Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions

The selective dopamine (DA) D-1 antagonist SCH 23390 antagonized the contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 in rats lesioned unilaterally with 6-hydroxy-DA but had a 600 times weaker effect against the preferential DA D-2 agonist pergolide. The D-2 antagonists clebopride and spiroperidol had the reverse selectivity. The mixed D-1/D-2 antagonists cis(Z)-flupentixol and cis(Z)-clopenthixol blocked the circling induced by either agonist. It is concluded that circling behaviour is mediated by closely related but independent DA D-1 and D-2 receptor sites.     

Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine,SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of ³H-DA in rabbit striatal slices (D-2) and the affinity to ³H-piflutixol (D-1) and ³H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists. Furthermore, the results indicate that both DA D-1 and D-2 receptors are involved in the effect of apomorphine, since selective antagonists induced maximally 50% inhibition. Complete blockade was only found in combination experiments and by the mixed D-1/D-2 antagonists cis(Z)-flupentixol, cis(Z)-clopenthixol, and clozapine.     

Molecular cloning and pharmacological characterization of rat melatonin MT1 and MT2 receptors

In order to interpret the effects of melatonin ligands in rats, we need to determine their activity at the receptor subtype level in the corresponding species. Thus, the rat melatonin rMT(1) receptor was cloned using DNA fragments for exon 1 and 2 amplified from rat genomic DNA followed by screening of a rat genomic library for the full length exon sequences. The rat rMT(2) receptor subtype was cloned in a similar manner with the exception of exon 1 which was identified by screening a rat genomic library with exon 1 of the human hMT(2) receptor. The coding region of these receptors translates proteins of 353 and 364 amino acids, respectively, for rMT(1) and rMT(2). A 55% homology was observed between both rat isoforms. The entire contiguous rat MT(1) and MT(2) receptor coding sequences were cloned, stably expressed in CHO cells and characterized in binding assay using 2-[(125)I]-Iodomelatonin. The dissociation constants (K(d)) for rMT(1) and rMT(2) were 42 and 130 pM, respectively. Chemically diverse compounds previously characterized at human MT(1) and MT(2) receptors were evaluated at rMT(1) and rMT(2) receptors, for their binding affinity and functionality in [(35)S]-GTPgammaS binding assay. Some, but not all, compounds shared a similar binding affinity and functionality at both rat and human corresponding subtypes. A different pharmacological profile of the MT(1) subtype has also been observed previously between human and ovine species. These in vitro results obtained with the rat melatonin receptors are thus of importance to understand the physiological roles of each subtype in animal models.     

Phosphorylation of membrane proteins in response to persistent stimulation of adenylate cyclsae-linked dopamine receptors in slices of striatum

Prolonged incubation of slices of striatum with agonists of D-1 dopamine receptors increased phosphorylation of at least 5 membrane protein bands. The extent of the increase in phosphate-incorporation depended on the concentration (10^?5 M?10^?4 M) of the agonist in the incubation medium and the duration of incubation (20 min or longer). Preincubation of slices with haloperidol (10^?6 M) greatly reduced, while ( ? )sulpiride (10^?6 M) failed to alter the increase of phosphorylation elicited by dopamine. Prolonged incubation of striatal slices with LY 141865 (10^?5 M) or isoproterenol (10^?5 M) increased the phosphate-incorporation only in one of the protein bands with an apparent molecular weight of 42,000. Incubation of striatal slices with cholera toxin increased the phosphorylation of protein bands in a similar way to those elicited by dopamine. The present results suggestthat the increased phosphorylation of certain protein bands elicited by prolonged exposure of striatal slices to D-1 dopamine receptor agonists may be associated with the desensitization of dopamine-sensitive adenylate cyclase.     

