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1.
The enteric nervous system (ENS) contains functional ionotropic and group I metabotropic glutamate (mGlu) receptors. In this study, we determined whether enteric neurons express group II mGlu receptors and the effects of mGlu receptor activation on voltage-gated Ca(2+) currents in these cells. (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a group II mGlu receptor agonist, reversibly suppressed the Ba(2+) current in myenteric neurons isolated from the guinea pig ileum. Significant inhibition was also produced by L-glutamate and the group II mGlu receptor agonists, (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) and (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine (L-CCG-I), with a rank order potency of 2R,4R-APDC > DCG-IV > L-glutamate > L-CCG-I, and was reduced by the group II mGlu receptor antagonist LY-341495. Pretreatment of neurons with pertussis toxin (PTX) reduced the action of mGlu receptor agonists, suggesting participation of G(i)/G(o) proteins. Finally, omega-conotoxin GVIA blocked current suppression by DCG-IV, suggesting modulation of N-type calcium channels. mGlu2/3 receptor immunoreactivity was displayed by neurons in culture and in the submucosal and myenteric plexus of the ileum. A subset of these cells displayed a glutamatergic phenotype as shown by the expression of vesicular glutamate transporter 2. These results provide the first evidence for functional group II mGlu receptors in the ENS and show that these receptors are PTX sensitive and negatively coupled to N-type calcium channels. Inhibition of N-type calcium channels produced by activation of group II mGlu receptors may modulate enteric neurotransmission.  相似文献   

2.
A homology model of the extracellular domain of the mGlu3 subtype of metabotropic glutamate (mGlu) receptor was generated and tested using site-directed mutagenesis, a radioligand-binding assay using the Group II selective agonist (2S,2'R,3'R)-2-(2',3'-[3H]dicarboxycyclopropyl) glycine ([3H]DCG-IV), and in a fluorescence-based functional assay in live transiently transfected human embryonic kidney cells. Ten of the 12 mGlu3 mutants (R64A, R68A, Y150A, S151A, T174A, D194A, Y222A, R277A, D301A and K389) showed either no binding or a 90% or greater loss of specific [3H]DCG-IV binding. Several analogous mutations in mGlu2 supported the results obtained with mGlu3. These results demonstrate that the binding of [3H]DCG-IV to mGlu3 is exceptionally sensitive to mutagenesis-induced perturbations. In silico docking of DCG-IV into the agonist binding pocket of mGlu3 facilitated the interpretation the mutagenesis results. Tyrosines 150 and 222, and arginine 277 show close contacts with the third carboxylic acid group in DCG-IV, which is not present in glutamate or (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I). Mutation of these three amino acids to alanine resulted in a near complete loss of receptor activation by DCG-IV and retention of near wild-type affinity for L-CCG-I. It is proposed that hydrogen bonding between this carboxylate and tyrosines 150 and 222 and arginine 277 provide a partial explanation for the high affinity and Group II selectivity of DCG-IV. These findings define the essential features of the ligand-binding pocket of mGlu3 and, together with other recent studies on mGlu receptors, provide new opportunities for structure-based drug design.  相似文献   

3.
Stimulation of astrocytes with the excitatory neurotransmitter glutamate leads to the formation of inositol 1,4,5-trisphosphate and the subsequent increase of intracellular calcium content. Astrocytes express both ionotropic receptors and metabotropic glutamate (mGlu) receptors, of which mGlu5 receptors are probably involved in glutamate-induced calcium signaling. The mGlu5 receptor occurs as two splice variants, mGlu5a and mGlu5b, but it was hitherto unknown which splice variant is responsible for the glutamate-induced effects in astrocytes. We report here that both mRNAs encoding mGlu5 receptor splice variants are expressed by cultured astrocytes. The expression of mGlu5a receptor mRNA is much stronger than that of mGlu5b receptor mRNA in these cells. In situ hybridization experiments reveal neuronal expression of mGlu5b receptor mRNA in adult rat forebrain but a strong neuronal expression of mGlu5a mRNA only in olfactory bulb. Signals for mGlu5a receptor mRNA in the rest of the brain were diffuse and weak but consistently above background. Activation of mGlu5 receptors in astrocytes yields increases in inositol phosphate production and transient calcium responses. It is surprising that the rank order of agonist potency [quisqualate > (2S,1 'S,2'S)-2-(carboxycyclopropyl)glycine = trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD) > glutamate] differs from that reported for recombinantly expressed mGlu5a receptors. The expression of mGlu5a receptor mRNA and the occurrence of 1S,3R-ACPD-induced calcium signaling were found also in cultured microglia, indicating for the first time expression of mGlu5a receptors in these macrophage-like cells.  相似文献   

