多巴胺和谷氨酸在纹状体脑片的相互作用:受体机制介导的CCDPKⅡ,PKA和LDH活性变化(英文)

目的:研究DA和Glu及其受体激动剂/拮抗剂对大鼠纹状体脑片Ca~(2 )/CaM依赖性蛋白激酶Ⅱ(CCDPKⅡ)、cAMP依赖性蛋白激酶(PKA)活性及乳酸脱氢酶(LDH)释放的影响,以探讨纹状体DA和Glu两个神经递质系统的相互作用。方法:用~(32)P掺入法测定大鼠纹状体脑片CCDPKⅡ和PKA活性,用比色法测定LDH的释放。结果:(1)NMDA受体拮抗剂MK-801能拮抗DA、D_1激动剂SKF 38393和D_2激动剂LY 171555对CCDPKⅡ活性的抑制作用。D_1拮抗剂SCH 23390和D_2拮抗剂spiperone均能拮抗Glu诱导的CCDPKⅡ活性降低。(2)DA和SKF 38393显著增加纹状体脑片PKA活性,MK-801可降低这种作用。(3)DA和Glu增加LDH的释放并与浓度成正比。MK-801拮抗DA诱导的LDH释放增加;spiperone能显著减少Glu诱导的纹状体神经元LDH释放。结论:DA和Glu的相互作用对调节纹状体神经元CCDPKⅡ和PKA活性及细胞功能是非常重要的。     

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。     

左旋千金藤立定拮抗D_2受体激动剂对大鼠突触体酪氨酸羟化酶活性的负反馈调节(英文)

目的:研究左旋千金藤立定(SPD)对大鼠纹状体突触体酪氨酸羟化酶(TH)活性的影响.方法:利用高效液相-电化学法(HPLC-ECD)检测ι-DOPA的含量变化.结果:选择性D_2受体激动剂N-0437和喹吡罗均能抑制大鼠纹状体TH的活性,D_1受体激动剂SKF 38393和SPD都不能抑制TH的活性;D_2受体阻滞剂螺哌隆和SPD均能拮抗D_2受体激动剂对TH的抑制作用.结论:D_2受体介导突触前DA受体的负反馈调控,SPD对D_2受体无激动作用,而是D_2受体的阻滞剂.     

甲氧氯普胺镇内脏痛的中枢多巴胺机制

在家兔内脏痛模型上观察了甲氧氯普胺(MCP)的镇痛作用。结果:MCP 8mg·kg~(-1)iv有明显的镇内脏痛作用.该作用可被多巴胺(DA)受体激动剂阿扑吗啡.D_1受体激动剂SKF38393.D_2受体激动剂LY171555 icv所拮抗。应用高效液相色谱—电化学检测法也观察到MCP8 mg·kg~(-1)iv20 min后.脑脊液中DA的代谢产物3-甲氧基-4-羟基苯乙酸明显升高。表明MCP的镇内脏痛作用与阻断脑内DA受体有关.D_1、D_2受体的激活均不利于MCP镇痛。     

左旋千金藤立定增强mPFC DA受体对皮层下NAc DA释放的抑制作用(英文)

目的:研究左旋千金藤立定(SPD)激动内侧前额皮层(mPFC)D_1受体对皮层下伏隔核DA诱发释放的影响。方法:6-羟基多巴胺损伤大鼠mPFC两周后,同侧皮层内微量注射SPD,微透析检测电刺激中脑腹侧被盖区(VTA)或苯丙胺(AMP)诱导的NAc DA释放。结果:mPFC DA耗竭未改变NAc DA的基础水平和电刺激VTA诱发的DA释放,却明显易化AMP灌流诱发的NAc DA释放,表明mPFC DA系统参与调节NAc DA的诱发释放。mPFC内微量注射SPD未能改变电刺激VTA诱发的DA释放,但显著减弱AMP对NAc DA的诱发释放;该作用可被D_1拮抗剂Sch-23390部分翻转,而D_2拮抗剂spiperone无作用。结论:SPD强化mPFC D_1受体对皮层下伏隔核DA释放的抑制性调节作用。     