GABA_B受体的最新进展:从药理学到分子生物学(英文)

Bicuculline-insensitive receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), GABAB receptors, are a distinct subclass of receptors that mediate depression of synaptic transmission and contribute to neu-ronal inhibition. When activated, these receptors reduce transmission at excitatory and inhibitory synapses, as a result of an increase in K conductance, or a decrease in voltage-dependent Ca2 currents. They are also linked to G-proteins, or intracellular effector systems in a very complex manner. The recent development of highly specific and potent agonists and antagonists for these receptors has led to a much better understanding of their physiology and pharmacology, including their heterogeneity, as well as their molecular biology. Over the past year, expression and cloning studies have contributed to major advances in characterizing GABAB receptor structure, with the discovery of the amino acid sequences of GABABRla/R1b splice variants and GABABR2 receptors. These isoforms are     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

Collateral efficacy as a pharmacological problem applied to new drug discovery

Before the direct measurement of G-protein-coupled receptor (GPCR) behaviour was possible, all GPCR ligand efficacy was assumed to be linear, that is, to emanate only from physiological activation of the receptor as observed through tissue response. Subsequent advances in technology have enabled the observation of the effects unrelated to GPCR response (e.g., receptor phosphorylation and internalisation), as well as separate response pathways independent of G protein activation (i.e., β-arrestin extracellular signal-related kinase [ERK1/2] activation). These increased vantage points have revealed ligands that have efficacies for some, but not all, GPCR behaviours; this is referred to as collateral efficacy. These ideas are explored, with examples, in the context of possibly more focused therapeutic application of agonists and antagonists.     

Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test

The role of genotype in the effects of selective D1 and D2 dopamine agonists and antagonists on behavioural despair (Porsolt's test) was studied. Mice of nine inbred strains showed significant interstrain differences in duration of immobility. The influence of dopaminergic drugs was assessed in six strains characterized by different levels of swimming activity. SKF 38393 (10 mg/kg), an agonist at D1 dopamine receptors, increased swimming activity, while the D1 antagonist SCH 23390 (0.2 and 0.5 mg/kg) reduced it, the effects being genotype dependent. The involvement of D2 dopamine receptors in the regulation of mouse behaviour in the forced swimming test was not so evident; the D2 agonist bromocriptine (10 mg/kg) produced no significant effect. The D2 agonist quinpirole (2.5 mg/kg) increased immobility in the majority of the mouse strains studied, while in CBA mice it resulted in a marked reduction of immobility. The D2 antagonist sulpiride (20 mg/kg) decreased immobility and increased active swimming only in two strains. The present results suggest a different role for D1 and D2 dopamine receptors in the regulation of swimming in the mouse.     

多巴胺D_2/血管紧张素AT_1嵌合受体:D_2受体第三细胞内环影响受体与配基结合以及与G蛋白偶联的特性(英文)

目的:研究受体第三细胞内环(IL_3)的长度对受体与配基结合及与G蛋白偶联特性的影响.方法:用目前已知的G蛋白偶联受体中IL_3最短的血管紧张素Ⅱ AT_1受体的IL_3替换野生型D_2受体较长的IL_3,组成D_2/AT,嵌合受体.结果:与野生型D_2受体相比,D_2/AT_1嵌合受体与拮抗剂的亲和性均降低,与激动剂的亲和性有的增高,有的降低.嵌合受体失去与G蛋白偶联的能力,也不能产生磷酸肌醇水解.结论:受体的IL_3对受体配基结合位点和空间构象有一定影响;受体与G蛋白的偶联不仅与IL_3有关,而且还受非IL_3区域的影响,而IL_3的长度是决定这两方面影响的因素之一.     