4.
The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 mm (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385-mediated anticonvulsant effect. The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures. Agonist-mediated actions at mGlu2/3 receptors by LY379268 (100 microm, 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo.  相似文献   

5.
Summary. Numerous pharmacological data indicate involvement of glutamate, the major excitatory neurotransmitter in the brain, in the pathophysiology of several neuropsychiatric disorders. It was shown in the preclinical studies that compounds which can reduce the excess of glutamate release (for example group III metabotropic receptors agonists) possess potential therapeutic properties. Thus we focused our interests on (−)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), which is a positive allosteric modulator of mGlu4 receptor. We examined the potential antidepressant-like activity of PHCCC after injection into the brain ventricles alone, or together with (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I), a nonselective group III mGlu receptor agonist, using the forced swimming test (FST) in rats. We found that ACPT-I induced a dose dependent antidepressant-like effect in FST, which was blocked by an antagonist of group III mGlu receptors (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). PHCCC injected intracerebroventricular was not effective, however when the compound was administered together with non-effective dose of ACPT-I, a profound antidepressant-like activity in FST was demonstrated. This effect was reversed by CPPG, group III mGlu receptors antagonist. Results of our studies indicate that a combined administration positive allosteric modulation of mGlu4 receptor and agonists of group III mGlu receptors may be a promising target in the future treatment of depressive disorder.  相似文献   

6.
Pancreatic islets contain ionotropic glutamate receptors that can modulate hormone secretion. The purpose of this study was to determine whether islets express functional group III metabotropic glutamate (mGlu) receptors. RT-PCR analysis showed that rat islets express the mGlu8 receptor subtype. mGlu8 receptor immunoreactivity was primarily displayed by glucagon-secreting alpha-cells and intrapancreatic neurons. By demonstrating the immunoreactivities of both glutamate and the vesicular glutamate transporter 2 (VGLUT2) in these cells, we established that alpha-cells express a glutamatergic phenotype. VGLUT2 was concentrated in the secretory granules of islet cells, suggesting that glutamate might play a role in the regulation of glucagon processing. The expression of mGlu8 by glutamatergic cells also suggests that mGlu8 may function as an autoreceptor to regulate glutamate release. Pancreatic group III mGlu receptors are functional because mGlu8 receptor agonists inhibited glucagon release and forskolin-induced accumulation of cAMP in isolated islets, and (R,S)-cyclopropyl-4-phosphonophenylglycine, a group III mGlu receptor antagonist, reduced these effects. Because excess glucagon secretion causes postprandial hyperglycemia in patients with type 2 diabetes, group III mGlu receptor agonists could be of value in the treatment of these patients.  相似文献   

7.
The syntheses of a range of ring and alpha-substituted 4-phosphonophenylglycines are described. A brief discussion of the antagonist activities of compounds 4-10 on group I, II and III metabotropic glutamate (mGlu) receptors expressed in the neonatal rat spinal cord is included.  相似文献   

