Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Mongolian gerbils, bilateral carotid occlusion (BCO) followed by reperfusion causes uniform destruction of the CA1 pyramidal neurons in the hippocampus, and this damage correlates with an increase in locomotor activity. Various drugs, such as NMDA antagonists, calcium channel blockers, and free radical scavengers, have provided neuroprotection against ischaemia-induced damage. More recently, the neuroprotective effects of dopamine have been investigated. A large release of dopamine has been shown to occur at the onset of ischaemia, and dopamine levels return to basal values following reperfusion. In the present study, we investigated the effects of vanoxeamine (GBR 12909) (5 or 10 mg/kg i.p., administered 1 h prior to occlusion) on behavioural and histological changes following global ischaemia in the Mongolian gerbil. Ischaemia was induced by bilateral carotid occlusion for 5 min. Both doses of GBR 12909 significantly potientiated the hyperactivity of the BCO animals measured in the home cage during the first 24 h following surgery and in the locomotor activity arena after 24 h and 48 h. Significant neuroprotection of cells in the CA1 region of the bippocampus was observed in drug-treated animals 96 h postsurgery. The neuroprotective effect of GBR 12909 may be ascribed to sensitisation of the dopamine D, autoreceptor, consequently reducing the release of dopamine that occurs following ischaemia. Alternatively, GBR 12909 may have a direct interaction with the Na+ ion channel-glutamate complex, resulting in reduced release of glutamate and thereby reducing NMDA receptor activation and neuronal damage.
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PMID:Protective effects of vanoxeamine (GBR 12909) against ischaemia-induced hyperactivity and neurodegeneration in the gerbil model of cerebral ischaemia. 913 Mar

The purpose of the present study was to evaluate the role of central alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate type of glutamate receptors in the control of ACTH and corticosterone release under basal and stress conditions. AMPA/ kainate competitive receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), which does not penetrate the blood-brain barrier, was administered intracerebroventricularly (i.c.v.). A modified method for i.c.v. drug administration in conscious freely moving rats was employed. DNQX or artificial cerebrospinal fluid (aCSF) was injected into lateral ventricle through a thin polyethylene cannula with a steel needle on the end which was inserted and moved via large polyethylene cannula to the guide stainless steel cannula. This procedure was performed out of the cage. ACTH and corticosterone release under basal conditions and during immobilization stress were investigated. Intracerebroventricular administration of DNQX resulted in an increase of ACTH and corticosterone in plasma reaching maximal values at 15 min after drug injection. During immobilization stress, i.c.v. DNQX induced a mild reduction in plasma ACTH levels compared to those in aCSF pretreated rats. Corticosterone secretion was high throughout the whole period of stress exposure. These findings indicate that endogenous excitatory amino acids (EAA) acting at AMPA/kainate receptors may interfere with the control of ACTH release under both basal and stress conditions, but the mechanisms involved remain to be elucidated.
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PMID:Effect of central administration of the non-NMDA receptor antagonist DNQX on ACTH and corticosterone release before and during immobilization stress. 937 80

Astrocytes exhibit a form of excitability and communication on the basis of intracellular Ca2+ variations (Cornell-Bell et al., 1990; Charles et al., 1991) that can be initiated by neuronal activity (Dani et al., 1992; Porter and McCarthy, 1996). A Ca2+ elevation in astrocytes induces the release of glutamate (Parpura et al., 1994; Pasti et al., 1997; Araque et al., 1998;Bezzi et al., 1998), which evokes a slow inward current in neurons and modulates action potential-evoked synaptic transmission between cultured hippocampal cells (Araque et al., 1998), suggesting that astrocytes and neurons may function as a network with bidirectional communication. Here we show that a Ca2+ elevation in astrocytes increases the frequency of excitatory as well as inhibitory miniature postsynaptic currents (mPSCs), without modifying their amplitudes. Thapsigargin incubation, microinjection of the Ca2+ chelator BAPTA, and photolysis of the Ca2+ cage NP-EGTA demonstrate that a Ca2+ elevation in astrocytes is both necessary and sufficient to modulate spontaneous transmitter release. This Ca2+-dependent release of glutamate from astrocytes enhances mPSC frequency by acting on NMDA glutamate receptors, because it is antagonized by D-2-amino-5-phosphonopentanoic acid (AP5) or extracellular Mg2+. These NMDA receptors are located extrasynaptically, because blockage specifically of synaptic NMDA receptors by synaptic activation in the presence of the open channel blocker MK-801 did not impair the AP5-sensitive astrocyte-induced increase of mPSC frequency. Therefore, astrocytes modulate spontaneous excitatory and inhibitory synaptic transmission by increasing the probability of transmitter release via the activation of NMDA receptors.
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PMID:Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. 971 53

