Effects of long-term application of dopamine HCl on dopamine agonist-induced cAMP production in rat renal cortex

目的：观察长期给予盐酸多巴胺对大鼠肾皮质多巴胺受体亚型所介导的腺苷酸环化酶活性的影响．方法：用放免分析法测定ｃＡＭＰ含量，作为反映多巴胺受体功能的指标．结果：长期给予盐酸多巴胺可显著减少肾皮质由非诺多泮引起的ｃＡＭＰ增加的量和在Ｓｃｈ２３３９０存在下由ＰＢＤＡ引起的ｃＡＭＰ降低的量，但其变量百分比则与对照组无显著差异．Ｓｃｈ２３３９０可阻断由非诺多泮和ＰＢＤＡ引起的ｃＡＭＰ的增加，而多潘立酮可阻断在Ｓｃｈ２３３９０存在下由ＰＢＤＡ引起的ｃＡＭＰ的降低．结论：长期应用多巴胺可使大鼠肾皮质的ＤＡ１和ＤＡ２受体均发生明显的“下调”，但余留受体的反应性不变．     

Is inhibitio of striatal synaptosomal tyrosine hydroxylation by dopamine agonists a measure of dopamine autoreceptor function?

Sumamry Rat striatal synaptosomal tyrosine hydroxylation was inhibited dose- and pH dependently by a number of dopamine agonists. The catecholic agonists apomorphine and (–)N-n-propylnorapomorphine inhibited synaptosomal tyrosine hydroxylase completely, with IC₅₀ values of around 0.3 mol/l at pH 6.6. The noncatechol agonists pergolide and bromocriptine and the putative dopamine autoreceptor agonists 3-PPP(–), 3-PPP(+), HW-165 and B-HT 920 produced only partial inhibition of synaptosomal tyrosine hydroxylation at high concentrations. Comparison of the inhibition of synaptosomal and soluble tyrosine hydroxylase indicated that the inhibition produced by apomorphine could be ascribed to a direct effect on the enzyme, whereas this was not the case for the noncatechol agonists. The inhibition produced by pergolide and 3-PPP(–) was not antagonised by either dopamine receptor or alpha-adrenoceptor antagonists. The present results have been compared with results reported in the literature for inhibition of synaptosomal tyrosine hydroxylation and for two other tests of dopamine autoreceptor agonist activity (inhibition of dopamine release from striatal slices in vitro, and inhibition of the gamma-butyrolactone induced increase in dopamine synthesis in vivo). It is concluded that inhibition of striatal synaptosomal tyrosine hydroxylation by dopamine agonists does not fulfil the criteria required for it to be considered as a useful measure of dopamine autoreceptor function.     

Uptake of dopamine by rat hepatocytes in vitro

The present results showed that uptake of dopamine (DA) by rat isolated hep-atocytes was mediated, in addition to simple diffusion, mainly by a transporter-involved process, with Km of 66. 8 μmol and Vmax of 52. 3 pmol·min-1/105 cells. The process was pH- and temperature-dependent and required an activation energy of 4. 12 kcal ·mol-1(Q10 = 1.25) in the range of 2.0-12.7 C and 13.0 kcal·mol -1(Q10 = 2. 0) in the range of 12.7 -39.0C. Cysteine residue having free thiol group was. unrelated to the activity of the transporter. Catecholamines, serotonin, and cocaine inhibited the DA transport , but tyramine (TA) and tryptamine, as well as benztropine and imipramine (which are potent inhibitors for hepatic TA transporter and neuronal DA transporter), had no inhibitory effect on the transport of DA in these cells. These results indicated that DA was taken up into hepatocytes by a distinct carrier. NaF and mastoparan influenced the transport activity in these cells further, suggesting that signal transduci     

Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine

-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.     

Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia.     

Development of a bivalent dopamine D₂ receptor agonist

Bivalent D? agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D? receptor antagonists of type 1, the bivalent agonist 2 was synthesized when a spacer built from 22 atoms was employed. Compared to the monovalent control compound 6 containing a capped spacer, the bis-aminoindane derivative 2 revealed substantial steepening of the competition curve, indicating a bivalent binding mode. Dimer-specific Hill slopes were not a result of varying functional properties because both the dopaminergic 2 and the monovalent control agent 6 proved to be D? agonists substantially inhibiting cAMP accumulation and inducing D? receptor internalization. Investigation of the heterobivalent ligands 8 and 9, containing an agonist and a phenylpiperazine-based antagonist pharmacophore, revealed moderate steepening of the displacement curves and antagonist to very weak partial agonist properties.     

