Publications (27)143.36 Total impact
-
Article: NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses.
[show abstract] [hide abstract]
ABSTRACT: Hippocampal mossy fiber synapses have been reported to lack NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA excitatory postsynaptic currents (EPSCs), unlike conventional glutamatergic synapses. An explanation for this difference may reside in the relatively low number of NMDARs at these synapses. Because mossy fiber synapses display LTP selective for NMDARs, we examined whether this would affect the plasticity rules at mossy fiber-CA3 synapses in mouse hippocampal slices. We found that LTP of NMDARs serves as a metaplastic switch making mossy fiber synapses competent for generating NMDAR-dependent LTP of AMPA EPSCs.Nature Neuroscience 06/2011; 14(6):691-3. · 15.53 Impact Factor -
Article: Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction.
[show abstract] [hide abstract]
ABSTRACT: The blockade of adenosine A(2A) receptors (A2AR) affords a robust neuroprotection in different noxious brain conditions. However, the mechanisms underlying this general neuroprotection are unknown. One possible mechanism could be the control of neuroinflammation that is associated with brain damage, especially because A2AR efficiently control peripheral inflammation. Thus, we tested if the intracerebroventricular injection of a selective A2AR antagonist (SCH58261) would attenuate the changes in the hippocampus triggered by intraperitoneal administration of lipopolysaccharide (LPS) that induces neuroinflammation through microglia activation. LPS administration triggers an increase in inflammatory mediators like interleukin-1β that causes biochemical changes (p38 and c-jun N-terminal kinase phosphorylation and caspase 3 activation) contributing to neuronal dysfunction typified by decreased long-term potentiation, a form of synaptic plasticity. Long-term potentiation, measured 30 min after the tetanus, was significantly lower in LPS-treated rats compared with control-treated rats, while SCH58261 attenuated the LPS-induced change. The LPS-induced increases in phosphorylation of c-jun N-terminal kinase and p38 and activation of caspase 3 were also prevented by SCH58261. Significantly, SCH58261 also prevented the LPS-induced recruitment of activated microglial cells and the increase in interleukin-1β concentration in the hippocampus, indicating that A2AR activation is a pivotal step in mediating the neuroinflammation triggered by LPS. These results indicate that A2AR antagonists prevent neuroinflammation and support the hypothesis that this mechanism might contribute for the ability of A2AR antagonists to control different neurodegenerative diseases known to involve neuroinflammation.Journal of Neurochemistry 01/2011; 117(1):100-11. · 4.06 Impact Factor -
Article: Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD.
[show abstract] [hide abstract]
ABSTRACT: Proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) domains play key roles in the assembly and regulation of cellular signaling pathways and represent putative targets for new pharmacotherapeutics. Here we describe the first small-molecule inhibitor (FSC231) of the PDZ domain in protein interacting with C kinase 1 (PICK1) identified by a screening of approximately 44,000 compounds in a fluorescent polarization assay. The inhibitor bound the PICK1 PDZ domain with an affinity similar to that observed for endogenous peptide ligands (K(i) approximately 10.1 microM). Mutational analysis, together with computational docking of the compound in simulations starting from the PDZ domain structure, identified the binding mode of FSC231. The specificity of FSC231 for the PICK1 PDZ domain was supported by the lack of binding to PDZ domains of postsynaptic density protein 95 (PSD-95) and glutamate receptor interacting protein 1 (GRIP1). Pretreatment of cultured hippocampal neurons with FSC231 inhibited coimmunopreciptation of the AMPA receptor GluR2 subunit with PICK1. In agreement with inhibiting the role of PICK1 in GluR2 trafficking, FSC231 accelerated recycling of pHluorin-tagged GluR2 in hippocampal neurons after internalization in response to NMDA receptor activation. FSC231 blocked the expression of both long-term depression and long-term potentiation in hippocampal CA1 neurons from acute slices, consistent with inhibition of the bidirectional function of PICK1 in synaptic plasticity. Given the proposed role of the PICK1/AMPA receptor interaction in neuropathic pain, excitotoxicity, and cocaine addiction, FSC231 might serve as a lead in the future development of new therapeutics against these conditions.Proceedings of the National Academy of Sciences 12/2009; 107(1):413-8. · 9.68 Impact Factor -
Article: Activity-dependent synaptic plasticity of NMDA receptors.