The effect of blocking NMDA glutamate receptors in adult rat cortex on experience-dependent synaptic plasticity of barrel cortex neurons was studied by infusing D-AP5 with an osmotic minipump over barrel cortex for 5 d of novel sensory experience. In acute pilot studies, 500 microM D-AP5 was shown to specifically suppress NMDA receptor (NMDAR)-dependent responses of single cells in cortical layers I-IV. To induce plasticity, all whiskers except D2 and D1 were cut close to the face 1 d after pump insertion. The animals were housed with 2 cage mates before recording 4 d later. This pairing of two whiskers for several days in awake animals generates highly significant biases in responses from D2 layer IV (barrel) cells to the intact D1 whisker as opposed to the cut D3 whisker. D-AP5 completely prevented the D1/D3 surround whisker bias from occurring in the D2 barrel cells (p > 0.6 for D1 > D3, Wilcoxon). Fast-spike and slow-spike barrel cells were affected equally, suggesting parity for inhibitory and excitatory cell plasticity. D-AP5 only partially suppressed the D1/D3 bias in supragranular layers (layers II-III) in the same penetrations (p < 0.042 for D1 > D3). In control animals, the inactive L-AP5 isomer allowed the bias to develop normally toward the intact surround whisker (p < 0.001 for D1 > D3) for cells in all layers. We conclude that experience-dependent synaptic plasticity of mature barrel cortex is cortically dependent and that modification of local cortical NMDARs is necessary for its expression.
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PMID:Experience-dependent plasticity of adult rat S1 cortex requires local NMDA receptor activation. 982 73

Early environmental effects including variation in maternal care, can modify hypothalamic-pituitary-adrenal (HPA) axis function. One of the more overt early effects, involving maternal care, is weaning restraint. In this study the effects of different patterns of weaning, in the rat (Rattus norvegicus), on both adult response to restraint stress and to dexamethasone administration were examined. Animals that as pups experienced a gradual lengthening time of separation from the mother, between 21 and 30 days of postnatal age (completely separated on 30 days), showed lower levels of systemic corticosterone and glutamate in the sensory cortex in response to restraint stress than seen in other groups. These animals also showed greater suppression of corticosterone by dexamethasone than did animals abruptly removed from the mother at 21 days of age. Animals left in the cage with the mother until either 30 or 40 days of age showed the greatest levels of corticosterone and glutamate in the sensory cortex in response to the stress and the least suppression by dexamethasone. These results suggest that changes in maternal contact at time of weaning can influence adult responsiveness to stress.
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PMID:Patterns of weaning and adult response to stress. 1060 54

We investigated the importance of endogenous amino acids in the locus coeruleus in inescapable electric shock and conditioned fear. In naive rats and in rats exposed to noise (N), light (L) and electric shock (S) or to N + L only, the locus coeruleus was superfused with artificial cerebrospinal fluid through a push-pull cannula and the release of GABA, taurine, glutamate, aspartate, serine and glutamine was determined in the superfusate by HPLC after derivatization with o-phthaldialdehyde. Locomotor activity, arterial blood pressure and heart rate were telemetrically monitored. The placement of naive rats or conditioned rats from their home cage to a chamber provided with a grid-floor for shock virtually did not change the release rates of the amino acids in the locus coeruleus. Motility was enhanced in naive and conditioned rats to a similar extent. Blood pressure and heart rate were enhanced in conditioned rats only. Exposure to N + L + S for 5 min greatly enhanced the release rates of all determined amino acids in the locus coeruleus. In conditioned rats the increase in release of most amino acids lasted longer than in naive rats. Electric shock also enhanced motility, blood pressure and heart rate. In conditioned rats, motility and cardiovascular changes were more pronounced and/or lasted longer than in naive rats. Exposure of conditioned rats to the conditioned stimuli N + L for 5 min led to an increased release of taurine and aspartate. The enhanced release of taurine lasted 30 min. Exposure to N + L did not affect the release rates of amino acids in naive rats. N + L did not influence motility but arterial blood pressure and heart rate were elevated in conditioned rats. The findings show that inescapable electric shock enhances the release of several amino acids in the locus coeruleus, while conditioned fear selectively increases the outflow of taurine and aspartate. Moreover, conditioned fear prolongs the response of excitatory and inhibitory amino acids to electric shock. The results suggest that an excitatory amino acid (aspartate) and an inhibitory amino acid (taurine) of the locus coeruleus are implicated in conditioned fear.
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PMID:Effects of inescapable shock and conditioned fear on the release of excitatory and inhibitory amino acids in the locus coeruleus. 1068 76

