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1.
Adenosine A2A receptors are a new target for drug development in Parkinson’s disease. Some experimental and clinical data suggest that A2A receptor antagonists can provide symptomatic improvement by potentiating the effects of -DOPA as well as a decrease in secondary effects such as -DOPA-induced dyskinesia. -DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of -DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A2A receptor agonist CGS 21680 and the A2A receptor antagonist MSX-3 on -DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. -DOPA-induced behavioral sensitization was determined as an increase in -DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyrosine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting -DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of -DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that -DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A2A and D2 receptor stimulation, since it was counteracted by MSX-3 and by the D2 receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson’s disease.  相似文献   

2.
Continuous dopaminergic receptor stimulation is now considered as an interesting approach for the control of motor complications often seen in parkinsonian patients treated chronically with levodopa. Cabergoline, which is a long-acting dopamine D2-like receptor agonist, has been tried recently with good results as an adjunct in patients already on levodopa-therapy. Thus, the present study was designed to test the effects of repeated s.c administration of cabergoline as sole therapeutic agent during a month in 3 drug-naive MPTP parkinsonian monkeys to see whether or not cabergoline, given every other day at 0.25 mg/kg, would have a sustained antiparkinsonian effect and would induce dyskinesias. The animals were rated to quantify the antiparkinsonian as well as the dyskinetic response and gross locomotor activity was monitored by photocells. The averaged locomotor response, initially greatly increased ( ∼ 9 times higher than after saline treatment in the same animals), decreased by ∼ 50% after 2 weeks but was thereafter maintained at this level until the end of the study. The parkinsonian features were improved in a sustained manner in all monkeys and transient dyskinesias (week 1 and 2) were present in 2 of 3 monkeys. After sacrifice receptor binding assays were performed on striatal and pallidal tissues homogenates with tritiated selective ligands and compared with those of 3 normal and 3 MPTP-exposed monkeys otherwise untreated. A significant decrease in dopamine D2-like receptor density in the putamen (−36% on average vs. untreated MPTP-exposed monkeys) may be involved in the behavioral partial tolerance to antiparkinsonian effect of cabergoline and the disappearance of dyskinesias. A reversal of the supersensitivity of GABAA receptor in the internal segment of the globus pallidus (−15% on average vs. untreated MPTP-exposed monkeys) may also be implicated in this latter behavioral effect.  相似文献   

3.
Expression of the early-gene c-fos is an useful method for studying potential sites of action of drugs active in the CNS. Stimulation of adenosine A2A receptors by CGS 21680 (5 mg/kg) induced an increase in Fos-like immunoreactivity in the rat nucleus accumbens shell, while in the rostral pole and core CGS 21680 induced Fos-like immunoreactivity only after a high dose. CGS 21680 (5 mg/kg) stimulated c-fos expression also in the lateral septal nucleus and dorso-medial striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A2A agonist HENECA (5 mg/kg) which displays higher selectivity for A2A receptors than CGS 21680. Administration of the selective A2A antagonist SCH 58261 counteracted CGS 21680-induced Fos-like immunoreactivity. Lesions of the dopaminergic mesostriatal projection by 6-hydroxydopamine and stimulation of dopamine D2/D3 receptors by quinpirole, prevented CGS 21680-induced Fos-like immunoreactivity in the nucleus accumbens shell. The present results show that stimulation of A2A receptors induces a profile of c-fos expression similar to that of atypical neuroleptics. A2A receptor stimulation has been reported to have dopamine antagonistic actions, it is therefore suggested that A2A agonists might have antipsychotic activity without producing extrapyramidal side effects.  相似文献   