[show abstract] [hide abstract]
ABSTRACT: Activity-dependent, bidirectional control of synaptic efficacy is thought to contribute to many forms of experience-dependent plasticity, including learning and memory. Although most excitatory synapses contain both AMPA and N-methyl-d-aspartate receptors (AMPARs and NMDARs), most studies have focused on the plasticity of synaptic AMPARs, and on the pivotal role of NMDA receptors for its induction. Here we review evidence that synaptic NMDARs themselves are subject to long-term activity-dependent changes by mechanisms that may differ from that of synaptic AMPARs. The bidirectional modulation of NMDAR-mediated synaptic responses is likely to have important functional implications for NMDAR-dependent forms of synaptic plasticity.The Journal of Physiology 10/2009; 588(Pt 1):93-9. · 4.72 Impact Factor -
Article: Spike-timing-dependent plasticity induces presynaptic changes at immature hippocampal mossy fiber synapses.
Journal of Neuroscience 08/2009; 29(26):8299-301. · 7.11 Impact Factor -
Article: Binding of the prototypical adenosine A2A receptor agonist CGS 21680 to the cerebral cortex of adenosine A1 and A2A receptor knockout mice
[show abstract] [hide abstract]
ABSTRACT: 2-p-(2-carboxyethylphenethylamino-5′-ethylcarboxamidoadenosine) (CGS 21680) is considered the reference compound to study adenosine A2A receptors. However, CGS 21680 binding in the cerebral cortex, where adenosine A1 receptors are predominant, displays a mixed A2A/A1 receptor pharmacology. We now use adenosine A1 and A2A receptor knockout mice to investigate the characteristics of cortical [3H]CGS 21680 binding.[3H]CGS 21680 binding to the cerebral cortex was strongly reduced in adenosine A1 receptor knockout mice, but only slightly reduced in A2A receptor knockout mice compared with the corresponding wild-type littermates.Another selective A2A receptor ligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine ([3H]SCH 58261), displayed a saturable binding to mouse cortical membranes, albeit with a binding density 20 times lower than that of striatal membranes, and this [3H]SCH58261 binding was abolished in both striatal and cortical membranes of A2A receptor knockout mice and unchanged in A1 receptor knockout mice.The presence of A2A receptors in cortical neurons was further confirmed by Western blot in mouse cortical nerve terminal membranes.It is concluded that, although A2A receptors are present in the cerebral cortex, the purportedly selective A2A receptor agonist [3H]CGS 21680 binds in the cerebral cortex to an entity that requires the presence of adenosine A1 receptors. Thus, CGS 21680 should be used with care in all preparations where adenosine A1 receptors out-number A2A receptors.British Journal of Pharmacology (2004) 141, 1006–1014. doi:10.1038/sj.bjp.0705692British Journal of Pharmacology 01/2009; 141(6):1006 - 1014. · 4.41 Impact Factor -
Article: Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms.
[show abstract] [hide abstract]
ABSTRACT: To investigate whether the motor and neuroprotective effects of adenosine A(2A) receptor (A(2A)R) antagonists are mediated by distinct cell types in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We used the forebrain A(2A)R knock-out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A(2A)Rs in forebrain neurons and glial cells to A(2A)R antagonist-mediated motor and neuroprotective effects. The selective deletion of A(2A)Rs in forebrain neurons abolished the motor stimulant effects of the A(2A)R antagonist KW-6002 but did not affect acute MPTP neurotoxicity. Intracerebroventricular administration of KW-6002 into forebrain A(2A)R knock-out mice reinstated protection against acute MPTP-induced dopaminergic neurotoxicity and attenuated MPTP-induced striatal microglial and astroglial activation. A(2A)R activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity.Annals of Neurology 04/2008; 63(3):338-46. · 11.09 Impact Factor -
Article: A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs.
[show abstract] [hide abstract]
ABSTRACT: The function of striatal adenosine A(2A) receptors (A(2A)Rs) is well recognized because of their high expression levels and the documented antagonistic interaction between A(2A)Rs and dopamine D(2) receptors in the striatum. However, the role of extrastriatal A(2A)Rs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A(2A)Rs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A(2A)Rs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A(2A)R knock-out (st-A(2A)R KO) mice in comparison with forebrain-specific A(2A)R KO (fb-A(2A)R KO) mice. In contrast to fb-A(2A)R KO (deleting A(2A)Rs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A(2A)R KO mice exhibited Cre-mediated selective deletion of the A(2A)R gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A(2A)R KO but attenuated in fb-A(2A)R KO mice. Furthermore, selective inactivation of the A(2A)Rs in extrastriatal cells by administering the A(2A)R antagonist KW6002 into st-A(2A)R KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A(2A)Rs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A(2A)Rs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A(2A)Rs.Journal of Neuroscience 04/2008; 28(12):2970-5. · 7.11 Impact Factor -
Article: Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses.