The repeated injection of cocaine causes an increase in the capacity of a subsequent acute injection to elevate extracellular glutamate levels in the nucleus accumbens, and the present study sought to determine if the elevation in extracellular glutamate is regulated by the pairing of environmental stimuli with drug administration. Three treatment groups were injected daily for seven days with saline or cocaine (15 mg/kg, ip); 1) injection of saline in the home cage, 2) injection of cocaine in the home cage (cocaine-unpaired), and 3) injection of cocaine in the test apparatus (cocaine-paired). Three weeks following the last daily injection dialysis probes were placed into the nucleus accumbens and all rats were injected with saline followed by cocaine. Basal levels of extracellular glutamate were significantly reduced in the cocaine-paired treatment group. Moreover, only in the cocaine-paired group did the cocaine injection elevate extracellular glutamate. Repeated administration of cocaine also produces an enduring increase in the motor stimulant response to an acute cocaine injection and it was previously found that administration of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainic acid glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione inhibited the sensitized, but not the acute motor, response to cocaine. In this study it was found that the motor stimulant response elicited by cocaine was blunted by pretreatment of the nucleus accumbens with 6-cyano-7-nitroquinoxaline-2,3-dione only in animals receiving daily cocaine injections in the paired environment. In contrast, the N-methyl-D-aspartate glutamate receptor antagonist R-(-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid did not significantly affect cocaine-induced motor activity in any treatment group. These data support a hypothesis that environmental stimuli previously associated with daily cocaine administration can modulate glutamate transmission in the nucleus accumbens in a manner affecting cocaine-induced behavior.
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PMID:Context-specific enhancement of glutamate transmission by cocaine. 1094 57

The pores of glutamate receptors and K(+) channels share sequence homology, suggesting a conserved secondary structure. Scanning mutagenesis with substitution of alanine and tryptophan in GluR6 channels was performed based on the structure of KcsA. Our assay used disruption of voltage-dependent polyamine block to test for changes in the packing of pore-forming regions. Alanine scanning from D567 to R603 revealed reduced rectification resulting from channel block in two regions. A periodic pattern from F575 to M589 aligned with the pore helix in KcsA, whereas a cluster of sensitive positions around Q590, a site regulated by RNA editing, mapped to the selectivity filter in KcsA. Tryptophan scanning from D567 to R603 revealed similar patterns, but with a complete disruption of spermine block for 7 out of the 37 positions and a pM dissociation constant for Q590W. Molecular modeling with KcsA coordinates showed that GluR6 pore helix mutants disrupting polyamine block pack against M1 and M2, and are not exposed in the ion channel pore. In the selectivity filter, tryptophan creates an aromatic cage consistent with the pM dissociation constant for Q590W. A scan with glutamate substitution was used to map the cytoplasmic entrance to the pore based on charge neutralization experiments, which established that E594 was uniquely required for high affinity polyamine block. In E594Q mutants, introduction of glutamate at positions S593-L600 restored polyamine block at positions corresponding to surface-exposed residues in KcsA. Our results reinforce proposals that the pore region of glutamate receptors contains a helix and pore loop analogous to that found in K(+) channels. At the cytoplasmic entrance of the channel, a negatively charged amino acid, located in an extended loop with solvent-exposed side chains, is required for high affinity polyamine block and probably attracts cations via a through space electrostatic mechanism.
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PMID:Structural similarities between glutamate receptor channels and K(+) channels examined by scanning mutagenesis. 1127 54