Dopaminergic neurons: An in vivo system for measuring drug interactions with presynaptic receptors

Summary An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.A partial account of this work was presented at the International Symposium on Antipsychotic Drugs, Pharmacodynamics and Pharmacokinetics held at the Wenner-Gren Center, Stockholm, Sweden on September 17–18, 1974     

In vivo assessment of release and metabolism of dopamine in the ventrolateral striatum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists

The ability of specific dopamine (DA) receptor agonists and antagonists to modify the release and metabolism of DA in the ventrolateral striatum of awake rats was assessed using in vivo microdialysis. The specific DA D₂ receptor antagonist, raclopride (0.1, 0.5 and 2.0mg/kg, i.p.), dose-dependently increased release of DA and levels of the metabolites DOPAC and HVA, while the D₂ receptor agonist, quinpirole (0.03, 0.1 and 0.3 mg/kg), decreased levels of DA, DOPAC and HVA. The DA D₁ receptor antagonist, SCH23390 ([R + (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-o]) (0.01, 0.05 and 0.25 mg/kg), produced an increase in DA, DOPAC and HVA but of a lesser magnitude than raclopride. The D₁ agonist SKF38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (1.0, 3.0 and 10.0 mg/kg) failed to affect the release of metabolism of DA at any dose. These results support previous findings that activation of D₂ receptors has greater control over in vivo DA function, than drugs specifically affecting D₁ receptors.     

Evidence for central selective dopamine receptor stimulation in the mediation of nomifensine-induced hyperalgesia and the effects of opiate antagonists

The hyperalgesic effects of nomifensine were studied using a modified tail immersion test in mice. Intracerebroventricular injection of the peripherally acting dopamine antagonist domperidone totally antagonized nomifensine-induced hyperalgesia but this blockade was not evident after peripheral administration of domperidone suggesting mediation of hyperalgesia at a central location. The dopamine antagonist cis-flupenthixol and also bromocriptine shifted the nomifensine-induced hyperalgesia dose-response curve to the right, whereas sulpiride had no antagonistic effect. These results are discussed in relation to the D-1 and D-2 classification of dopamine receptors, and their putative agonists and antagonists. Naloxone produced a blockade of nomifensine-induced hyperatgesia, but another opiate antagonist MR 1452, though inherently hyperalgesic, did not modify the hyperalgesia produced by nomifensine. These findings do not rule out the participation of an opiate receptor in the mechanism of opiate antagonist blockade of nomifensine-induced hyperalgesia. However, they may suggest that MR 1452-induced hyperalgesia depends on a different mechanism from that of induced by nomifensine since they were not synergistic.     

Differential influence of D1 and D2 dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum

1. The effects exerted by D₁ and D₂ dopamine agonists and antagonists on the acute opiate withdrawal induced by μ- and κ-receptor agonists were investigated in vitro.
2. Following a 4 min in vitro exposure to morphine (moderately selective μ-agonist), [D-Ala², Me-Phe⁴, Gly-ol⁵]enkephalin (DAMGO, highly selective μ-agonist) or U-50488H (highly selective κ-agonist) the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone.
3. The non-selective dopamine receptor antagonist haloperidol when added before or after the opioid agonists, was able dose-dependently to prevent or to reverse the naloxone-induced contracture after exposure to μ- (morphine and DAMGO) and κ- (U-50488H) opioid agonists. The non-selective dopamine receptor agonist, apomorphine, was able to exert the same effects only at the highest concentration used.
4. The selective D₂ dopamine receptor antagonist, sulpiride, was also able to reduce dose-dependently both μ- and κ-opioid withdrawal, whereas the D₁-receptor selective antagonist SCH 23390 did not affect either μ- or κ-opioid withdrawal.
5. Bromocriptine, a D₂ selective dopamine receptor agonist was able to increase significantly, and in a concentration-dependent manner, the naloxone-induced contracture by μ- and κ-opioid agonists, whereas SKF 38393, a D₁ selective dopamine receptor agonist, increased only the withdrawal after morphine or U50-488H.
6. Our data indicate that both D₁ and D₂ dopamine agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the dopaminergic system and opioid withdrawal at both the μ- and κ-receptor level.
7. Furthermore, the ability of sulpiride to block strongly opiate withdrawal when compared to SCH 23390, as well as the effect of bromocriptine to increase opiate withdrawal suggest that D₂ dopamine receptors may be primarily involved in the control of opiate withdrawal.