[show abstract] [hide abstract]
ABSTRACT: The physiological conditions under which adenosine A2A receptors modulate synaptic transmission are presently unclear. We show that A2A receptors are localized postsynaptically at synapses between mossy fibers and CA3 pyramidal cells and are essential for a form of long-term potentiation (LTP) of NMDA-EPSCs induced by short bursts of mossy fiber stimulation. This LTP spares AMPA-EPSCs and is likely induced and expressed postsynaptically. It depends on a postsynaptic Ca2+ rise, on G protein activation, and on Src kinase. In addition to A2A receptors, LTP of NMDA-EPSCs requires the activation of NMDA and mGluR5 receptors as potential sources of Ca2+ increase. LTP of NMDA-EPSCs displays a lower threshold for induction as compared with the conventional presynaptic mossy fiber LTP; however, the two forms of LTP can combine with stronger induction protocols. Thus, postsynaptic A2A receptors may potentially affect information processing in CA3 neuronal networks and memory performance.Neuron 02/2008; 57(1):121-34. · 14.74 Impact Factor -
Article: Short-term plasticity of kainate receptor-mediated EPSCs induced by NMDA receptors at hippocampal mossy fiber synapses.
[show abstract] [hide abstract]
ABSTRACT: Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors that play a variety of functions in the regulation of the activity of synaptic networks. Little is known about the regulation of the function of synaptic KARs in the brain. In the present study, we found that a conditioning activation of synaptic NMDA receptors (NMDARs) induces short-term depression of KAR-EPSCs but not of AMPA receptor-EPSCs at synapses between mossy fibers and CA3 pyramidal cells. Short-term depression of KAR-EPSCs by synaptic NMDARs peaked at 1 s and reversed within 20 s, was likely induced and expressed postsynaptically, and was homosynaptic. It depended on a rise of Ca2+ in the postsynaptic cell and on the activation of the phosphatase calcineurin that likely binds to the GluR6b (glutamate receptor subunit 6b) subunit splice variant allowing the dephosphorylation of KARs and inhibition of activity. Finally, we show in the current-clamp mode that short-term depression of KAR-EPSPs is induced by the coincident discharge of action potentials in the postsynaptic cell together with synaptic stimulation. Hence, this study describes a form of short-term synaptic plasticity that is postsynaptic, depends on the temporal order of presynaptic and postsynaptic spiking, and likely affects the summation properties of mossy fiber EPSPs.Journal of Neuroscience 05/2007; 27(15):3987-93. · 7.11 Impact Factor -
Article: Toxic effects of cobalt in primary cultures of mouse astrocytes. Similarities with hypoxia and role of HIF-1alpha.
[show abstract] [hide abstract]
ABSTRACT: Cobalt is suspected to cause memory deficit in humans and was reported to induce neurotoxicity in animal models. We have studied the effects of cobalt in primary cultures of mouse astrocytes. CoCl(2) (0.2-0.8mM) caused dose-dependent ATP depletion, apoptosis (cell shrinkage, phosphatidylserine externalization and chromatin rearrangements) and secondary necrosis. The mitochondria appeared to be a main target of cobalt toxicity, as shown by the loss of mitochondrial membrane potential (DeltaPsi(m)) and release from the mitochondria of apoptogenic factors, e.g. apoptosis inducing factor (AIF). Pre-treatment with bongkrekic acid reduced ATP depletion, implicating the involvement of the mitochondrial permeability transition (MPT) pore. Cobalt increased the generation of oxygen radicals, but antioxidants did not prevent toxicity. There was also an impaired response to ATP stimulation, evaluated as a lower raise in intracellular calcium. Similarly to hypoxia and dymethyloxallyl glycine (DMOG), cobalt triggered stabilization of the alpha-subunit of hypoxia-inducible factor HIF-1 (HIF-1alpha). This early event was followed by an increased expression of HIF-1 regulated genes, e.g. stress protein HO-1, pro-apoptotic factor Nip3 and iNOS. Although all of the three stimuli activated the HIF-1alpha pathway and decreased ATP levels, the downstream effects were different. DMOG only inhibited cell proliferation, whereas the other two conditions caused cell death by apoptosis and necrosis. This points to cobalt and hypoxia not only inducing HIF-1alpha regulated genes but also affecting similarly other cellular functions, including metabolism.Biochemical Pharmacology 04/2007; 73(5):694-708. · 4.70 Impact Factor -
Article: CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action.
