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At least 559 records · Page 31Linked to original sources
PubMed2001

GABA(B) receptors play a role in the development of tolerance to ethanol in mice.

RATIONALE: There is evidence that drugs that improve or impair learning can facilitate or block ethanol tolerance, respectively. Since GABA(B) receptors have been shown to be involved in processes related to learning, it is possible that this system could play a role in the development of rapid tolerance to ethanol. OBJECTIVES: The aim of this study was to verify the influence of one GABA(B) agonist and two GABA(B) antagonists on tolerance to the effect of ethanol on motor coordination. METHODS: Male Swiss mice were trained on a continuously accelerating rota-rod device. Animals were pretreated with the GABA(B) agonist (-)-baclofen (3, 5, or 7 mg kg(-1)) or saline, 30 min before ethanol (1.75 g kg(-1)), and were tested 5, 10, and 15 min later on the rota-rod. In another set of experiments, mice were pretreated with the GABA(B) antagonists CGP36742 (1, 3, 10, or 30 mg kg(-1)) or CGP56433 (0.1, 0.3, 1.0, or 3.0 mg kg(-1)), or saline, 30 min before the test under ethanol. Rapid tolerance was evaluated 24 h after the first ethanol injection, by injecting all animals with ethanol and retesting them on the rota-rod. RESULTS: The results showed that (-)-baclofen (5 mg kg(-1)) significantly (ANOVA + Tukey's test) blocked rapid tolerance, whereas CGP36742 (3 and 10 mg kg(-1)) and CGP56433 (0.3, 1, and 3 mg kg(-1)) facilitated rapid tolerance in a dose-dependent way. The blockade of rapid tolerance by (-)-baclofen was antagonized by previous administration of CGP36742 or CGP56433. CONCLUSIONS: The current results suggest that rapid tolerance to ethanol is subjected to inhibition by a GABAergic GABA(B) receptor-mediated system in the mouse.

Animals↗
PubMed1998

The modulatory effects of high affinity GABA(B) receptor antagonists in an active avoidance learning paradigm in rats.

It has been reported that selective GABA(B) receptor antagonists can enhance cognitive performance in a variety of learning paradigms. This prompted us to examine the effects of some more potent and newly synthesised GABAB antagonists CGP 71982, CGP 62349 and CGP 55845A in an active avoidance test in rats. A two-way active avoidance test with negative reinforcement was performed for the first 5 of 12 days of antagonist administration. CGP 71982 and CGP 55845A at all doses applied (0.01-1.0 mg/kg) had an improving effect on learning, and memory retention on day 12; the rats made more avoidances in both sessions compared to controls. CGP 62349 was only active at the lowest dose tested (0.01 mg/kg). The present study confirms that GABA(B) receptor antagonists can enhance cognitive performance but provides no insight into the mechanism of action of these novel antagonists.

Animals↗
PubMed2002

Comparison of receptive field expansion produced by GABA(B) and GABA(A) receptor antagonists in raccoon primary somatosensory cortex.

Recordings were made from 62 neurons in the forepaw representation of primary somatosensory cortex in anesthetized raccoons. Microiontophoretic administration of a specific GABA(B) receptor antagonist, CGP 55845, produced receptive field expansion in 74% of 46 neurons, in which it was tested first. The mean receptive field area was approximately doubled, with increases ranging from 12 to 500%. The GABA(B) receptor agonist baclofen reduced the receptive field in most (11 of 16) neurons, but increased the size in 4 neurons. Comparison of the effects of GABA(B) and GABA(A) antagonists in the same cells showed that GABA(A) receptor blockade produced greater expansion than GABA(B) blockade (144% vs 114%, respectively). Simultaneous administration of the two antagonists produced additional expansion in 16 of 25 neurons. There was no evidence of separate skin regions being masked by the two GABA receptor subtypes, as the larger expansion usually included the skin that was unmasked by the less effective drug. These results indicate that both GABA(B) and GABA(A) receptors play a role in shaping the normal receptive fields in somatosensory cortex.

