16 ± 2 to 53 ± 6 pmol/l at 2 h.     

Dopamine genes and migraine

Migraine is a common chronic disorder with an etiology still mostly unknown. Several neurotransmitters such as dopamine and serotonin are considered to be involved in the pathogenesis of the disease and the study of their systems is crucial in the understanding of migraine. Dopaminergic receptors are variously represented in human CNS and periphery. The hypothesis that a hypersensitivity of the dopaminergic system may have a role in migraine is based on clinical and genetic data. Genetic data are represented by association studies using dopaminergic genes as candidate genes which show that the D2 receptor gene appears to be involved in the pathogenesis of migraine.     

Actions and possible hormonal functions of circulating neurotensin

Summary. Neurotensin is one of the new peptides of the CNS and of the gut. In the periphery neurotensin is found in endocrine cells scattered diffusely in the gut mucosa and also in sympathetic nerves. This distribution indicates that the peptide may function as a hormone of the paracrine or endocrine type and as a neurotransmitter or neuromodulator. The purpose of this review is to present studies related to the distribution of neurotensin in peripheral organs, its pharmacological actions and possible physiological function as an endocrine hormone. Wc will also shortly discuss some of the pathophysiological implications based on available experimental data.     

Dopamine dependence in hypocalcemic patients

Two patients admitted for decompensated chronic obstructive pulmonary disease developed arterial hypotension requiring the prolonged infusion of dopamine. They had no sign of acute circulatory failure and their blood lactate levels were normal. In the two patients, the correction of unsuspected hypocalcemia allowed the rapid discontinuation of the dopamine infusion.     

Dopamine, depression and antidepressants

Abstract The relationship between depression and dopamine deficiency in the mesolimbic pathway has been hypothesized for many years. The experimental studies with animal models of depression and the human studies implicate the role of the dopamine system in depression. Not only do dopaminergic receptor agonists, but also antagonists such as olanzapine exhibit antidepressant effects associated with standard antidepressants in patients with treatment-resistant depression. This paradoxical result suggests that further investigations are necessary to understand the role played by dopamine in depression.     

多巴胺和多巴酚丁胺对临床部分生化检测项目的干扰

目的评估多巴胺和多巴酚丁胺对基于过氧化物和过氧化物酶反应原理的6个生化检测项目[肌酐(Cr)、尿酸(UA)、葡萄糖(Glu)、总胆固醇(TC)、甘油三酯(TG)、糖化血清蛋白(GSP)]的影响。方法配制含有100.00、50.002、5.00、12.506、.253、.131、.57μg/mL不同药物(多巴胺、多巴酚丁胺)浓度的血清,采用日立7600全自动生化仪(简称日立7600)测定血清Cr、UA、Glu、TC、TG、GSP浓度;采用强生VITROSR○5.1 FS干式生化仪(简称强生VITROS)检测Cr、UA和Glu浓度。计算不同血药浓度对各个项目干扰的程度。结果随着药物浓度逐渐增加,6个检测项目的检测结果均逐渐下降。血药浓度≤1.57μg/mL时对除GSP外的5个日立7600检测项目的负干扰<10%;血药浓度≥50μg/mL时对强生VITROS的Cr、UA测定结果的负干扰>10%。各个浓度的药物对强生VITROS检测Glu没有明显影响(<10%)。结论高浓度的多巴胺和多巴酚丁胺(≥1.57μg/mL)对日立7600的检测Cr、UA、Glu、TC、TG和GSP呈明显负干扰。强生VITROS抗多巴胺和多巴酚丁胺的干扰能力明显强于日立7600上的相应检测项目。     

Characterization and autoradiographic localization of neurotensin binding sites in human sigmoid colon

Radioiodinated neurotensin ((125)I-NT) was used to characterize and localize NT binding sites in normal human sigmoid colon. Specimens were obtained from patients (30-77 years old) undergoing resection for colon carcinoma. Specific binding of (125)I-NT to sigmoid circular muscle membranes was enhanced by o-phenanthroline (1 mM) but other peptidase inhibitors were ineffective. (125)I-NT bound to a high-affinity site of K(d) = 0.88 +/- 0.09 nM and B(max) = 4.03 +/- 0.66 fmol/mg of wet weight tissue (n = 14), although in the majority of patients another site, of low but variable affinity, could also be detected. Specific binding of 50 pM (125)I-NT was inhibited by NT(8-13) > NT > SR142948A > or = neuromedin N > or = SR48692, consistent with binding to the NT1 receptor. In autoradiographic studies, dense specific binding of (125)I-NT was seen over myenteric and submucosal ganglia, moderate binding over circular muscle, and sparse binding over longitudinal muscle and taenia coli. Levocabastine, which has affinity for the NT2 receptor, did not inhibit specific binding of (125)I-NT in membrane competition or autoradiographic studies. NT contracted sigmoid colon circular muscle strips with a pD(2) value of 6.8 +/- 0.2 nM (n = 25). The contractile responses to NT were significantly potentiated in the presence of tetrodotoxin (1 microM), indicating a neural component. Results from functional studies support actions for NT on both muscle and enteric neurons, consistent with the presence of NT receptors on circular muscle and ganglia of human sigmoid colon. The lack of inhibition by levocabastine suggests that the second binding site detected does not correspond to the NT2 receptor.     