[show abstract] [hide abstract]
ABSTRACT: Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D1 receptors.Molecular Pharmacology 11/2006; 70(4):1236-45. · 4.88 Impact Factor -
Article: Trkb receptors modulation of glutamate release is limited to a subset of nerve terminals in the adult rat hippocampus.
[show abstract] [hide abstract]
ABSTRACT: Brain-derived neurotrophic factor (BDNF) modulates glutamatergic excitatory transmission in hippocampal primary cultures by acting at a presynaptic locus. Although it has been suggested that BDNF also modulates adult hippocampus glutamatergic transmission, this remains a matter of controversy. To clarify a putative role for this neurotrophin in the modulation of glutamate release we applied exogenous BDNF to isolated adult rat hippocampal nerve terminals. BDNF, at 100 ng/ml, potentiated by 25% the K(+)-evoked release of [(3)H]glutamate from hippocampal synaptosomes. The small effect of BDNF on [(3)H]glutamate release correlated with a modest increase in phospholipase Cgamma (PLCgamma) phosphorylation, and with the lack of effect of BDNF on extracellular-signal regulated kinase (ERK) and Akt phosphorylation. Immunocytochemistry studies demonstrated that only about one-third of glutamatergic synaptosomes were positive for TrkB immunoreactivity. Furthermore, biotinylation and subsynaptic fractionation studies showed that only one-fourth of total full-length TrkB was present at the plasma membrane, evenly distributed between the presynaptic active zone and the postsynaptic density. These results indicate that BDNF modulates synaptic transmission presynaptically in a small subset of hippocampal glutamatergic synapses that contain TrkB and that express the receptor on the plasma membrane.Journal of Neuroscience Research 05/2006; 83(5):832-44. · 2.74 Impact Factor -
Article: Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers.
[show abstract] [hide abstract]
ABSTRACT: The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.Journal of Neuroscience 03/2006; 26(7):2080-7. · 7.11 Impact Factor -
Article: Different roles of adenosine A1, A2A and A3 receptors in controlling kainate-induced toxicity in cortical cultured neurons.
[show abstract] [hide abstract]
ABSTRACT: Adenosine is a neuromodulator that can control brain damage through activation of A(1), A(2A) and A(3) receptors, which are located in both neurons and other brain cells. We took advantage of cultured neurons to investigate the role of neuronal adenosine receptors in the control of neurotoxicity caused by kainate and cyclothiazide. Both A(1), A(2A) and A(3) receptors were immunocytochemically identified in cortical neurons. Activation of A(1) receptors with 100 nM CPA did not modify the extent of neuronal death whereas the A(1) receptor antagonist, DPCPX (50 nM), attenuated neurotoxicity by 28 +/- 5%, and effect similar to that resulting from the removal of endogenous adenosine with 2U/ml of adenosine deaminase (27 +/- 3% attenuation of neurotoxicity). In the presence of adenosine deaminase, DPCPX had no further effect and CPA now exacerbated neurotoxicity by 42 +/- 4%. Activation of A(2A) receptor with 30 nM CGS21680 attenuated neurotoxicity by 40 +/- 8%, an effect prevented by the A(2A) receptor antagonists, SCH58261 (50 nM) or ZM241385 (50 nM), which by themselves were devoid of effect. Finally, neither A(3) receptor activation with Cl-IB-MECA (100-500 nM) nor blockade with MRS1191 (5 microM) modified neurotoxicity. These results show that A(1) receptor activation enhances and A(2A) receptor activation attenuates neurotoxicity in cultured cortical neurons, indicating that these two neuronal adenosine receptors directly control neurodegeneration. Interestingly, the control by adenosine of neurotoxicity in cultured neurons is similar to that observed in vivo in newborn animals and is the opposite of what is observed in adult brain preparations where A(1) receptor activation and A(2A) receptor blockade are neuroprotective.Neurochemistry International 11/2005; 47(5):317-25. · 2.86 Impact Factor -