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of parkinson's disease — the differential effects of D1 dopamine antagonists in the primate

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D₁ DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine) and A66359 (1-[2-bromo-4, 5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4 tetrahydroisoquinoline), but not the D₂ DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D₁ DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3-CH₃ analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D₁ DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D₁ DA agonists. These findings demonstrate that the behavioural effects of benzazepine D₁ DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D₁ DA receptor sites, although in the primate, stimulation of D₂ DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D₁ DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D₁ DA antagonists may indicate the involvement of multiple D₁ DA receptor subtypes in mediating benzazepine D₁ DA agonist induced behaviours in the MPTP-treated marmoset.     

Effects of tetrahydroprotoberberines on dopamine D_2 receptors in ventral tegmental area of rat

阐明四氢原小檗碱同类物（ＴＨＰＢ）对大鼠中脑腹侧被盖区（ＶＴＡ）多巴胺（ＤＡ）受体的作用特性，并比较它们的作用强度．方法：采用大鼠在体胞外单位放电记录．结果：观察了１１个ＴＨＰＢ均可完全地翻转ＤＡ受体激动剂阿扑吗啡（２０μｇ·ｋｇ－１）所产生的放电抑制作用，为Ｄ２受体拮抗剂的作用特性．ＴＨＰＢ对Ｄ２受体的作用与Ｃ２位上的ＯＨ基团有密切的关系．它们的作用强度（ＥＤ５０，μｇ·ｋｇ－１）：ＴＨＰＢ１４３（５６）＞ＳＰＤ（８５）＞Ｉｓｏ（１７０）＞ＴＨＰ（３３）＞ＴＨＢ（４８）＞ＴＨＰＢ１８（６６）＞ＴＨＰＢ１（１７９）＞ＴＨＰＢ１９（４０８）＞ＴＨＰＢ１２６（５１０）＞ＴＨＰＢ１０４（１０１９）＞ＴＨＰＢ１０（４８１５）．结论：１１个ＴＨＰＢ均为ＶＴＡＤ２受体拮抗剂，以Ｃ２位上有ＯＨ基团的ＴＨＰＢ１４３作用最强．     

What can be learned from studies of multisubstrate mechanisms of neuronal dopamine transport?

The dopamine transporter (DAT) is a Na+- and Cl--dependent transporter and, with respect to its three apparent substrates, both partially random sequential as well as ordered mechanisms have been reported. Here we describe some of the features of DAT, such as the coupling of energy to concentrate dopamine and the properties of slippage and leakage. Further, in considering the regulation of transport velocities by DAT few have considered issues related to substrate regulation of DAT activity. Specifically, what effect do changes in the constants (K) for the participation of Na+ and Cl- have on dopamine transport velocity? It is shown that DAT may possess properties of slippage, an argument is made that leakage may be important in neuronal systems containing DAT, and the influence of changing values of K for the participation of Na+ and Cl- in transport is shown to produce large effects on DAT activity depending on the multisubstrate kinetic mechanism.     

Synthesis and pharmacological evaluation of fluorine-containing D₃ dopamine receptor ligands

A series of fluorine-containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized, and their affinities for human dopamine D(2), D(3), and D(4) receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e, and 21e, which bind with high affinity at D(3) (K(i) = 0.17-5 nM) and moderate to high selectivity for D(3) vs D(2) receptors (ranging from ～25- to 163-fold). These compounds were also evaluated for intrinsic activity at D(2) and D(3) receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D(2) vs D(3) receptors. These compounds may be useful for behavioral pharmacology studies on the role of D(2)-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D(3) receptor (K(i) = 0.17 nM for D(3), 163-fold selectivity for D(3) vs D(2) receptors), represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D(3) receptor expression.     

Is Na+ required for the binding of dopamine, amphetamine, tyramine, and octopamine to the human dopamine transporter?

