慢性给予左旋千金藤立定对纹状体多巴胺D1和D2受体密度和更新…

目的：观察慢性给予左旋千金藤立定（ＳＰＤ）对纹状体多巴胺（ＤＡ）受体密度和更新率的影响，推论ＳＰＤ的药理性质。方法：应用ＥＥＤＱ失活ＤＡ受体，用放射受体结合分析法测定受体的密度，计算有关的动力学参数。结果：慢性给予ＳＰＤ２１ｄ便纹状体Ｄ１与Ｄ２受体密度分别增加４１．５％和４３．７％。并且慢性给予ＳＰＤ改变ＤＡ受体的更新率，使Ｄ１受体的生成速度由对照组的１．７７ｐｍｏｌ·ｈ＾－１／ｇ ｐｒｏｔｅｉｎ     

左旋千金藤立定对大鼠纹状体缺血性损伤的拮抗作用

AIM: To elucidate the protection of l-stepholidine (SPD) on neuronal morphology and function against the striatal ischemic injury in rat. METHODS: The forebrain ishemia to Sprague Dawley rats was induced with four-vessel occlusion. Histological examination was performed on the dorsolateral striatum with cresylviolet stain. In striatal slices of rat as an in vitro ischemic model, the activity of calcium/calmodulin-dependent protein kinase II (CCDPK) and lactate dehydrogenase (LDH) was examined by the method of 32P-incorporation and colorimetry, respectively. RESULTS: In the SPD-treated groups, most of the neurons in the striatum kept the normal morphological appearance after 30-min ischemia followed by 6-h or 12-h reperfusion. The number of neurons was much more in SPD groups than that in vehicle group. The sparse and abnormal neurons were observed in the vehicle group. SPD attenuated the ischemic effect on the CCDPK activity in striatal slices. In addition, SPD inhibited the leakage of LDH from neurons induced by ischemia in incubated striatal slices. CONCLUSION: SPD protected striatal neurons against ischemic injury and antagonized the inhibitory action on CCDPK activity induced by ischemia. SPD reduced the leakage of LDH from striatal neurons induced by ischemia.     

四氢原小檗碱类对小牛纹状体D_1和D_2多巴胺受体结合的特性(英文)

目的:研究四氢原小檗碱类(THPB)对脑内多巴胺受体D_1和D_2亚型的结合特性,并阐明它们之间的构效关系.方法:放射配位体测定结合双位点模型分析.结果:4个THPB与D_1受体以R_H和R_L双位点结合,它们在C_2和C_9或C_2和C_(10)位有两个羟基,另外11个THPB与D_1受体以单位点结合.对于D_2受体,11个被检测的化合物均以单位点结合,其中,在C_2位有羟基的THPB亲和力最强.结论:在C_2和C_9或C_2和C_(10)位有双羟基的THPB具有D_1受体激动剂的内在活性,其它THPB则无此活性.11个THPB均为D_2受体拮抗剂.     

左旋千金藤立定加强尾核脑片多巴胺释放(英文)

观察左旋千金藤立定((-)-stepholidine,SPD)对家兔尾核脑片多巴胺(DA)释放的影响.方法:以[~3H]DA预孵脑片,测定DA放射性.结果:选择性D_2受体激动剂LY171555以剂量依赖方式抑制电诱发的兔尾核脑片[~3H]DA释放.SPD可翻转LY 171555对[~3H]DA释放的抑制作用,并以剂量依赖方式加强[~3H]DA释放,在无电刺激条件下,SPD诱发大鼠尾核[~3H]DA释放被蛋白激酶C(protein kinase C,PKC)激活剂咐波酯所加强.结论:SPD对突触前D_2自身受体是阻滞剂.     

多巴胺D_1和D_2受体拮抗剂对乙醇引起大鼠纹状体抗坏血酸释放的影响

应用脑内透析技术结合高效液相色谱电化学检测研究了多巴胺Ｄ１和Ｄ２受体拮抗剂对乙醇引起大鼠纹状体抗坏血酸（ＡＡ）释放的影响。乙醇（３．０ｇ·ｋｇ－１,ｉｐ）显著增加纹状体抗坏血酸释放,高于基础水平的２００％左右。多巴胺Ｄ２受体拮抗剂舒必利（２００ｍｇ·ｋｇ－１,ｉｐ）能显著拮抗乙醇引起的纹状体ＡＡ释放,而Ｄ１受体拮抗剂ＳＣＨ２３３９０（０．５,１．０ｍｇ·ｋｇ－１,ｓｃ）则能协同增加其释放。非选择性多巴胺受体拮抗剂氯丙嗪、氟哌啶醇、氯波必利对纹状体ＡＡ基础释放及乙醇引起纹状体ＡＡ释放均无显著影响。联合使用舒必利（１００ｍｇ·ｋｇ－１,ｉｐ）和ＳＣＨ２３３９０（０．５ｍｇ·ｋｇ－１,ｓｃ）对乙醇引起的纹状体ＡＡ的释放也无影响。此结果提示,多巴胺Ｄ１受体和Ｄ２受体的阻断对乙醇引起的大鼠纹状体ＡＡ释放具有相反的调节作用。     

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.     