     

多巴胺受体系统在诱发产生的大麻酚类戒断症状中不起主要作用(英文)

AIM: To determine the dopaminergic systeminvolvement in precipitated cannabinoid withdrawalsyndrome. METHODS: The dopamine D_1 receptorantagonist SCH23390 or the dopamine D_2 receptorantagonost sulpiride was administered to rats chronicallytreated with either △~9-tetrahydrocannabinol (THC) orvehicle. Subjects were then injected with eitherSR141716A or vehicle and behavior was observed for1 h. RESULTS: Administration of the cannabinoidreceptor antagonist SR141716A to animals chronicallytreated with THC as described by Tsou et al (1995)     

G protein-coupled receptor binding and pharmacological evaluation of indole-derived thiourea compounds

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT_2A and 5-HT_2C receptors, as well as their functional activities at the 5-HT_1A and D₂ receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT_1A receptor, showing, at the same time, significant selectivity over the studied 5-HT₂ and D₂ receptor subtypes. The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity.     

Biphasic firing response of nucleus accumbens neurons elicited by THPB-18 and its correlation with DA receptor subtypes

AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antagonist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was recorded in the nucleus accumbens (NAc) neurons of naive and unilateral-6-hydroxydopamine (6-OHDA)-lesioned Sprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by thechange of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced a decrease-increase biphasic firing pattern in the NAc neurons during cumulative doses. High dose of THPB- 18 was capable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on NAc firing activity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which wasreversed by the D1 selective antagonist SCH23390. The tested NAc neurons were effectively inhibited byiontophoretically applied THPB- 18 in 90 % of 6-OHDA-lesioned rats, while THPB- 18 caused variable effects on thefiring of NAc neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked byiontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to l-stepholidine,THPB-18 also possesses the “D1 agonistic-D2 antagonistic“ dual action on the VTA-NAc DA system.AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antago-nist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was re-corded in the nucleus accumbens (NAc) neurons of naive and unilateral-6-hydroxydopamine (6-OHDA)-lesionedSprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by thechange of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced adecrease-increase biphasic firing pattern in the NAc neurons during cumulative doses. High dose of THPB- 18 wascapable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on NAc firingactivity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which wasreversed by the D1 selective antagonist SCH23390. The tested NAc neurons were effectively inhibited byiontophoreticaUy applied THPB- 18 in 90 % of 6-OHDA-lesioned rats, while THPB- 18 caused variable effects on thefiring of NAc neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked byiontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to l-stepholidine,THPB-18 also possesses the “D1 agonistic-D2 antagonistic“ dual action on the VTA-NAc DA system.     

Differential dopaminergic modulation of executive control in healthy subjects

Rationale Executive control (EC) has different subcomponents, e.g., response inhibition (measured, for example, by the Stroop task) and working memory (WM—measured, for example, by delayed response tasks, DRT). EC has been associated with networks involving the prefrontal cortex (PFC). Moreover, there is evidence that dopamine agonists, especially those with a D1 profile, may modulate EC, since in the PFC D1 subtype receptors are more abundant.Objective This study aimed to selectively distinguish whether D1 versus D2 dopamine agonism differentially influences EC related to the inhibition of irrelevant information and WM. Because of its D1 component, we predicted that the administration of pergolide (mixed D1/D2 agonist), in comparison with bromocriptine (D2 selective agonist) and placebo, would enhance performance in both EC tasks. Using a lateralized Stroop task, we predicted a decrease in the interference effect, as well as error rates, while no increase in facilitation effects. For the DRT task, we predicted fewer error scores in the delay condition.Methods Forty male healthy subjects participated in this randomized, double-blind, placebo-controlled, crossover study.Results For the Stroop task no superiority of pergolide was found; however, with bromocriptine, decreased interference was found. No modulation of lateralization effects was shown in interference measures. Moreover, subjects on pergolide showed an absence of facilitation effects. No effects of either agonist were found for the DRT.Conclusion Our findings suggest that dopamine agonists modulate two EC tasks differently. Furthermore, there seems to be a selective modulation of different aspects of the Stroop task.     