Afferent Pathways↗
PubMed2002

Effect of GABAB receptor blockade on receptive fields of raccoon somatosensory cortical neurons during reorganization.

Single unit recordings were made in the fourth digit representation of raccoon somatosensory cortex after amputation of the fourth digit. The receptive fields of neurons in this "reorganized" cortex were studied before and after microiontophoretic application of a highly specific GABA(B) receptor antagonist, CGP 55845. When the recordings were performed early in the reorganization process, 3-5 weeks after amputation, CGP 55845 produced a greater expansion of the receptive field (184%) than at longer post-amputation intervals (17-34 weeks, 137% increase) or previously reported in intact animals (105%). Most of the receptive fields in these animals were restricted to either an adjacent digit or the palm and the expansion was adjacent to the predrug receptive field. However, in some cases block of GABA(B) receptors unmasked new responsive areas that were separated from the predrug field. In addition, GABA(B) receptor block often revealed higher threshold fields on an adjacent digit or palm. These results reinforce previous studies that used a GABA(A) receptor antagonist, and together they reveal the importance of GABAergic synapses in regulating the various inputs to cortical somatosensory neurons during reorganization.

Amputation, Surgical↗
PubMed1998

Prolonged GABA(B) receptor-mediated synaptic inhibition in the cat spinal cord: an in vivo study.

In pentobarbitone-anaesthetised spinal cats, a comparison was made of the effects of intravenous bicuculline hydrochloride, a GABA(A)-receptor antagonist, and several (-)-baclofen (GABA(B)-receptor) antagonists (CGP 35348, 4638 , 56999A) on the prolonged inhibition of extensor-muscle monosynaptic reflexes, recorded from lumbar ventral roots, by brief or continuous tetanic stimulation of low-threshold afferent fibres of hindlimb flexor muscles. Two components of brief tetanus inhibition were detected. Whilst possibly of similar central latency, the inhibition associated with GABA(B) receptors had a longer time course than that reduced by bicuculline. Furthermore, whereas bicuculline reduced primary afferent depolarization, generated by the inhibitory volleys, and detected as dorsal-root potentials, such potentials were generally enhanced by intravenous baclofen antagonists. The inhibition of reflexes during and after continuous (333 Hz) tetanic flexor-nerve stimulation appeared to be predominantly associated with the activation of GABA(B) receptors. In the period following continuous tetanic flexor-nerve stimulation, during which monosynaptic extensor reflexes were reduced in amplitude, the action potentials of the intraspinal terminations of extensor-muscle group-Ia afferent fibres were reduced in duration, as detected by the time course of the recovery of the threshold to extracellular microstimulation following the arrival of an orthodromic impulse. A reduction in termination action-potential duration also accompanied the reduction by microelectrophoretic (-)-baclofen of the release of excitatory transmitter from group-Ia terminations, both presynaptic effects being blocked by microelectrophoretic baclofen antagonists. However, the reduction of the duration of the action potential of individual group-Ia terminations, which followed continuous flexor-nerve stimulation, was not sensitive to the baclofen antagonist CGP 55845A, but was diminished by bicuculline methochloride. Intravenously administered bicuculline hydrochloride, however, had little or no effect on the inhibition of reflexes following continuous flexor-nerve stimulation. These observations are discussed in the context of possible intraspinal pathways and pre- and postsynaptic mechanisms for GABA(A) and GABA(B) receptor-mediated inhibition of the monosynaptic excitation of spinal motoneurones and of the functional significance of central GABA(B) receptor-associated inhibitory processes, given the relatively minimal effects on motor activity and behaviour produced by baclofen antagonists that penetrate the mammalian blood-brain barrier.

Animals↗
PubMed1986

The effect of cholesterol on glycerophosphono- and glycerophosphinocholines. Permeability measurements in lipid vesicles.