8.
Metabotropic glutamate receptors (mGluRs) were identified in olfactory receptor neurons of the channel catfish, Ictalurus punctatus, by polymerase chain reaction. DNA sequence analysis confirmed the presence of two subtypes, mGluR1 and mGluR3, that were coexpressed with each other and with the putative odorant receptors within single olfactory receptor neurons. Immunocytochemical data showed that both mGluR subtypes were expressed in the apical dendrites and some cilia of olfactory neurons. Pharmacological analysis showed that antagonists to each mGluR subtype significantly decreased the electrophysiological response to odorant amino acids. α-Methyl-L -CCG1/(2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG), a known antagonist to mGluR3, and (S)-4-carboxyphenylglycine (S-4CPG), a specific antagonist to mGluR1, each significantly reduced olfactory receptor responses to L -glutamate. S-4CPG and MCCG reduced the glutamate response to 54% and 56% of control, respectively, which was significantly greater than their effect on a neutral amino acid odorant, methionine. These significant reductions of odorant response by the antagonists, taken with the expression of these receptors throughout the dendritic and ciliated portions of some olfactory receptor neurons, suggest that these mGluRs may be involved in olfactory reception and signal transduction. © 1998 John Wiley & Sons, Inc. J Neurobiol 35: 94–104, 1998  相似文献   

9.
Expression of group III metabotropic glutamate receptors (mGluR) was established by RT-PCR and immunocytochemistry on a cultured clonal human neural stem/progenitor cell (hNSPC) line derived from fetal ventral mesencephalon (VM). Selective activation of these receptors by the group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) prevented increases in cAMP levels following forskolin stimulation, suggesting these receptors are coupled to their canonical G-protein coupled signal transduction pathway. Tonic exposure of undifferentiated cultures to l-AP4 resulted in a decrease in cellular metabolism and proliferation in the absence of toxicity, as measured by MTT and LDH assays, in a dose-dependent manner. This was confirmed by a reduction in BrdU incorporation into nuclear DNA, suggestive of an anti-proliferative effect of l-AP4. This effect was rescued by co-addition of the broad-spectrum group III mGluR competitive antagonist (RS)-a-cyclopropyl-4-phosphonophenylglycine (CPPG), demonstrating a receptor-mediated mechanism, but not mimicked by application of the cell permeable cAMP analogue dibutyrl cAMP (db-cAMP). The potency of these effects of l-AP4 indicates that this is an mGlu7 subtype-mediated effect. Tonic exposure of undifferentiated cultures to the mGlu7 selective allosteric agonist N,N′-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082), but not the mGlu4 selective allosteric agonist (±)-cis-2-(3,5-dicholorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), or the mGlu8 selective agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) resulted in an identical anti-proliferative effect to l-AP4, confirming the involvement of the mGlu7 subtype. In differentiating cultures, tonic exposure to l-AP4 or AMN082 resulted in a significant shift towards an astrocyte cell fate. The mGlu7 receptor therefore provides a new opportunity to influence the proliferation and differentiation of ventral mesencephalon-derived hNSPC.  相似文献   

10.
Group I mGlu receptors have been implicated in the control of brain dopamine release. However, the receptor subtype involved and the precise site of action have not been determined. In this study we show that (R,S)3,5-dihydroxyphenylglycine (DHPG; 6 and 60 nmol ICV), a selective group I mGlu receptor agonist, raised extracellular dopamine respectively by 176% and 243% of basal values in the medial prefrontal cortex as assessed by in vivo microdialysis in conscious rats. (R,S)2-chloro-5-hydroxyphenylglycine (60 nmol ICV), a selective mGlu5 receptor agonist, raised extracellular dopamine by 396% of basal values. Intra-VTA DHPG (0.6–6 nmol) mimicked ICV injection whereas intracortical infusion (1–1000 µmol/L) had no effect. DHPG-induced rise of extracellular dopamine was reversed by tetrodotoxin and by the selective mGlu1 and mGlu5 receptor antagonists 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate (CPCCOEt) and 2-methyl-6-(phenylethynyl)pyridine (MPEP) either ICV or into the ventrotegmental area (VTA), suggesting that neuronal release and both mGlu1 and mGlu5 receptors were involved. These results support the existence of functional mGlu1 and mGlu5 receptors in the VTA regulating the release of dopamine in the medial prefrontal cortex.  相似文献   

