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1.
The globus pallidus plays a critical role in movement regulation. Glutamate being an important excitatory neurotransmitter modulates the activity of pallidal neurons through both ionotropic and metabotropic glutamate receptors (mGluRs). Morphological studies have shown that group III mGluRs are generally located presynaptically in the globus pallidus. Up to now, little is known about the in vivo electrophysiological effects of group III mGluRs on the pallidal neurons. This study investigated the electrophysiological and behavioral effects of group III mGluRs on pallidal neurons in both normal and 6‐hydroxydopamine (6‐OHDA) lesioned parkinsonian rats. Micropressure ejection of group III mGluR agonist, l ‐2‐amino‐4‐phosphonobutyrate (l ‐AP4), increased or decreased the firing rate of pallidal neurons in both normal and parkinsonian rats. The l ‐AP4‐induced excitatory effects on the lesioned side of parkinsonian rats (117.4 ± 17.2%) were stronger than that in normal rats (64.3 ± 10.1%). While the proportion of neurons that were unresponsive to l ‐AP4 on the lesioned side of parkinsonian rats (50%) was more than that of normal rats (13%). Unilateral microinjection of l ‐AP4 into the globus pallidus induced a contralateral dystonic posturing in the presence of systemic haloperidol administration. The selective group III mGluRs antagonist, (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine, had no effect on pallidal neurons when used alone and could block both l ‐AP4‐induced electrophysiological and behavioral effects. Combining electrophysiological and behavioral findings, we concluded that activation of group III mGluRs modulate the activity of pallidal neurons under both normal and parkinsonian state. Synapse 67:831–838, 2013 . © 2013 Wiley Periodicals, Inc.  相似文献   
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目的:阐明大鼠小脑绒球中代谢性谷氨酸受体I组在前庭代偿过程中的作用。方法:用RT-PCR方法对单侧迷路切除术后前庭代偿过程中代谢性谷氨酸受体I组在小脑绒球中的表达进行研究。结果:代谢性谷氨酸受体I组在双侧绒球中均有表达,双侧的手术组和对照组比较均差异有统计学意义,而双侧之间无差异。结论:大鼠小脑绒球存在代谢性谷氨酸受体I组,在前庭代偿过程中有变化,表明其参与前庭代偿的过程。  相似文献   
4.
Human cocaine addicts show altered function within the basal ganglia and the medial prefrontal cortex (mPFC) and altered glutamate function within these areas is postulated to be critical for cocaine addiction. The present project utilized a highly valid animal model of cocaine addiction, to test whether excessive use of cocaine alters glutamate function within these brain areas. Rats were trained to lever‐press for i.v. saline vehicle or cocaine (0.25 mg/infusion) over seven 1‐h daily sessions, after which, saline controls and half of cocaine self‐administering animals (brief access condition) received 10 more 1‐h daily sessions, whereas the remaining cocaine animals received 10 additional 6‐h daily sessions (extended access condition). One, 14, or 60 days after the last self‐administration session, animals were sacrificed. Tissue samples from the ventral tegmental area (VTA), nucleus accumbens (N.Acc) core and shell, and mPFC were analyzed by immunoblotting for expression of Homer1b/c, Homer2a/b, mGluR1, mGluR5, NR2a, and NR2b subunits of the NMDA receptor. Brief and extended access to cocaine failed to alter protein levels within the VTA, and produced transient and similar changes in N.Acc protein expression, which were more pronounced in the core subregion. In contrast, extended access to cocaine resulted in distinct and long lasting alterations of protein expression within the mPFC that included: increased levels of Homer1b/c at 1 day, NR2b at 14 days, and NR2a at 60 days, of withdrawal. These data support the notion that altered NMDA function within the mPFC may contribute, in part, to the transition to excessive uncontrolled consumption of cocaine. Synapse 63:598–609, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   
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Hypo-function of N-methyl d-aspartate (NMDA) receptors is strongly involved in the brain pathophysiology of schizophrenia. Several excitatory amino acids, such as endogenous glutamate, glycine, serine and alanine, which are involved in glutamate neurotransmission via NMDA receptors, were studied to further understand the pathophysiology of schizophrenia and to find a biological marker for this disease, particularly in peripheral blood. In this literature review, we connect several earlier clinical studies and several studies of excitatory amino acid levels in peripheral blood in a historical context. Finally, we join these results and our previous studies, the Juntendo University Schizophrenia Projects (JUSP), which investigated plasma glutamatergic amino acid levels in detail, and considered whether these amino acid levels may be diagnostic, therapeutic, or symptomatic biological markers. This review concludes that peripheral blood levels of endogenous glycine and alanine could be a symptomatic marker in schizophrenia, while peripheral blood levels of exogenous glycine and alanine in augmentation therapies could be therapeutic markers. Noteworthy peripheral blood levels of endogenous d-serine could reflect its brain levels, and may prove to be a useful diagnostic and therapeutic marker in schizophrenia. In addition, measurements of new endogenous molecules, such as glutathione, are promising. Finally, for future therapies with glutamatergic agents still being examined in animal studies, the results of these biological marker studies may lay the foundation for the development of next-generation antipsychotics.  相似文献   