脑卒中患者血浆神经降压素水平及其动态变化

目的:观察脑出血、脑梗死、蛛网膜下腔出血患者血浆神经降压素(neurotensin,NT)水平改变及其动态变化,探讨NT参与各型脑卒中及其伴发病中的病理生理机制及对功能预后评估的意义。方法:2002-03/2003-09,实验在济南长城医院神经内科、山东大学附属第二医院神经内科、山东省立医院、山东大学齐鲁医院神经内科与泰山医学院微循环研究所完成。选择脑卒中138例,其中脑出血组46例,脑梗死组62例,蛛网膜下腔出血组30例。病例依病情轻重、病灶大小、病程、伴发病积分、有无高血压史等分组,选择28例健康查体者作为对照组。用放免法检测血浆NT浓度。结果:脑梗死组NT水平(467.31±363.42)ng/L显著高于对照组(76.54±59.53)ng/L(t=4.638,P<0.0001),于发病后24h内显著升高(228.10±123.13)ng/L,4～7d达高峰(648.01±337.38)ng/L,8～15d开始下降(525.67±264.11)ng/L,15d后仍在较高水平(392.57±262.35)ng/L;重型(762.91±446.0)ng/L与大灶组(404.39±206.49)ng/L显著高于轻型(153.86±130.47)ng/L与小灶组(200.27±137.64)ng/L(P<0.01),伴发病积分≥6分组NT水平(623.11±377.97)ng/L显著高于<6分组(236.74±132.22)ng/L(t=3.506,P<0.001),高血糖组NT水平(673.26±331.00)ng/L显著高于正常血糖组(328.16±216.69)ng/L(t=     

Dopamine and Isoproterenol in Imipramine Intoxication in the Dog

Abstract

Artificially ventilated anesthetized dogs were given imipramine 7.5?mg/kg/hr i.v. In the first group (n=6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 + 6.6?mg/kg (mean ± sd). When aortic flow had decreased to 75% of its initial value, in a second group (n=5) of experiments dopamine 10 μg/kg/min and in a third group (n=5) isoproterenol 1 μg/kg/min were administered i.v. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 ± 13.3 in the dopamine and 42.5 ± 8.0?mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 > p > 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 ± 0.66, in the second 3.36 ± 0.66 and in the third 3.32 ± 1.10?mg/1. Desipramine concentrations were 0.078 ± 0.06, 0.162 ± 0.076 and 0.383 ± 0.09?mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.     

Dopamine clearance in critically ill patients

Objective: To examine the validity of the low-dose “renal” dopamine regimen in critically ill patients by investigating the steady-state clearance of dopamine. Design: A prospective clinical study. Setting: Teaching hospital intensive care unit. Patients: 48 haemodynamically stable patients receiving a dopamine infusion. Interventions: Sampling of arterial blood and dopamine infusates. Measurement and results: Plasma and infusate dopamine levels were measured by liquid chromatography with electrochemical detection. Steady-state clearance was determined by dividing the actual infusion rate by the steady-state plasma concentration. Dopamine clearance for the whole group was 46.4 ± 35.9 ml/kg per min (mean ± SD), which is significantly lower than 70 ± 15.2 ml/kg per min reported for elective surgical patients (p = 0.01). Twelve patients with renal dysfunction had significantly lower dopamine clearances (36 ± 16.6 ml/kg per min) than the remaining 36 patients (61 ± 38.5 ml/kg per min, p = 0.022). There was a very poor correlation between plasma dopamine level and infusion rate for the group as a whole (r = 0.47), and this worsened (r = 0.31)when only those patients on a “renal” dose of 2–5 μg/kg per min were considered (n = 30). Conclusion: Plasma dopamine clearance is lower in critically ill patients and there is a large interindividual variation. It is therefore impossible to predict the plasma level from the infusion rate. Consequently, the concept of a selective renovascular low-dose dopamine infusion is invalid in critically ill patients. Received: 12 January 1998 Accepted: 15 July 1998     

Dopamine receptors and psychiatric drug treatment

The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain. Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine-containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals. The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro-striatal and tubero-infundibular mechanisms in the neurological and neuroendocrine effects of these drugs. Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques, providing more direct evidence of dopamine receptor blockade by neuroleptic drugs. Further research is needed especially in studying the nature of the time-dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain. The different subtypes of dopamine receptors in the brain, currently called D1 and D2 dopamine receptors, seem to be parallel, although in many respects independently-acting regulatory systems. Dopamine D2 receptor-selective antagonists such as sulpiride seem to cause selective D2 receptor up-regulation. Prolactin secretion seems to be regulated by D2 dopamine receptors. The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known. Sulpiride and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action, the former having strong and selective antidopaminergic action, the latter combining a number of non- dopaminergic mechanisms with rather slight effects on dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.