The role of Na(+) in the recognition of blockers by the dopamine transporter is accomodated by a model with a cation site that overlaps with the blocker binding domain, and a distal Na(+) site that interacts with this cation site and perhaps with the blocker binding domain itself. The present study addresses the application of this model to the recognition of substrates by the dopamine transporter, focusing on conditions that should reveal a stimulatory effect, if present, of Na(+) on substrate binding. Recognition was studied via the inhibition of binding of [(3)H]WIN 35,428 (2beta-carbomethoxy-3beta-(4-fluorophenyl) [(3)H]tropane), a cocaine analog, to the human dopamine transporter in human embryonic kidney 293 cells. Little or no changes in binding were noted for dopamine, d-amphetamine, p-tyramine, or dl-octopamine by increasing [Na(+)] from 2 mM to 20 mM with co-varying Br(-), both at pH 7.4 and 7.0. In 74-mM Tris-HBr or -HCl, only dopamine and d-amphetamine showed binding increases upon raising Na(+), leveling off with NO(3)(-) or SO(4)(2-) but not Br(-) as anion at approximately 60 mM Na(+), consonant with a partly stimulatory action of Br(-). An Na(+) free, low 5-mM Tris-HEPES buffer was used for studying Na(+) curves truly starting at 0 mM, and, with SO(4)(2-) as the anion, no stimulation of binding by Na(+) was observed. This suggested that the stimulations observed in high (74 mM) Tris(+) buffer by Na(+) were not a direct effect of Na(+) but rather a disinhibitory effect of Na(+) in removing Tris(+) inhibition that depended upon substrate. Tris(+) IC(50) values in Na(+) free buffer were not lower for dopamine and d-amphetamine than p-tyramine and dl-octopamine. No evidence was found for a stronger inhibitory effect of Na(+) for dopamine and dl-octopamine potentially offsetting Tris(+) disinhibition. All results together support the existence of a substrate domain overlapping with a cation site that also binds Tris(+); a distal Na(+) site interacts with this cation site and with the substrate domain by negative allosterism and is additionally impacted by Cl(-). Importantly, interactions between sites vary with the type of substrate, and, in membrane preparations, Na(+) is not required for, or stimulatory to, the binding of any of the four substrates studied unlike the binding of the cocaine analog WIN 35,428.     

Rapid regulation of the dopamine transporter: role in stimulant addiction?

Dopamine (DA) and the DA transporter (DAT) play important roles in psychomotor stimulant behavioral activation and reward. By understanding how DAT activity is regulated, we will better appreciate its contribution to normal neurotransmission and to brain diseases like drug addiction. DAT is regulated long-term by chronic drug administration. It is also regulated in a rapid, dynamic fashion by many factors--including brief exposure to DAT substrates, e.g. DA and amphetamine, and inhibitors, e.g. cocaine. We found that individual differences in the initial and sensitized locomotor responsiveness of rats to cocaine reflect differences in in vivo DAT function. Our ex vivo studies have further suggested that differences in basal and/or rapid cocaine-induced expression of functional DATs in striatum contribute to the differences in initial responsiveness. Studies in model systems have demonstrated that short-term DAT regulation occurs by altered transporter trafficking, and thereby cell surface expression. For example, a rapid, complex regulation of DAT by DA is suggested. Amphetamine causes DAT internalization into early endosomal compartments whereas cocaine appears to up-regulate surface expression of DAT. Future studies are needed to confirm these observations in neurons, as well as to elucidate the mechanisms of rapid DAT endocytic trafficking at neuronal synapses.     

Do neuroleptics prevent the penetration of dopamine agonists into the brain?

A new, specific and highly sensitive method for the determination of apomorphine based on high performance liquid chromatography on a C18 reverse-phase column, coupled with electrochemical detection has been developed. The limit of detection of the assay is approximately 0.5 ng/sample (2 pmol). Haloperidol, cis-flupenthixol, metoclopramide and reserpine prevented the accumulation of apomorphine equally in "dopaminergic" as well as in "non-dopaminergic" brain areas. The non-neuroleptic trans-isomer of flupenthixol was without effect. Suppression of the accumulation of the dopamine agonist 6,7-ADTN (administered as the prodrug dibenzoyl-6,7-ADTN) was seen after combined treatment with haloperidol or reserpine, whereas cis- and trans-flupenthixol were without effect. The results imply that certain behavioural, biochemical and neuropharmacological studies, based on apomorphine in combination with other drugs, may need reinterpretation.     

Is dopamine neurotransmission altered in prodromal schizophrenia? A review of the evidence

It is known that early treatment improves the outcome in patients with schizophrenia. Treatment interventions prior to the onset of frank psychosis hold the promise of even better outcomes. Since schizophrenia typically has a year long prodromal phase before becoming clinically manifest, the field has made increasing efforts to define reliable criteria for subjects who are at high risk for psychosis (at-risk mental state, ARMS subjects). Still, no single test exists that would be sensitive and specific enough to justify individual treatment decisions in ARMS subjects. The most prominent theory on the pathogenesis of schizophrenia, the dopamine hypothesis, has undergone several modifications since its formulation more than half a century ago. Although there is nearly indisputable evidence for increased dopamine neurotransmission in schizophrenia, recent theories suggest that increased dopamine function is not causal, but can be seen as a final common pathway mediating psychosis in schizophrenia. Dopaminergic and glutamatergic neurons interact at striatal interneurons to control striatal output and information processing in fast glutamatergic networks. Both, glutamatergic and dopaminergic neurotransmission, are believed to be already altered in prodromal phases of schizophrenia. Results from neuroimaging studies indicate that dopamine transmission is altered before the outbreak of psychosis, and recent findings also suggest alterations in dopamine-glutamate coupling in ARMS subjects. Improved methods for imaging dopamine and glutamate function in the living brain have thus the potential to identify young people at ultra-high risk who would most likely benefit from early psychological and pharmacological interventions.     