11.
Autoradiographical studies revealed that 10 nM [3H]N-acetyl-aspartyl-glutamate (NAAG) labelled grey matter structures, particularly in the hippocamus, cerebral neocortex, striatum, septal nuclei and the cerebellar cortex. The binding was inhibited by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG IV), an agonist at group II metabotropic glutamate receptors (mGluR II). (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-cyclopropyl-4-phosphonoglycine (CPPG) and (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE), all antagonists at mGluR II and mGluR III, also inhibited [3H]NAAG binding. Other inhibitors were (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a broad-spectrum mGluR agonist with preference for groups I and II and the mGluR I agonists/mGluR II antagonists (S)-3-carboxy-4-hydroxyphenylglycine (3,4-CHPG) and (S)-4-carboxy-3-hydroxyphenylglycine (4,3-CHPG). Neither the mGluR I specific agonist (S)-dihydroxyphenylglycine nor any of the ionotropic glutamate receptor ligands such as kainate, AMPA and MK-801 had strong effects (except for the competitive NMDA antagonist CGS 19755, which produced 20-40% inhibition at 100 microM) suggesting that, at low nM concentrations, [3H]NAAG binds predominantly to metabotropic glutamate receptors, particularly those of the mGluR II type. Several studies have indicated that NAAG can interact with mGluR II and the present study supports this notion by demonstrating that sites capable of binding NAAG at low concentrations and displaying pharmacological characteristics of mGluR II exist in the central nervous tissue. Furthermore, the results show that autoradiography of [3H]NAAG binding can be used to quantify the distribution of such sites in distinct brain regions and study their pharmacology at the same time.  相似文献   

12.
A new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using a parallel chemistry approach. Amongst 65 molecules tested on mGlu4, mGlu6 and mGlu8 subtypes, (2S,4S)-4-amino-1-[(E)-3-carboxyacryloyl]pyrrolidine-2,4-dicarboxylic acid (8a06-FP0429) has been shown to be a full mGlu4 agonist and a partial mGlu8 agonist. In addition, 8a06 was shown to be selective versus group I and II mGlu subtypes. A possible explanation for this efficacy difference is proposed by docking experiment performed with molecular model of the receptor.  相似文献   

13.
Cultured human melanocytes express mGlu5 metabotropic glutamate (mGlu) receptors, as shown by RT-PCR, immunocytochemistry, Western blot analysis, and measurement of agonist-stimulated polyphosphoinositide hydrolysis. The mGlu5 receptor agonists (S)-3, 5-dihydroxyphenylglycine and quisqualate increased [(3)H-methyl]thymidine incorporation and melanocyte proliferation in subconfluent cultures, but impaired cell viability in confluent cultures. Both effects were prevented by 2-methyl-6-(2-phenyl-1-ethynyl)-pyridine, a potent and highly selective mGlu5 receptor antagonist. Agonists of other mGlu receptor subtypes (such as the mGlu2/3 receptor agonist, 2S,2'R,3'R-2-2', 3'-dicarboxycyclopropylglycine, or the mGlu4/6/7/8 receptor agonist, L-2-amino-4-phosphonobutanoate) or selective agonists of ionotropic glutamate receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, and kainate) did not affect melanocyte proliferation or viability. The presence of a receptor for glutamate, the major excitatory neurotransmitter, in human melanocytes is intriguing. mGlu5 receptors may be involved in the control of melanocyte proliferation (and perhaps in other functions), but harbor a potential toxicity and may therefore contribute to cell damage under pathological conditions.  相似文献   

14.
The (2S,4R)- and (2S,4S)-4-hydroxyglutamates activate cloned mGlu(1a), mGlu(2), and mGlu(8a) receptors with different potencies. Best results were obtained with the (2S,4S) isomer being almost as potent as glutamate on mGlu(1a)R and mGlu(8a)R. Data are interpreted on the basis of the binding site model and X-ray structure.  相似文献   