Evidence that apomorphine and pergolide induce rotation in rats by different actions on D1 and D2 receptor sites

Apomorphine and the ergot derivative pergolide induced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation of the ascending dopamine pathways. This was interpreted as an action on supersensitive receptors. However, large differences were found when comparing apomorphine and pergolide dose-response curves as well as the patterns of rotational behaviour the compounds elicited. Pergolide had a steep dose-response curve, while apomorphine had a flatter curve reaching a plateau at the dose of 1 mg/kg s.c. In doses higher than 1 mg/kg, apomorphine induced self-mutilation, while this was infrequent after pergolide. Apomorphine induced a two-peak pattern of rotation that never occurred when the same rats were tested with the ergot derivative. Both drugs induced dose-dependent ipsilateral rotation in animals with unilateral striatal kainic acid lesions but at doses 100 times higher. This effect was interpreted as an action on normosensitive receptors situated on the intact side. The differences between apomorphine and pergolide may be explained in terms of actions on different dopamine receptors, since the agonists were differently inhibited by neuroleptics acting on D1- or D2-type receptors. The D1/D2 antagonist cis-flupenthixol blocked both apomorphine and pergolide with similar potency, while sulpiride, a substituted benzamide devoid of any effect on D1 receptors, was a poor inhibitor of the apomorphine response. In contrast, sulpiride blocked pergolide rotation at doses 1000 times lower than those needed to block apomorphine rotation. Our results suggest the existence of functionally distinct sites related to the D1/D2 receptor classification.     

大鼠多巴胺D_1受体介导二氢埃托啡位置偏爱效应(英文)

目的:研究不同的多巴胺(DA)受体拮抗剂对二氢埃托啡(DHE)奖赏效应的影响,方法:采用条件性位置偏爱模型评价DHE的奖赏效应,DA受体拮抗剂采取外周给药或直接到伏隔核内,结果:DHE(0.05、0.5和5.0μg·kg~(-1),sc)产生位置偏爱效应,氟哌啶醇、Sch-23390 sc或直接注射到伏隔核都能抑制DHE(0.5μg·kg~(-1),sc)的偏爱效应;而l-舒必利和螺哌隆在这两种给药途径下都不影响DHE的偏爱效应,结论:伏隔核中D_1受体(而不是D_2受体)在DHE偏爱效应中起关键作用。     

激动多巴胺受体抑制大鼠纹状体脑片Ca^2＋—钙调蛋白依赖性蛋白激酶Ⅱ活性

目的：研究缺氧时纹状体多巴胺能神经毒性的机制。方法：采用大鼠纹状体脑片体外培养模型。以底物磷酸化^32P-掺入法测定Ca^2 -钙调蛋白依赖性蛋白激酶Ⅱ（CCDPKⅡ）的活性。结果：缺氧30min,纹状体脑片CCDPKⅡ活性降低75％,慢性利血平化使得缺氧诱导的酶活性降低程度减轻,与对照组相比大约降低40％。外源性多巴胺显著降低纹状体脑片CCDPKⅡ活性。去除胞外Ca^2 后,多巴胺诱导的酶活性降低作用被削弱。阿扑吗啡（非特异性多巴胺受体激动剂）、SKF38393（特异性D1样受体激动剂）和喹吡罗（特异性D2样受体动剂）均可显著降低CCDPKⅡ的活性。Sch-23390(特异性D1样受体拮抗剂）和吗丁啉（特异性D2样受体拮抗剂）均可拮抗多巴胺所诱导的酶活性的抑制作用。结论：多巴胺参与缺氧诱导的纹状体CCDPKⅡ活性抑制,其作用机制与D1样和D2样受体的激活以及胞外Ca^2 的内流有关,从而导致多巴胺介导的纹状体神经损伤。