丁螺环酮加强戊四氮致小鼠惊厥作用

新型非苯二氮(艹卓)类抗焦虑剂丁螺环酮(Bus)(1～10 mg·kg~1)使戊四氮(PTZ)致惊厥作用的CD_(50)下降12～37％,具有剂量依赖性和时间效应关系.色氨酸羟化酶抑制剂对氯苯丙氨酸(250 mg·kg~1)和单胺耗竭剂利血平(2mg·kg~1)均可增强PTZ致惊厥作用,但同时减弱Bus的增强作用.而α_2受体激动剂可乐定和赛拉嗪以及DA受体激动剂阿朴吗啡,拮抗剂氟哌啶醇均不影响Bus的增强作用.结果表明,Bus的增强作用有5-HT能神经元的参与.     

多巴胺诱导大鼠海马脑片Ca~(2 )-钙调素依赖性蛋白激酶Ⅱ活性的抑制作用(英文)

目的:研究多巴胺(DA)对大鼠海马脑片Ca~(2 )-钙调素依赖性蛋白激酶Ⅱ(CCDPK Ⅱ)活性的影响。方法:采用大鼠海马脑片体外培养模型,以~(32)P-掺入法测定CCDPK Ⅱ的活性。结果:外源性DA可显著降低大鼠海马脑片CCDPK Ⅱ活性,并有一定的浓度依赖性和时间依赖性。去除胞外的Ca~(2 )对不同浓度DA诱导的CCDPK Ⅱ活性抑制有部分或完全保护作用。阿扑吗啡(非特异性DA受体激动剂)、SKF38393(特异性D_1样DA受体激动剂)和喹吡罗(特异性D_2样DA受体激动剂)均可显著降低CCDPK Ⅱ的活性。Sch-23390(特异性D_1样DA受体拮抗剂)和多潘立酮(特异性D_2样DA受体拮抗剂)均可拮抗DA所诱导的酶活性抑制。结论:DA抑制海马CCDPK Ⅱ的活性,其作用机制与D_1样和D_2样受体以及胞外Ca~(2 )的内流有关。     

培高利特对黑质多巴胺神经元放电活动的激动作用

研究Ｄ２受体激动剂培高利特（Ｐｅｒｇｏｌｉｄｅ，Ｐｅｒ）对大鼠黑质多巴胺（ＤＡ）神经元放电活动的影响，并与溴陷亭（ｂｒｏｍｏｃｒｉｐｔｉｎｅ，Ｂｒｏ）作比较，同时验证Ｐｅｒ在整体动物有无Ｄ１激动剂性质。胞外单细胞电活动记录技术。二个药物均能抑制敏感及不敏感的ＤＡ神经元自发放电活动。     

左旋千金藤立定对溴隐亭诱导的哺乳期大鼠促乳素水平低下的拮抗作用

目的:研究左旋千金藤立定(SPD)对溴隐亭(Bro)诱导的促乳素(PRL)水平低下的对抗作用。方法:哺乳期母鼠sc Bro 0.5mg·kg~(-1)·d~(-1),PRL显著降低,乳腺组织发育不良,而且仔鼠体重增长缓慢。用放免法测定母鼠PRL,检查乳腺发育状况,评价SPD的对抗作用。结果:SPD30及100mg·kg~(-1)·d~(-1)ip,能够显著对抗Bro诱导的母鼠PRL降低,分娩后d15PRL为11±4及23±6μg·L~(-1)(生理盐水为7±2),而且乳腺组织发育正常,仔鼠在出生后d11—15内迅速生长发育。结论:SPD能阻断大鼠脑垂体前叶的D_2受体,是一个D_2受体的拮抗剂。     

左旋千金藤立定对大鼠血清中催乳素水平的影响(英文)