4.
Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor–receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D2 receptor may operate as the ‘hub receptor’ within these complexes. The constitutive adenosine A2A/dopamine D2 RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A2A/D2 interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A2A antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A2A/D2/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor–receptor interactions within this RM involving synergism between A2A/mGluR5 to counteract D2 signaling, has led to the proposal of using combined mGluR5 and A2A antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A2A agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D2-like signaling in the ventral striatum. Recently, A2A receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A2A receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably representing a compensatory up-regulation to counteract the cocaine-induced increases in dopamine D2 and D3 signaling. Therefore, A2A agonists, through antagonizing D2 and D3 signaling within A2A/D2 and A2A/D3 RM heteromers in the nucleus accumbens, may be found useful as a treatment for cocaine dependence. Furthermore, antagonistic cannabinoid CB1/D2 interactions requiring A2A receptors have also been discovered and possibly operate in CB1/D2/A2A RM located principally on striatal glutamate terminals but also on some ventral striato-pallidal GABA neurons, thereby opening up a new mechanism for the integration of endocannabinoid, DA and adenosine mediated signals. Thus, A2A, mGluR5 and/or CB1 receptors can form integrative units with D2 receptors within RM displaying different compositions, topography and localization. Also galaninR/5-HT1A RM probably participates in the transmission of the ascending 5-hydroxytryptamine neurons, where galanin receptors antagonize 5-HT1A recognition and signaling. Subtype specific galanin receptor antagonists may therefore represent novel antidepressant drugs. These results suggest the importance of a complete understanding of the function of these RM with regard to disease. Ultimately receptor–receptor interactions within RM that modify dopaminergic and serotonergic signaling may give new strategies for treatment of a wide range of diseases associated with altered dopaminergic and serotonergic signaling.  相似文献   

5.
Recent advances in molecular biology, biochemistry, cell biology and behavioral pharmacology together with the development of more selective ligands to the various adenosine receptors have increased our understanding of the functioning of central adenosine A2A receptors. The A2A receptor is one of four adenosine receptors found in the brain. Its expression is highest in striatum, nucleus accumbens and olfactory tubercles, although it also occurs in neurons and microglia in most other brain regions. The receptor has seven transmembrane domains and couples via Gs to adenyl cyclase stimulation. Antagonistic interactions between A2A receptors and dopamine D2 receptors have been described, as stimulation of the A2A receptor leads to a reduction in the affinity of D2 receptors for D2 receptor agonists. The A2A receptor is thought to play a role in a number of physiological responses and pathological conditions. Indeed, A2A receptor antagonists may be useful for the treatment of acute and chronic neurodegenerative disorders such as cerebral ischemia or Parkinson's disease. A2A receptor agonists may treat certain types of seizures or sleep disorders. This review discusses the characteristics, distribution, pharmacochemical properties and regulation of central A2A receptors, as well as A2A receptor-mediated behavioural responses and their potential role in various neuropsychiatric disorders.  相似文献   

6.
Adenosine-dopamine interactions revealed in knockout mice   总被引:1,自引:0,他引:1  
Neurochemical and pharmcological evidence obtained over the past 300 yr has indicated that adenosine and dopamine interact functionally in the basal ganglia and that such interactions have pathophysiological and theraputic implications. The receptors implicated are adenosine A1 and A2A, and dopamine D1 and D2. There is evidence that dopamine D2 receptor activation in vivo antagonizes tonic activation of adenosine A2A receptors. Thus, acute blockade of dopamine D2 receptors, or disruption of dopamine transmission, unmasks strong adenosine A2A activation. Effects of dopamine D2 blockade are different after adenosine A2A blockade or in A2A knockout mice. Possibly as an adaptation to this increase in adenosine A2A signaling, there is a decreased coupling of A2A receptors to biological effects in dopamine D2 knockout mice. Compared to wild-type mice, adenosine A2A knockout mice show decreased neurodegeneration after treatment with 1-myeyl-1,2,3,6-tetrahydropyridine (MPTP) and show improved motor performance in models of Parkinson’s disease Adenosine A1 receptors are not spccifically located with any dopamine receptor, as is the A2A receptor with D2 receptors. Many A1 receptors are located presynaptically, where they regulate transmitter release. In A1 knockout mice, glutamatergic and dopaminergic transmission is therefore modified.  相似文献   