The kinetics of spontaneous chloride ion efflux and valinomycin-mediated rubidium-86 efflux from vesicles prepared from synthetic phospholipids with carbon-phosphorus linkages were investigated at temperatures above the gel-to-liquid-crystalline phase transition. The rate constants for the movement of chloride and rubidium ions were reduced by incorporation of cholesterol into bilayers of phosphono- and phosphinocholines. Nonisosteric phosphonolipids in which the oxygen was removed from the glycerol side of phosphorus without substitution by a methylene group interacted less with cholesterol than the analogous isosteric derivatives, as judged from the magnitude of the decrease in the rate constants for chloride and rubidium ion efflux. The experiments reported in this study suggest that steric factors in the glycerol side of the phosphorus function are important in phosphatidylcholine-cholesterol interaction. However, the oxygen atom on the choline side of the phosphorus in the phosphatidylcholine molecule is not required for strong phosphatidylcholine-cholesterol interaction, since isosteric glycerophosphinocholines interacted as well as the corresponding isosteric glycerophosphonocholines. Furthermore, steric requirements on the choline side of phosphorus are not important in this interaction since phosphinates whose head-group structures are -P(O-)CH2CH2N+(CH3)3 and -P(O-)CH2CH2CH2N+(CH3)3 interacted equally well with cholesterol, as estimated by these permeability studies.

Chlorides↗
PubMed1990

The temperature dependence of human erythrocyte transport of phosphate, phosphite and hypophosphite.

The temperature dependence of the erythrocyte anion transport protein (Band 3 or AE1) mediated influx of three nonspherical substrates, the divalent anions phosphate and phosphite, and the monovalent hypophoshite, were determined. Phase transitions were found in the temperature dependence of the influxes of all three anions. The 95% confidence limits for the transition temperatures were: 34.6-38.1 degrees C, 7.4-9.1 degrees C and 6.7-9.7 degrees C for phosphate, phosphite and hypophosphite, respectively, while the critical influx rates at the transitions were 29-50, 64-102 and 26-58 ions/s per carrier, respectively. That the critical rates rather than the transition temperatures are of similar magnitude indicates that the transitions are related to transport mechanisms rather than to thermal protein conformational changes. These critical rates are two orders of magnitude lower than those reported for the self-exchange of Cl- and Br- (Brahm, J. (1977) J. Gen. Physiol. 70, 283-306). The critical rate of monovalent hypophosphite is similar to that of divalent phosphate and phosphite, but not to that of Cl- indicating that this effect is mediated by the structure of the substrate rather than by its charge. The disparity in the rates rc at which phase transitions occur in AE1-mediated transport of spherical and nonspherical anions indicates a difference in the interaction between the two classes of anions and the protein.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1985

Reactivation of carboxylester hydrolase following inhibition by 4-nitrophenyl organophosphinates.

Porcine liver carboxylester hydrolase (EC 3.1.1.1; carboxylesterase) was rapidly inhibited by 4-nitrophenyl organophosphinates containing aryl or heteroaryl groups directly bound to phosphorus. The most potent inhibitor was 4-nitrophenyl di-2-thienylphosphinate for which the median inhibitory concentration was 7.4 X 10(-9) M. Rabbit liver monomeric carboxylester hydrolase was inhibited, separated from excess inhibitor by gel permeation chromatography, and observed for spontaneous or 1,1'-trimethylene-bis(4-formylpyridinium bromide) dioxime (TMB-4)-induced reactivation. Recovery was most rapid (k = 4 to 7 X 10(-4) min-1) from phosphinyl groups containing one alkyl substituent smaller than isopropyl and one aryl or heteroaryl group smaller than naphthyl. The di-2-thienylphosphinylated enzyme was an exception since it recovered rapidly while lacking an alkyl substituent. Oxime reactivation by TMB-4 doubled rates of recovery.

Animals↗
PubMed1985

Aldehyde dehydrogenase activity as the basis for the relative insensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorines.