目的:观察左旋千金藤立定(SPD)对血清催乳素(PRL)水平的影响,研究SPD的药理作用。方法:成熟♀鼠ip多巴胺受体激动剂、拮抗剂或SPD后断头取血,然后用放射免疫法测定血清中的催乳素水平。结果:SPD引起血清PRL水平迅速而显著的增加,效应持续约1h,具有剂量依赖性。SPD的半数有效剂量为3.7mg·kg~(-1)(95％可信限为2.6—4.3mg·kg~(-1))。剂量为20mg·kg~(-1)时产 生最大效应,使血清PRL水平达到448±64μg·L~(-1),0.2mg·kg~(-1)则无效。对于多巴胺受体激动剂培高利特(pergolide)引起的PRL水平低下,SPD5mg·kg~(-1)有部分对抗作用,10mg·kg~(-1)能够完全对抗。结论:SPD是D_2多巴胺受体拮抗剂。     

脊髓以上多巴胺D2受体介导左旋四氢巴马汀的镇痛作用

目的：研究ＤＡ受体与左旋四氢巴马汀（ｌ－ＲＨＰ）镇痛作用的关系,以阐明ｌＴＨＰ的镇痛机制。方法：腹腔（ＩＰ）与鞘内（ＩＴＨ）给药,以大鼠甩尾反应观测热伤害性致痛阈。结果：ｉｐ ｌ－ＴＨＰ或Ｄ２受体拮抗剂螺哌隆产生剂量依赖性镇痛效应,并能被Ｄ２受体激动剂喹吡罗翻转,蛤不被纳洛酮翻转。而ｉｔｈ ｌＴＨＰ或螺哌隆无镇痛效应,但它们能拮抗ｉｔｈ喹吡罗引起的镇痛效应。结论：激动脊髓Ｄ２受体或阻滞脊髓以上水平     

大鼠多巴胺D1受体介导二氢埃托啡位置偏爱效应

AIM: To study the influence of dopamine (DA) receptor antagonists upon the rewarding property of dihydroetorphine (DHE). METHODS: Conditioned place preference (CPP) paradigm was used to characterize the rewarding effect of DHE. DA receptor antagonists were injected administered subcutaneously or peritoneally and microinjected into nucleus accumbens (NAcc). RESULTS: DHE (0.05, 0.5, and 5.0 micrograms.kg-1, s.c.) produced place preference (P < 0.01). Both the DA receptor antagonist haloperidol and the selective D1 receptor antagonist Sch-23390 attenuated the place preference produced by DHE (0.5 microgram.kg-1, s.c.). l-Sulpiride and spiperone, selective D2 receptor antagonists, had no such effects. CONCLUSION: The D1 (but not D2) receptors in NAcc are crucial in the mediation of the rewarding effect of DHE.     

Dopaminergic effects on kidney function and responsiveness of aldosterone, plasma renin activity, prolactin, catecholamines, and blood pressure to stimulation in patients with prolactinoma. Comparison of the efficacy of pergolide and bromocriptine therapy

8 beta-[(Methylthio)methyl]-6-propylergoline (pergolide) is a new, potent, long-acting dopaminergic DA2 receptor agonist currently being investigated for therapeutic use in patients with hyperprolactinemia, acromegaly or Parkinsons's disease. Since the influence of bromocriptine, a well-established dopaminomimetic compound, on aldosterone responsiveness and plasma renin activity is still a matter of debate, the efficacies of both compounds on these parameters and on kidney function, blood pressure, catecholamine release and prolactin levels were compared in 16 patients with prolactinoma. Supine and furosemide (40 mg i.v.)-stimulated plasma renin activity and aldosterone levels were similarly decreased by bromocriptine (2.5-30 mg/d) and pergolide (50-500 micrograms/d). Suppression of blood pressure, inhibition of stimulated norepinephrine release, increase in creatinine clearance, and decrease in base-line prolactin levels were similarly pronounced during treatment with both compounds. Metoclopramide (10 mg i.v.)-induced stimulation of aldosterone and prolactin levels, however, were suppressed only by bromocriptine and not by pergolide. It remains to be studied whether this difference between bromocriptine and pergolide is due to a potential agonist effect of pergolide on dopaminergic DA1 receptors which are influenced by bromocriptine in an antagonistic manner, or whether pergolide can be more readily displaced from its receptors than bromocriptine.     