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Two glutamate receptor agonists, NMDA (N-methyl-d-aspartic acid) and ACPD (cis-(1S/3R)-1-aminocyclopentane-1,3-dicarboxylic acid), induce the reactive oxygen species (ROS) production in rat cerebellum granule cells, whereas the third one, 3-HPG (3-hydroxyphenylglycine), decreases this parameter. The simultaneous presence of 3-HPG, together with NMDA or ACPD, prevents the generation of ROS by neuronal cells. A similar effect of these ligands on Na+/K+-ATPase can be demonstrated: NMDA and ACPD inhibited the enzyme activity, but 3-HPG activated Na+/K+-ATPase and prevented its inhibition by NMDA or ACPD. In terms of current classification, NMDA is an agonist of ionotropic glutamate receptors of the so-called NMDA class, whereas ACPD and 3-HPG belong to metabotropic agonists, the former primarily being an activator of metabotropic glutamate receptors (mGluRs) of groups 2 and 3, and the latter, that of mGluRs of groups 1 and 5. Thus, the data presented illustrate the existence of diverse mechanisms of the cross talk between Na+/K+-ATPase and different glutamate receptors, as well as that between glutamate receptors of different classes.  相似文献   
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Group I metabotropic glutamate receptors (mGluRs) play critical roles in synaptic plasticity and drug addiction. To characterize potential sites whereby these receptors mediate their effects in the ventral striatum, we studied the subcellular and subsynaptic localization of mGluR1a and mGluR5 in the shell and core of the nucleus accumbens in rat and monkey. In both species, group I mGluRs are mainly postsynaptic in dendrites and spines, with rare presynaptic labeling in unmyelinated axons. Minor, yet significant, differences in proportions of specific immunoreactive elements were found between the accumbens shell and the accumbens core in monkey. At the subsynaptic level, significant differences were found in the proportion of plasma membrane-bound mGluR5 labeling between species. In dendrites, spines, and unmyelinated axons, a significantly larger proportion of mGluR5 labeling was bound to the plasma membrane in rats (50-70%) than in monkeys (30-50%). Conversely, mGluR1a displayed the same pattern of immunogold labeling in the two species. Electron microscopic colocalization studies revealed 30% colocalization of mGluR1a and mGluR5 in dendrites and as much as 50-65% in spines in both compartments of the rat accumbens. Both group I mGluRs were significantly expressed in D1-immunoreactive dendritic processes (60-75% colocalization) and spines (30-50%) of striatal projection neurons as well as dendrites of cholinergic (30-70%) and parvalbumin-containing (70-85%) interneurons. These findings highlight the widespread expression of group I mGluRs in projection neurons and interneurons of the shell and core of the nucleus accumbens, providing a solid foundation for regulatory and therapeutic functions of group I mGluRs in reward-related behaviors and drug addiction.  相似文献   
8.
Several recent reports implicate an important role played by c-Jun N-terminal kinases (JNKs) in long-term potentiation (LTP). However, little is known about how the isoforms of JNKs participate in synaptic plasticity. Here we showed that short-term synaptic plasticity was impaired in the hippocampal area CA1 of JNK1-deficient (JNK1-/-) mice; these mice showed normal LTP in response to a strong tetanus and no alteration of N-methyl-D-aspartate receptor-dependent long-term depression (LTD) in the hippocampus. However, LTD induced either by group I metabotropic glutamate receptors (mGluRs) agonist dihydroxyphenylglycine or by paired-pulse low-frequency stimulation was absent in both the JNK1-/- slices and in JNK inhibitor anthrax [1, 9-cd] pyrazol-6(2H)-1 (SP600125)-pretreated slices. Induction of mGluR-dependent LTD resulted in an increase in phosphorylation of JNK1 substrates, including p-c-Jun and p-ATF2 in wild-type (WT) mice, and these increases failed to occur in the JNK1-/- or SP600125-pretreated mice. These results demonstrated that JNK1 played a crucial role in the short-term synaptic plasticity and mGluR-dependent LTD, whereas hippocampus LTP was not affected by JNK1 deficiency.  相似文献   
9.