The ex vivo sensitivity of murine pluripotent hematopoietic stem cells (CFU-S) and myeloid progenitor cells (CFU-GM) to 4-hydroperoxycyclophosphamide, ASTA Z 7557, phosphoramide mustard, acrolein, melphalan, and cis-platinum was determined in the absence and presence of known (disulfiram, diethyldithiocarbamate, cyanamide) or suspected [ethylphenyl(2-formylethyl)phosphinate] inhibitors of aldehyde dehydrogenase activity. As compared to CFU-GM, CFU-S were less sensitive to the oxazaphosphorine agents, 4-hydroperoxycyclophosphamide and ASTA Z 7557. The two cell populations were approximately equisensitive to acrolein as well as to the non-oxazaphosphorine cross-linking agents, phosphoramide mustard, melphalan and cis-platinum. All four inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of the oxazaphosphorines toward CFU-S; they did not potentiate the cytotoxic action of acrolein or the non-oxazaphosphorines toward these cells. The inhibitors did not potentiate the cytotoxic action of the oxazaphosphorines, non-oxazaphosphorines, or acrolein toward CFU-GM. Pyridoxal, a substrate for aldehyde oxidase, did not potentiate the cytotoxic action of oxazaphosphorines toward CFU-S. Cellular NAD-linked aldehyde dehydrogenases are known to catalyze the oxidation of the major transport form of cyclophosphamide, 4-hydroxycyclophosphamide/aldophosphamide, to an inactive metabolite, carboxyphosphamide. Our observations suggest that (1) aldehyde dehydrogenase activity is an important determinant of the sensitivity of a cell population to the oxazaphosphorines, (2) CFU-GM lack the relevant aldehyde dehydrogenase activity, and (3) the phenotypic basis for the relative insensitivity of CFU-S to oxazaphosphorines is the aldehyde dehydrogenase activity contained by these cells.

Acrolein↗
PubMed1985

Spontaneous reactivation of phosphinylated human erythrocyte acetylcholinesterase and human serum butyrylcholinesterase.

This report documents studies on the spontaneous reactivation of human erythrocyte acetylcholinesterase and human serum butyrylcholinesterase following inhibition by organophosphinate esters. The spontaneous reactivation reactions were carried out at 26.0 degrees C in 0.10 M phosphate buffer of pH 7.6. Based upon results at 24 h, human serum butyrylcholinesterase inhibited with 4-nitrophenyl methyl (4-methoxyphenyl) phosphinate was the most responsive (92.5% recovery) of the nine esters studied. Using the same criteria, the most active compound in the human erythrocyte acetylcholinesterase studies was 4-nitrophenyl methyl(phenyl)phosphinate (74.2% recovery). With seven of the nine compounds examined the response was greater from the serum enzyme than from the erythrocyte enzyme.

Acetylcholinesterase↗
PubMed1993

CGP 55845A: a potent antagonist of GABAB receptors in the CA1 region of rat hippocampus.

The new GABAB receptor antagonist CGP 55845A was tested on pre- and post-synaptic GABAB receptors in the hippocampus. CGP 55845A (1 microM) blocked (-)-baclofen (5-10 microM)-induced postsynaptic hyperpolarization and depression of evoked IPSPs and EPSPs. It also blocked three physiological consequences of GABAB receptor activation: the late IPSP, paired-pulse depression of IPSCs, and heterosynaptic depression of EPSPs. Therefore, CGP 55845A is an antagonist at pre- and post-synaptic GABAB receptors in the hippocampus and is approximately three orders of magnitude more potent than previously described GABAB receptor antagonists.

Animals↗
PubMed1987

Studies on catalase in ageing Zaprionus paravittiger (Diptera) with special reference to an antioxidant feeding.

Zaprionus paravittiger fed with an antioxidant (sodium hypophosphite, 1 X 10(3) microM) supplemented diet exhibited adaptive compensatory responses in catalase activity (quantitative as well as qualitative). The longevity and catalase activity were found to be positively linked. The study denotes that free radical formation and antioxygenic defenses are closely associated and are the possible determinants of life span and ageing.

Aging↗