Octanoic acid prevents reduction of striatal dopamine in the MPTP mouse model of Parkinson’s disease

Background

Parkinson’s disease (PD) is a progressive neurodegenerative process leading to the loss of dopaminergic neurons and their projections. 1-methyl-4-phenol-1,2,5,6-tetrahydropyridine (MPTP) toxicity is a well-recognized animal model of PD. It is suggested that the impairment of mitochondrial function in the substantia nigra plays an important role in both the onset and the progression of PD.Octanoic acid (C8), a fatty acid that is the main constituent of the medium-chain triglyceride ketogenic diet, increases the metabolic activity of mitochondria; hence, it seemed interesting to investigate whether C8 exhibits neuroprotective effects in the MPTP model of PD and whether it affects mitochondria function in the striatum.

Advances in dopamine receptor agonists for the treatment of Parkinson’s disease

Introduction: Dopamine agonists (DA) are a class of agents which directly stimulate dopamine receptors mimicking the endogenous neurotransmitter dopamine. At first used as adjunctive therapy in the advanced phases of the disease, over the years a significant role was found for DA monotherapy as a first approach in the initial stage of Parkinson’s disease (PD). Several reviews have already reported efficacy and safety of DA in PD and differences between DA and levodopa. Therefore the objective of this review is to gather recent updates in DA therapy. A thorough knowledge of recent literature evidences, would help clinician in the management of treatment with DA.

Areas covered: Our review investigates recent updates on DA therapy, the role of these compounds in controlling non-motor symptoms (NMS) as well as new formulations under clinical evaluation and newly emerged post-marketing safety considerations. A literature search has been performed using Medline and reviewing the bibliographies of selected articles.

Expert opinion: DA represents a very important option in the treatment of PD, even though there are still some criticisms and unmet needs. A better knowledge of dopamine receptors could lead to identification of new compounds able to better balance clinical efficacy and side effects.     

Lack of epinine formation in adrenal medulla and brain of rats during cold exposure and inhibition of dopamine β-hydroxylase

Summary Cold exposure of rats for 4 h and simultaneous inhibition of dopamine -hydroxylase by FLA-63 (25 mg/kg) led to a reduction of the catecholamine content of the adrenal medulla by 46% and of the brain by 68%. Additional injections of 5 mg/kg FLA-63 4 and 9 h after beginning of the experiments, respectively, kept the catecholamine content on this low level (brain) or decreased in further (adrenal medulla). Administration of 5 mg/kg (-)DOPA together with the mono-amine oxidase inhibitor pargyline (50 mg/kg) 24 h after the first injection of FLA-63 stimulated the resynthesis. It amounted for the adrenal medulla to 20 g/kg body weight/8 h and for the brain to 45 ng/g tissue wet weight/8 h. Paper chromatographic analyses of the extracts of adrenal medulla and brain, respectively, performed at each time of the different injections, clearly identified adrenaline, noradrenaline and dopamine (in traces) in the adrenal medulla as well as noradrenaline and dopamine in the brain; epinine on the contrary could not be demonstrated, not even in traces. Since at least 25 ng of epinine can be detected with certainty by our method, it can be concluded that epinine is not formed in amounts greater than 75 ng/pair adrenal glands or 37.5 ng/brain. The present results support the view that the main pathway of adrenaline biosynthesis in the suprarenal medulla and the brain proceeds via noradrenaline and not via epinine.     

Effects of striatal lesions with kainic acid on morphine-induced “catatonia” and increase of striatal dopamine turnover

Summary The influence of striatal lesions (head of the caudate nucleus) with kainic acid on catatonia and on the increase of the dopamine metabolite DOPAC in the striatum after systemic morphine administration was measured in rats. These lesions strongly prevented the morphine-induced muscular rigidity, measured as activity in the electromyogram (EMG) of the gastrocnemius-soleus muscle of non-anesthesized animals. On the other hand, the decrease of locomotion (akinesia) measured using an Animex Activity Meter and an acitivity wheel, was not prevented or reduced. The lesions did not influence the inhibitory effect of morphine on the activation of flexor -motoneurones, either. These results suggest that the head of the caudate nucleus plays an important role in mediating morphine rigidity, but not akinesia or inhibition of the activation of flexor -motoneurones. Opioid-induced catatonia ought to be regarded as a mixture both of rigidity and of akinesia.Morphine led to a rapid decrease, followed by a slow increase of striatal DOPAC concentration. Lesions induced by kainic acid slightly inhibited the decrease and markedly enhanced the increase of DOPAC. Accordingly, an intact nigro-striato-nigral loop is not necessary for the increase of striatal dopamine turnover, observed after morphine administration. The different sites of action, which are likely to mediate all these effects of morphine, are discussed.