左旋千金藤立定对大鼠血清中催乳素水平的影响

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增加，效应持续效约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     

Age related decrease in the density of dopamine D1 and D2 receptors in corpus striatum of rats

The densities (Bmax) and apparent dissociation constants (Kd) of D1 and D2 receptors in striatum and of 5-HT2 receptors in cortex of rats aged 1, 3, 7 and 12 months have been determined using 3H-SCH 23390, 3H-spiperone and 3H-ketanserin, respectively, as ligands. No changes in Kd's were seen. The density of D1 receptors decreases continuously from 1 month, attaining approximately 65% at 12 months of age. The density of D2 receptors increases slightly from 1 to 3 months, followed by a decrease until 12 months of age, where the level is approximately 80% of the 1 month value. The rise D2 receptor density is less apparent when calculated on a protein basis due to a concomitant increase in protein content of corpus striatum. The ratio between D1 and D2 receptors remains constant, approximately 4.2, from 1 to 12 months of age. The density of 5-HT2 receptors decreased from 1 to 7 months and remained at this level also after 12 months.     

Chronic neuroleptic treatment increases D-2 but not D-1 receptors in rat striatum

In vitro binding of [3H]cis(Z)-flupentixol (FPT) to rat striatal membranes was evaluated as an assay for D-1 receptors. It was found that under the appropriate assay conditions [3H]FPT bound to a single saturable site which was most abundant in striatum and bound dopaminergic agonists in the potency order that these drugs demonstrate for adenylate cyclase. These data support previous work suggesting that [3H]FPT labels the D-1 receptor. Next, rats received haloperidol or fluphenazine for 54 days and striatal dopamine receptors were assayed 72 h later. The drug treatments increased the density of D-2 receptors as measured by [3H]spiperone binding by 40% and 25% respectively. However, no change was observed in D-1 receptor density. We conclude that effects of chronic neuroleptic treatment that depend upon increased dopamine receptor density are mediated via the D-2 receptor subtype.     

Chronic treatment with diisopropylfluorophosphate increases dopamine turnover in the striatum of the rat

Following the administration of a single dose of diisopropylfluorophosphate (DFP) there is a rise of acetylcholine (ACh) in the rat striatum and frontal cortex. With chronic treatment, striatal ACh content returns to normal, but frontal cortex ACh remains elevated. In striatum but not frontal cortex, there is a rise of dopamine (DA) content and turnover after chronic DFP treatment. We speculate that DA content and turnover are increased after chronic DFP because the nigrostriatal neuronal feedback loop and local feedback loops are activated to compensate for increased cholinergic tone.     

Characteristics of tetrahydroprotoberberines on dopamine D1 and D2 receptors in calf striatum.

AIM: To study the characteristics of tetrahydroprotoberberines (THPB) on dopamine D1 and D2 receptors and elucidate their structure-activity relationship. METHODS: Radioligand assay in vitro with a two-site model program analysis. RESULTS: Four THPB with two hydorxyl groups on C2 and C9 or C2 and C10 exhibited RH and RL two binding sites to D1 receptors and guanosine triphosphate regulated the RH binding site of SPD and THPB-132A in competition assay, while eleven THPB including nonhydroxy-THPB, monohydroxy-THPB, and THPB with two hydroxyl groups attaching to C3 and C10 showed one binding site to D1 receptors under the same conditions. However, the tested eleven THPB all manifested one binding site to D2 receptors in competition assay, and the 2-hydroxy-THPB had the most potent affinity for D2 receptors. CONCLUSION: Dihydroxy-THPB with two hydroxyl groups attaching to C2 and C9 or C2 and C10 possess the intrinsic activity of agonist to D1 receptors, while the other THPB do not. The tested eleven THPB all are the antagonists of D2 receptors.     

Effects of （-）stepholidine in animal models for schizophrenia

AIM: (-)Stepholidine (SPD) is an active ingredient of the Chinese herb Stephania intermedia, which binds to the dopamine D(1) and D(2) like receptors. Biochemical, electrophysiological and behavioural experiments have provided strong evidence that SPD is both a D(1) and a D(2) antagonist, which could make SPD a unique antipsychotic drug. The present study aimed to investigate the antipsychotic properties of SPD in two animal models for schizophrenia. METHODS: The effects of SPD, clozapine and haloperidol in increasing forelimb and hindlimb retraction time in the paw test and in reversing the apomorphine and MK801-induced disruption of prepulse inhibition was investigated. RESULTS: In the paw test, clozapine and SPD increased the hindlimb retraction time, with only a marginal effect on the forelimb retraction time, whereas haloperidol potently increased both. In the prepulse inhibition paradigm, all three drugs reverse the apomorphine-induced disruption in prepulse inhibition, while none of the drugs could reverse the MK801-induced disruption. SPD even slightly, but significantly, potentiated the effects of MK801. CONCLUSION: The data show that SPD showed antipsychotic-like effects in both the prepulse inhibition paradigm and in the paw test. Moreover, the results of the paw test suggest that SPD has an atypical character with a relatively small potency to induce extrapyramidal side effects.     