Using the KcsA bacterial K+ channel crystal structure [Doyle, D. A., et al. (1998) Science 280, 69-74] and the model of the outer vestibule of the Na+ channel [Lipkind, G. M., and Fozzard, H. A. (2000) Biochemistry 39, 8161-8170] as structural templates, we propose a structural model of the outer vestibule and selectivity filter of the pore of the Ca2+ channel (alpha1C or Ca(v)1.2). The Ca2+ channel P loops were modeled by alpha-helix-turn-beta-strand motifs, with the glutamate residues of the EEEE motif located in the turns. P loops were docked in the extracellular part of the inverted teepee structure formed by S5 and S6 alpha-helices with backbone coordinates from the M1 and M2 helices of the KcsA crystal structure. This construction results in a conical outer vestibule that tapers to the selectivity filter at the bottom. The modeled selectivity ring forms a wide open pore ( approximately 6 A) in the absence of Ca2+. When Ca2+ is present ( approximately 1 microM), all four glutamate side chains move to the center and form a cage around the dehydrated Ca2+ ion, blocking the pore. In the millimolar concentration range, Ca2+ also interacts with two low-affinity sites located externally and internally, which were modeled by the same carboxylate groups of the selectivity filter. Calculation of the resulting electrostatic potentials show that the single Ca2+ ion is located in an electrostatic trap. Only when three Ca2+ ions are bound simultaneously in the high- and low-affinity sites of the selectivity filter is Ca2+ able to overcome electrostatic attraction, permitting Ca2+ flux.
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PMID:Modeling of the outer vestibule and selectivity filter of the L-type Ca2+ channel. 1138 92

The glutamatergic system is deeply involved in the development of opiate dependence and in the manifestation of opiate abstinence syndrome. In this study the effect of the increase in the endogenous glutamate (GLU) release due to 4-aminopyridine (4-AP), a potassium channel blocker, during the development of morphine (M) physical dependence and during the naloxone (NL)-precipitated abstinence syndrome was investigated. For the development of physical dependence M was intraperitoneally (i.p.) injected for 9 days 105 min following i.p. saline administration to a group of rats. In the first 3 days the dose of M was 10 mg x kg(-1). In the second 3 days the initial dose was doubled (20 mg x kg(-1)) and in the last 3 days the dose of M was raised to 40 mg x kg(-1). On day 10, the rats were divided into three groups at random and these three groups were i.p. given saline 105 min before 80 mg x kg(-1)M, 2 mg x kg(-1) 4-AP 105 min after 80 mg x kg(-1) M, and 80 mg x kg(-1) M 105 min before 2 mg x kg(-1) 4-AP, respectively. In a second group of rats, the rats were i.p. given 2 mg x kg(-1) 4-AP 105 min prior to M administration, which was increased every 3 days (10 mg x kg(-1), 20 mg x kg(-1), 40 mg x kg(-1)). On day 10, the rats were divided into two groups whose first injection was saline and 2 mg x kg(-1) 4-AP, respectively. The second injections of both groups after an interval of 105 min following the first one contained 80 mg x kg(-1) M. In contrast, one group of rats received only i.p. saline at every other injection time (the control group). Furthermore, another group of rats was i.p. administered 2 mg x kg(-1) 4-AP once a day, as the first injection. At the second injection time they were i.p. given saline. After a period of 15 min following the last administration on day 10, the rats belonging to all groups were i.p. injected with 2 mg x kg(-1) NL and immediately placed in a metal cage. Body weight loss (g), teeth chattering, rearing, wet-dog shaking, grooming, and jumping were determined or counted for 15 min. Penile erection, defecation, and diarrhoea were separately scored with one point for every individual occurrence, and the total score was named 'total number of others'. The administration of 4-AP before M appeared to intensify the development of dependence, and was most probably due to the Ca2+-induced inactivation of NMDA receptors as a result of excess release of GLU when the 4-AP took effect. The inactivation of NMDA receptors should have acted as a transient blockade of the receptors during the chronic administration period, and as well as after a single administration on day 10 before M injection and before abstinence. The intensification of the abstinence syndrome may be dependent on the excessive GLU released by 4-AP.
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PMID:The effects of different 4-aminopyridine and morphine combinations on the intensity of morphine abstinence. 1140 16


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