Article: Long‐term Effect of Convulsive Behavior on the Density of Adenosine A1 and A2A Receptors in the Rat Cerebral Cortex
[show abstract] [hide abstract]
ABSTRACT: Purpose: Adenosine is a neuromodulator that has been proposed to act as an anticonvulsant mainly via inhibitory A1 receptors, but recent data show that genetic deletion of facilitatory A2A receptors might also attenuate convulsions. Since both A1 and A2A receptors are prone to down- and upregulation in different stressful situations, we investigated if convulsive behavior leads to a long-term change in A1 and A2A receptor density in the rat cerebral cortex.Methods: Stage 4-5 convulsions (Racine's scale) were induced in adult Wistar rats either through amygdala stimulation (kindling) or by intraperitoneal injection of kainate (10 mg/ml). Rats were killed after 4 weeks to evaluate adenosine A1 and A2A receptor density in the cerebral cortex using both Western blot and membrane binding assays.Results: The binding density of the A1 antagonist, 3H-DPCPX, decreased by 40. ± 4.4% and by 20.7 ± 0.5% after kindling or kainate injection. Likewise, A1 receptor immunoreactivity in cortical membranes from kindled or kainate-injected rats decreased by 19.1 ± 3.3% and 12.7 ± 5.7%, respectively. In contrast, the binding density of the A2A receptor antagonist 3H-SCH 58261 increased by 293 ± 34% and by 159 ± 32% in cortical membranes from kindled or kainate-injected rats, and A2A receptor immunoreactivity also increased by 151 ± 12% and 79.6 ± 7.0%.Conclusions: This indicates that after convulsive behavior there is a long-term decrease of A1 receptors accompanied by an increased density of A2A receptors, suggesting that A2A antagonists rather than A1 agonists may be more promising anticonvulsive drugs.Epilepsia 06/2005; 46:159 - 165. · 3.96 Impact Factor -
Article: Co-localization and functional interaction between adenosine A(2A) and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum.
[show abstract] [hide abstract]
ABSTRACT: The anti-Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A(2A) receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinson's disease. mGluR5 and A(2A) antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the anti-Parkinsonian and neuroprotective effects of A(2A) and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A(2A) agonist, CGS21680 (1-30 nM) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A(2A) antagonist, SCH58261 (50 nM). The mGluR5 agonist, CHPG (300-600 mum) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 microm). Both mGluR5 and A(2A) receptors were located in the active zone and 57 +/- 6% of striatal glutamatergic nerve terminals possessed both A(2A) and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 nM) and CHPG (100 microm) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 nM CGS21680 was prevented by 10 microm MPEP, whereas facilitation by 300 microm CHPG was prevented by 10 nM SCH58261. These results provide the first direct evidence that A(2A) and mGluR5 receptors are co-located in more than half of the striatal glutamatergic terminals where they facilitate glutamate release in a synergistic manner. This emphasizes the role of the modulation of glutamate release as a likely mechanism of action of these receptors both in striatal neuroprotection and in Parkinson's disease.Journal of Neurochemistry 03/2005; 92(3):433-41. · 4.06 Impact Factor -
Article: Long-term effect of convulsive behavior on the density of adenosine A1 and A 2A receptors in the rat cerebral cortex.