Parallel decrease in the density of dopamine D1 and D2 receptors in corpus striatum of rats from 3 to 25 months of age

The density (Bmax) and apparent dissociation constant (KD) of dopamine D1 and D2 receptors in striatum was estimated in rats of different ages (from 3.5 to 25 months) using 3H-SCH 23390 and 3H-spiperone as ligands. The density of D1 and D2 receptors decreases with age attaining 70 and 69% of the 3.5 months' value, respectively, whereas the KD's remain constant. The decreases in density of D1 and D2 receptors are parallel. Thus, throughout life the ratio between the density of D1 and D2 receptors remains constant.     

The responsiveness of D1- and D2-dopamine receptors in the striatum and hypothalamus of spontaneous and vasopressin hypertensive rats.

Low doses of apomorphine (20-50 micrograms/kg) induced an increase in the activity of an endogenous inhibitor of cAMP dependent protein Kinases (type I inhibitor) in the striatum, anterior and posterior hypothalamus of normotensive rats by stimulating D2-dopamine receptors. In contrast, high doses of the compound (2-10 mg/kg) produced a dose dependent decrease in type I inhibitor activity. In the posterior hypothalamus of vasopressin hypertensive rats and SHR the maximal increase of type I inhibitor activity was markedly higher than in normotensive animals. Moreover, apomorphine induced the increase of type I inhibitor activity in a much wider range of doses. Only as high dose of the compound as 10 mg/kg was able to decrease type I inhibitor activity. This points to a marked supersensitivity of D2 receptors and suggests the subsensitivity of D1 receptors in this brain area of hypertensive rats. In contrast, in the striatum and anterior hypothalamus of hypertensive rats the apomorphine dose response curves were similar to those in normotensive rats. Thus, it seems tha hypertension is associated with the alteration in sensitivity of D2 and D1 receptors in the posterior hypothalamus, the brain area involved in regulation of blood pressure.     

Chronic treatment with MK-801 increases the quinolinic acid-induced loss of D-1 dopamine receptors in rat striatum

Following withdrawal from short-term treatment with the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 (1 mg/kg per day) there was no significant change in the Bmax or KD of [3H]SCH23390 binding to dopamine D-1 receptors in rat striatum. Intrastriatal injection of the excitotoxin quinolinic acid (100 nmol) produced a significant decrease in [3H]SCH23390 binding. In rats withdrawn from chronic MK-801 treatment quinolinic acid produced a significantly greater loss of [3H]SCH23390 binding sites than in rats not treated with MK-801. These data indicated that striatal neurons are hypersensitive to the neurotoxic actions of quinolinic acid following withdrawal from chronic MK-801 treatment.     

Differential affinity of dopaminergic agonists and antagonists for D1 and D2 dopamine receptors in rat striatum

Dopamine (DA) receptors have been classified into two types, D1 and D2, on the basis of their pharmacological specifities and localization. We now report that lesions of striatal dopaminergic neurons by kainic acid (KA) injection or cerebral neocortex (CN) ablation, differentially affect the potency of DA agonists and antagonists in displacing 3H-spiroperidol specific binding. In particular, agonists show a preferential affinity in displacing 3H-spiroperidol from those receptors situated on intrastriatal neurons, following CN lesion. On the other hand, antagonists show a higher displacing activity for those receptors mainly located on cortical terminals following KA lesion. These data support the hypothesis of the existence of different types of DA receptors with a differential anatomical location.     

Changes in muscle tone are regulated by D1 and D2 dopamine receptors in the ventral striatum and D1 receptors in the substantia nigra.

Muscle rigidity associated with antipsychotic drug treatment is believed to result from reduced striatal dopamine neurotransmission. In the current study the regulatory roles of dopamine D1 and D2 receptor subfamilies in the dorsal (DSTR) and ventral striatum (VSTR) and substantia nigra (SN) were investigated on muscle tone, assessed as increases in tonic electromyographic (EMG) activity. Rats were injected with the irreversible D1/D2 antagonist N-ethoxycarbonyl-2-ethoxy, -1,2-dihydroquinoline (EEDQ), the reversible D1 antagonist SCH23390, or D2 antagonist sulpiride. Increased EMG activity was observed following injection of EEDQ and SCH23390 into the SN or VSTR, and sulpiride into the VSTR. Mapping, using quantitative autoradiographic analysis of dopamine receptor occupancy after striatal injections, showed D1 and D2 receptors in discrete ventral sites were associated with EMG increases. Overall the results support roles for dopamine D1 and D2 receptors in the ventral striatum, and D1 receptors in the substantia nigra, in the regulation of muscle tone.