Dopamine receptor subtypes: in vivo biochemical evidence for functional interaction

SKF 38393, a selective D-1 dopamine (DA) agonist, enhanced the ability of spiperone, a D-2 antagonist, to increase rat striatal DA metabolite concentrations. Conversely, SKF 38393 reduced the abilities of pergolide and LY 171555, D-2 agonists, to decrease striatal DA metabolite concentrations. These findings are discussed in terms of a possible functional interaction between D-1 and D-2 DA receptors.     

Selective inactivation of dopamine D1 and D2 receptors in 6-hydroxydopamine-lesioned rats: evidence that the effect of D1 and D2 agonists can be expressed in the absence of the heterologous DA receptor

EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) markedly decreased the density of dopamine (DA) D1 and D2 receptors in the lesioned and normal striatae of rats lesioned unilaterally with 6-hydroxy-DA. By treatment with either the D1 antagonist SCH 23390 or the D2 antagonist raclopride, together with EEDQ selective inactivation of D2 and D1 receptors, respectively, are obtained. In rats with decreased density of D1 receptors the circling behaviour response to the D1 agonist SK&F 38393 was markedly inhibited 24 hours after EEDQ treatment, whereas the similar response to the D2 agonist pergolide was unchanged. In rats with decreased density of D2 receptors the effects of pergolide and the partial D2 agonist (-)-3-PPP were antagonized, while the effect of SK&F 38393 was unchanged. These results indicate that the effect of D1 and D2 agonists can be expressed in the absence of normal densities of the heterologous DA receptor. In contrast, the responses from homologous DA receptors, mediating the circling behaviour from the denervated side of the brain, are highly sensitive to the inactivating effect of EEDQ.     

Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025–2.0 mg/kg) and bromocriptine (0.25–6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05–0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects.The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhabitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.     

多巴胺对大鼠纹状体突触前和突触后膜 Na+,K+-ATP 酶活性调节的差异

用蔗糖-Ficol梯度不连续离心法制备大鼠纹状体突触前膜和突触后膜,研究多巴胺(DA)受体对突触前和突触后膜Na⁺,K⁺-ATP酶活性的调节作用。结果表明,DA(10^-8～10^-5mol·L^-1)显著抑制突触后膜Na⁺,K⁺-ATP酶的活性,单独用选择性D1(SKF38393)或D2(LY171555)受体激动剂均无抑制作用,而当二者合用时则产生与DA相似的抑制效应。DA对Na⁺,K⁺-ATP酶的抑制效应可被单独用选择性D1(SCH23390)或D2(spiperone)受体拮抗剂而逆转。相反,DA却能显著激活突触前膜Na⁺,K⁺-ATP酶的活性,单用spiperone即可逆转此激活效应。结果提示,突触前和突触后DA受体对Na⁺,K⁺-ATP酶的调节存在差异,可能与它们的不同生理功能有关。     

Pergolide elevation of MHPG sulphate concentration in rat hypothalamus blocked by spiperone and mimicked by other dopamine agonists

Pergolide increased the concentration of MHPG sulphate (3-methoxy-4-hydroxy-phenylethylene glycol sulphate) in rat hypothalamus, and the increase was prevented by pretreatment with spiperone, a dopamine antagonist. An increase in hypothalamic MHPG sulphate concentration similar to that caused by pergolide was found after injection of quinpirole, a 'partial ergoline' that is a selective D2 agonist not affecting alpha-adrenoceptors, and by (-)-N-propylnorapomorphine, a dopamine agonist not related to the ergolines. Although the increase in MHPG sulphate concentration produced by pergolide had earlier been assumed to result from blockage of alpha-adrenoceptors, the present data indicate that it is an effect produced by dopamine D2 receptor stimulation.