[show abstract] [hide abstract]
ABSTRACT: Adenosine is a neuromodulator that has been proposed to act as an anticonvulsant mainly via inhibitory A1 receptors, but recent data show that genetic deletion of facilitatory A 2A receptors might also attenuate convulsions. Since both A1 and A 2A receptors are prone to down- and upregulation in different stressful situations, we investigated if convulsive behavior leads to a long-term change in A1 and A 2A receptor density in the rat cerebral cortex. Stage 4-5 convulsions (Racine's scale) were induced in adult Wistar rats either through amygdala stimulation (kindling) or by intraperitoneal injection of kainate (10 mg/ml). Rats were killed after 4 weeks to evaluate adenosine A1 and A 2A receptor density in the cerebral cortex using both Western blot and membrane binding assays. The binding density of the A1 antagonist, 3H-DPCPX, decreased by 40. +/- 4.4% and by 20.7 +/- 0.5% after kindling or kainate injection. Likewise, A1 receptor immunoreactivity in cortical membranes from kindled or kainate-injected rats decreased by 19.1 +/- 3.3% and 12.7 +/- 5.7%, respectively. In contrast, the binding density of the A 2A receptor antagonist 3H-SCH 58261 increased by 293 +/- 34% and by 159 +/- 32% in cortical membranes from kindled or kainate-injected rats, and A 2A receptor immunoreactivity also increased by 151 +/- 12% and 79.6 +/- 7.0%. This indicates that after convulsive behavior there is a long-term decrease of A1 receptors accompanied by an increased density of A 2A receptors, suggesting that A 2A antagonists rather than A1 agonists may be more promising anticonvulsive drugs.Epilepsia 02/2005; 46 Suppl 5:159-65. · 3.96 Impact Factor -
Article: Co‐localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum
[show abstract] [hide abstract]
ABSTRACT: The anti-Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A2A receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinson's disease. mGluR5 and A2A antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the anti-Parkinsonian and neuroprotective effects of A2A and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A2A agonist, CGS21680 (1–30 nm) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A2A antagonist, SCH58261 (50 nm). The mGluR5 agonist, CHPG (300–600 μm) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 μm). Both mGluR5 and A2A receptors were located in the active zone and 57 ± 6% of striatal glutamatergic nerve terminals possessed both A2A and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 nm) and CHPG (100 μm) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 nm CGS21680 was prevented by 10 μm MPEP, whereas facilitation by 300 μm CHPG was prevented by 10 nm SCH58261. These results provide the first direct evidence that A2A and mGluR5 receptors are co-located in more than half of the striatal glutamatergic terminals where they facilitate glutamate release in a synergistic manner. This emphasizes the role of the modulation of glutamate release as a likely mechanism of action of these receptors both in striatal neuroprotection and in Parkinson's disease.Journal of Neurochemistry 01/2005; 92(3):433 - 441. · 4.06 Impact Factor -
Article: Binding of the prototypical adenosine A(2A) receptor agonist CGS 21680 to the cerebral cortex of adenosine A(1) and A(2A) receptor knockout mice.
[show abstract] [hide abstract]
ABSTRACT: 1. 2-p-(2-carboxyethylphenethylamino-5'-ethylcarboxamidoadenosine) (CGS 21680) is considered the reference compound to study adenosine A(2A) receptors. However, CGS 21680 binding in the cerebral cortex, where adenosine A(1) receptors are predominant, displays a mixed A(2A)/A(1) receptor pharmacology. We now use adenosine A(1) and A(2A) receptor knockout mice to investigate the characteristics of cortical [(3)H]CGS 21680 binding. 2. [(3)H]CGS 21680 binding to the cerebral cortex was strongly reduced in adenosine A(1) receptor knockout mice, but only slightly reduced in A(2A) receptor knockout mice compared with the corresponding wild-type littermates. 3. Another selective A(2A) receptor ligand, [(3)H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine ([(3)H]SCH 58261), displayed a saturable binding to mouse cortical membranes, albeit with a binding density 20 times lower than that of striatal membranes, and this [(3)H]SCH58261 binding was abolished in both striatal and cortical membranes of A(2A) receptor knockout mice and unchanged in A(1) receptor knockout mice. 4. The presence of A(2A) receptors in cortical neurons was further confirmed by Western blot in mouse cortical nerve terminal membranes. 5. It is concluded that, although A(2A) receptors are present in the cerebral cortex, the purportedly selective A(2A) receptor agonist [(3)H]CGS 21680 binds in the cerebral cortex to an entity that requires the presence of adenosine A(1) receptors. Thus, CGS 21680 should be used with care in all preparations where adenosine A(1) receptors out-number A(2A) receptors.British Journal of Pharmacology 04/2004; 141(6):1006-14. · 4.41 Impact Factor
Top co-authors
Top Journals
Institutions
-
2009–2011
-
University of Bordeaux
Bordeaux, Aquitaine, France
-
-
2002–2011
-
University of Coimbra
- Faculdade de Medicina
Coimbra, Distrito de Coimbra, Portugal
-
-
2007
-
French National Centre for Scientific Research
Lyon, Rhone-Alpes, France
-
-
2004
-
University of Lisbon
- Faculdade de Medicina
Lisbon, Lisbon, Portugal
-