Glutamate disruption is thought to have a major role in schizophrenia brain processes, possibly involving NMDA hypofunction. The metabotropic glutamate receptors are distributed in brain regions related to schizophrenia and seem to affect glutamate release in a moderate way. Compounds modulating these receptors are being investigated in animal models of schizophrenia, in an attempt to discover new antipsychotics. This article reviews the current research data regarding the role of these receptors in schizophrenia animal models. It was found that more research was done on Group I and II metabotropic receptors while investigation of group III receptors is still trailing behind. Accumulating evidence shows that mGluR5 antagonists by themselves do not necessarily disrupt pre-pulse inhibition (PPI), but can exacerbate disruption of PPI caused by MK-801 and PCP, while positive modulation of this receptor has beneficial effects on these models of psychosis. Group II agonists are also showing beneficial effects in animal models. It seems that metabotropic glutamate receptor modulators could be developed into a novel treatment of schizophrenia by altering glutamate release, thus overcoming the putative NMDA hypofunction. Although the implications from these pre-clinical studies to human schizophrenia patients are premature, the data obtained with some compounds point to promising results for drug development. More studies, with agents active at other mGluRs in animal models and schizophrenia patients as well as with human subjects are needed in order to clarify the role of the metabotropic glutamate receptors in the pathophysiology and pharmacotherapy of schizophrenia.  相似文献   
10.
  1. The pharmacological features of the pre- and postsynaptic metabotropic glutamate receptors (mGluRs) present in the guinea-pig olfactory cortex, were examined in brain slices in vitro by use of a conventional intracellular current clamp/voltage clamp recording technique.
  2. Bath-application of trans-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) (50 μM) produced a sustained membrane depolarization, increase in cell excitability and induction of a post-stimulus inward (afterdepolarizing) tail current (IADP) (measured under ‘hybrid'' voltage clamp) similar to those evoked by the muscarinic receptor agonist oxotremorine-M (OXO-M, 2 μM).
  3. L-Glutamate (0.25–1 mM, in the presence of 20 μM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 100 μM DL-amino-5-phosphono valeric acid (DL-APV)) or the broad spectrum mGluR agonists 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 10 μM), 1S,3S-ACPD (50 μM), ibotenate (Ibo; 25 μM, in the presence of 100 μM DL-APV), the selective mGluR I agonists (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG, 10 μM), (S)-3-hydroxyphenylglycine ((S)-3HPG, 50 μM), or quisqualate (10 μM, in the presence of 20 μM CNQX), but not the mGluR II agonist 2S,1′S,2′S-2-(2′-carboxycyclopropyl)-glycine (L-CCGI, 1 μM) or mGluR III agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 1 mM), were all effective in producing membrane depolarization and inducing a post-stimulus IADP. Unexpectedly, the proposed mGluR II-selective agonist (2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)-glycine (DCG-IV, 10 μM, in the presence of 100 μM DL-APV) was also active.
  4. The excitatory effects induced by 10 μM 1S,3R-ACPD were reversibly antagonized by the mGluR I/II antagonist (+)-α-methyl-4-carboxyphenylglycine ((+)-MCPG, 0.5–1 mM), as well as the selective mGluR I antagonists (S)-4-carboxyphenylglycine ((S)-4CPG) and (S)-4-carboxy-3-hydroxyphenyl glycine ((S)-4C3HPG) (both at 1 mM), but not the nonselective mGluR antagonist L(+)-2-amino-3-phosphonopropionic acid (L-AP3, 1 mM) or the selective mGluR III antagonist (S)-α-methyl-L-AP4 (MAP4, 1 mM).
  5. The excitatory postsynaptic potentials (e.p.s.ps), induced by single focal stimulation of cortical excitatory fibre tracts, were markedly reduced by 1S,3R-ACPD or L-AP4 (both at 10 μM), and by the selective mGluR II agonists (mGluR I antagonists) (S)-4CPG or (S)-4C3HPG (both at 1 mM) but not (S)-3,5-DHPG or (S)-3HPG (both at 100 μM).
  6. The inhibitory effects of 1S-3R-ACPD, but not L-AP4, were reversibly blocked by (+)-MCPG (1 mM), whereas those produced by L-AP4, but not 1S,3R-ACPD, were blocked by the selective mGluR III antagonist MAP4 (1 mM).
  7. It is concluded that a group I mGluR is most likely involved in mediating excitatory postsynaptic effects, whereas two distinct mGluRs (e.g. group II and III) might serve as presynaptic inhibitory autoreceptors in the guinea-pig olfactory cortex.
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