15.
In this study we have tested the effects of a wide range of metabotropic glutamate receptor ligands on (i) depolarisation-evoked efflux of pre-accumulated d-[3H]aspartic acid (d-[3H]asp) from rapidly superfused rat cerebrocortical minislices, and (ii) Na+-dependent uptake of d-[3H]asp into cerebrocortical tissue. Transient elevations in extracellular K+ produced concentration-dependent increases in d-[3H]asp efflux. A submaximally effective concentration (50 mm) was used in all subsequent experiments. The broad-spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; EC50 17.8 microm], the group I mGlu-selective agonist (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG; EC50 0.5 microm] and the mGlu5 receptor subtype-selective agonist (RS)-2-chloro-5-hydroxyphenylglycine [(RS)-CHPG; EC50 7.3 microm] all concentration-dependently potentiated high K+-evoked d-[3H]asp efflux in the absence of effects on basal outflow of radiolabel. At concentrations selective for mGlu1 receptors, the antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid [(RS)-AIDA; 10-300 microm]; (+)-2-methyl-4-carboxyphenylglycine [LY367385; 1-100 microm] and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylate ethyl ester [CPCCOEt, 1-30 microm] all failed to inhibit responses to (S)-3,5-DHPG. However, the broad-spectrum mGlu receptor antagonist (S)-alpha-methyl-4-carboxyphenylglycine [(S)-MCPG; IC50 88.5 microm] together with the recently described mGlu5-selective antagonists, 2-methyl-6-(phenylethynyl)-pyridine (MPEP; IC50 0.6 microm), 6-methyl-2-(phenyl-azo)-3-pyridinol (SIB-1757; IC50 4.4 microm) and (E)-2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893; IC50 3.1 microm), at mGlu5-selective concentrations, all powerfully and concentration-dependently inhibited (S)-3,5-DHPG-evoked responses. Two selective excitatory amino acid (EAA) uptake inhibitors, l-trans-2,4-pyrrolidine dicarboxylate (l-trans-2,4-PDC; IC50 229 microm) and dl-threo-beta-benzyloxyaspartate (dl-TBOA; IC50 665 microm) both inhibited the Na+-dependent uptake of d-[3H]asp into cerebrocortical minislices. Importantly, none of the mGlu ligands utilized in the present study significantly inhibited d-[3H]asp uptake at concentrations shown to potentiate K+-evoked efflux. These data demonstrate for the first time that mGlu5 ligands modulate extracellular EAA concentrations by a direct effect on mGlu5-type autoreceptors on EAA nerve terminals as they evoke clear changes in EAA release in the absence of any effects on EAA uptake. Selective mGlu5 receptor antagonists that show high potency and good central bioavailability may provide novel classes of neuroprotective agents for the treatment of brain disorders associated with abnormal EAAergic neurotransmission.  相似文献   

16.
Regulation of microglial reactivity and neurotoxicity is critical for neuroprotection in neurodegenerative diseases. Here we report that microglia possess functional group II metabotropic glutamate receptors, expressing mRNA and receptor protein for mGlu2 and mGlu3, negatively coupled to adenylate cyclase. Two different agonists of these receptors were able to induce a neurotoxic microglial phenotype which was attenuated by a specific antagonist. Chromogranin A, a secretory peptide expressed in amyloid plaques in Alzheimer's disease, activates microglia to a reactive neurotoxic phenotype. Chromogranin A-induced microglial activation and subsequent neurotoxicity may also involve an underlying stimulation of group II metabotropic glutamate receptors since their inhibition reduced chromogranin A-induced microglial reactivity and neurotoxicity. These results show that selective inhibition of microglial group II metabotropic glutamate receptors has a positive impact on neuronal survival, and may prove a therapeutic target in Alzheimer's disease.  相似文献   