7.
Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT2 receptor antagonism of the drug combined with less potent dopamine D2 antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED50 = 0.067mg/kg). Nearly full occupancy (80%) was achieved before H1, D2, α1 andα2 receptors became occupied (ED50 = 0.45, 0.66, 0.75and3.7mg/kg, respectively). Clozapine displayed occupancy of H1 andα1 receptors at low doses (ED50 = 0.15and0.58mg/kg, respectively) and of 5-HT2, 5-HT1C, D2, α2, cholinergic muscarinic and 5-HT1A receptors at higher dosesED50 = 1.3, 1.8, 9.0, 9.5, 11and15mg/kg, respectively). Haloperidol occupied D2 andα1 receptors at low doses (ED50 = 0.13and0.42mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED50 = 2.6mg/kg). Occupancy of receptor types occurred with similar ED50-values in various brain areas, e.g. D2 receptors in striatum and mesolimbic areas. The ED50-values for the ex vivo measured occupancy of 5-HT2 and D2 receptors were in good agreement with ED50-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D2 receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D2 receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol. It was also suggested that a strong 5-HT2 receptor blockade preceding a low occupancy of D2 receptors underlies the beneficial effects on the negative symptoms of schizophrenia and reduces incidence of EPS. At dosages inducing 25% D2 receptor occupancy in the caudate-putamen, risperidone (0.11 mg/kg) showed 60% occupancy of 5-HT2 receptors and less than 25% occupancy of the other receptors including H1 receptors. At 25% D2 receptor occupancy, clozapine (3.1 mg/kg) resulted in 65% occupancy of 5-HT2 receptors, but also in more than 80% occupancy ofα1 receptors and full occupancy of H1 receptors. At 25% D2 receptor occupancy, haloperidol (0.048 mg/kg) virtually did not interfere with other receptors. Our study provides evidence that risperidone shows an in vivo receptor occupancy profile in the rat brain that is compatible with the one that is apparently required for beneficial clinical effects, i.e. predominant 5-HT2 receptor occupancy concomitant with low D2 receptor occupancy; the gradual increase in D2 receptor occupancy with increasing dosages provides a wider therapeutic window before EPS-inducing high D2 receptor occupancy is reached.  相似文献   

8.
Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A2A receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A2A receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A2A receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A2A receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A2A receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A2A receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A2A receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A2A receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A2A receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS.  相似文献   

9.
Serotonin (5-HT)1A receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT1A receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT1A receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT2A/D2 receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0.03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01–1.0 mg/kg), potent D2 receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1–0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT2A receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT1A receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT2A receptors. The significance of these results for EPS and antipsychotic action is discussed.  相似文献   

10.
We have previously found, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) increases the dissociation constants of high- (Kh) and low-affinity (Kl) dopamine D2 binding sites (labelled with the selective dopamine D2 antagonist [3H]raclopride) without changing the proportion of high affinity binding sites (Rh). In the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both Kh and Kl values, stimulation of adenosine A2 receptors is associated with an increase in Rh. These result suggest that, in the adult rat, adenosine A2 stimulation may inhibit the behavioural effects induced by dopamine D2 stimulation both by decreasing the affinity and the transduction of dopamine D2 receptors. We have also studied the intramembrane A2-D2 receptor interaction in an experimental model of Parkinson's disease, namely in rats with a unilateral 6-OH-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is associated with a higher density of striatal dopamine D2 receptors in the order of 20%, without any change in their affinity compared with the unlesioned neostriatum. Furthermore, the density (Bmax values) of dopamine D2 receptors in the contralateral neostriatum was significantly higher (about 20%) than in the striatum from native animals. This finding suggests that an unilateral dopamine denervation also induces compensatory long-lasting changes of dopamine D2 receptors in the contralateral neostriatum. In addition to the hightened sensitivity to dopamine agonists, it is known that the dopamine denervated striatum is more sensitive to adenosine antagonists like methylxanthines. If the adenosine A2-dopamine D2 interaction is the main mechanism of action mediating the central effects of methylxanthines, the dopamine denervation might also potentiate this interaction, i.e., dopamine D2 receptors could be not only more sensitive to dopamine but also to adenosine A2 receptor activation. Our results support this hypothesis, since membrane preparations from the denervated neostriatum are more sensitive to the effect of CGS 21680 on dopamine D2 receptors. Thus a low dose of CGS 21680 (3 nM), which is not effective in membrane preparations from the neostriatum of naive animals, is still effective in membranes from the denervated neostriatum. These results underline the potential antiparkinsonian activity of adenosine A2 antagonists.  相似文献   

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