17.
To examine the relationship between glutamate receptors and the action of NC-1900 on a step-through passive avoidance (PA) task in mice, MK-801, an NMDA receptor blocker, and (S)-4-carboxyphenylglycine (4CPG), a group I metabotropic receptor antagonist, were administered intraventricularly (i.c.v.) singly or as co-injections. The i.c.v. injection of MK-801 (0.8 microg) or 4CPG (2 microg) decreased the latency on the PA task. NC-1900 (1 ng/kg, subcutaneously (s.c.)) alone prolonged the latency on the retention trial in the PA task. MK-801 (0.2 and 0.8 microg) or 4CPG (0.5 and 2 microg) significantly inhibited the action of NC-1900, while the s.c. injection of NC-1900 did not affect latency in mice that received i.c.v. co-injection of MK-801 and 4CPG at any of the doses tested. These results suggest that glutamate receptors participate in the action of NC-1900 on learning and memory in PA task performance.  相似文献   

18.
The major excitatory neurotransmitter in the central nervous system, (S)-glutamic acid , activates both ionotropic and metabotropic excitatory amino acid receptors. Its importance in connection to neurological and psychiatric disorders has directed great attention to the development of compounds that modulate the effects of this endogenous ligand. Whereas L-carboxycyclopropylglycine (L-CCG-1) is a potent agonist at, primarily, group II metabotropic glutamate receptors, alkylation of at the alpha-carbon notoriously result in group II mGluR antagonists, of which the most potent compound described so far, LY341495, displays IC(50) values of 23 and 10 nM at the group II receptor subtypes mGlu2 and mGlu3, respectively. In this study we synthesized a series of structural analogues of in which the xanthyl moiety is replaced by two substituted-phenyl groups. The pharmacological characterization shows that these novel compounds have very high affinity for group II mGluRs when tested as their racemates. The most potent analogues demonstrate K(i) values in the range of 5-12 nM, being thus comparable to LY341495.  相似文献   

19.
Anoxia in the first week of life can induce neuronal death in vulnerable brain regions usually associated with an impairment of cognitive function that can be detected later in life. We set-up a model of subneurotoxic anoxia based on repeated exposures to 100% nitrogen during the first 7 days of post-natal life. This mild post-natal exposure to anoxia specifically modified the behaviour of the male adult rats, which showed an attention deficit and an increase in anxiety, without any impairment in spatial learning and any detectable brain damage (magnetic resonance imaging and histological analysis). Post-anoxic rats showed a reduction in the expression of group-I metabotropic glutamate receptors (i.e. mGlu1 and mGlu5 receptors) in the hippocampus and cerebral cortex, whereas expression of the mGlu 2/3 receptors, the NR1 subunit of NMDA receptors, and the GluR1 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors was unchanged. mGlu1 and mGlu5 receptor signalling was also impaired in postanoxic rats, as revealed by a reduced efficacy of the agonist (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) to stimulate polyphosphoinositide hydrolysis in hippocampal slices. We conclude that rats subjected to subneurotoxic doses of anoxia during the early post-natal life develop behavioural symptoms that are frequently encountered in the inattentive subtype of the attention deficit hyperactivity disorder, and that group-I mGlu receptors may be involved in the pathophysiology of these symptoms.  相似文献   

20.
We found that centrally administered prostaglandin (PG) E(2) exhibited anxiolytic-like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP(1) and EP(4) receptors, among four receptor subtypes for PGE(2), mimicked the anxiolytic-like activity of PGE(2). The anxiolytic-like activity of PGE(2) was blocked by an EP(1) or EP(4) antagonist, as well as in EP(4) but not EP(1) knockout mice. Central activation of either EP(1) or EP(4) receptors resulted in anxiolytic-like activity. The PGE(2)-induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT(1A), dopamine D(1) and GABA(A) receptors. Taken together, PGE(2) exhibits anxiolytic-like activity via EP(1) and EP(4) receptors, with downstream involvement of 5-HT(1A), D(1) and GABA(A) receptor systems.  相似文献   

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