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At least 1,279 records · Page 71Linked to original sources
PubMed2006

Anxiolytic-like effects of the selective metabotropic glutamate receptor 5 antagonist MPEP after its intra-amygdaloid microinjection in three different non-conditioned rat models of anxiety.

The intercalated islands, clusters of dopamine D1-rich GABAergic neurons, are interposed between the basolateral and central nuclei of the amygdala, and control the traffic of nerve impulses between these two structures. Metabotropic glutamate receptor 5- (mGluR5)-like immunoreactivity was studied by immunohistochemistry in this part of the amygdala and was found to be mainly restricted to the central and basolateral nuclei and to a lesser extent to the medial paracapsular intercalated islands. The role of the metabotropic glutamate receptor 5 in the modulation of anxiety has been studied in this region by microinjection of small volumes of the mGluR5 antagonist 2-methyl-6(phenylethenyl) pyridine (MPEP), with restricted diffusion from its injection site, into the rostral amygdala near the basolateral and central amygdaloid nuclei and the intercalated islands, and the behavior of the animals was evaluated using three non-conditioned models of anxiety. Anxiolytic-like effects were observed after MPEP administration in all tests used. In the White and Black Box test, MPEP (2 nmol per side) significantly increased the time spent in the white compartment of the box. In line with these results, MPEP (8 nmol per side) increased the exploration of the open arms of the Elevated Plus-Maze. Burying behavior latency was increased and burying behavior itself was decreased in the Shock-Probe Burying test. It is suggested that anxiolytic effects of MPEP may be mediated by blockade of mGluR5 in the basolateral and/or central amygdaloid nuclei, reducing glutamate transmission in the basolateral amygdaloid nuclei and glutamate output from the central amygdala.

Amygdala↗
PubMed2004

A longitudinal study of gender-related cognition and behaviour.

Gender schema theory proposes that children's acquisition of gender labels and gender stereotypes informs gender-congruent behaviour. Most previous studies have been cross-sectional and do not address the temporal relationship between knowledge and behaviour. We report the results of a longitudinal study of gender knowledge and sex-typed behaviour across three domains in children tested at 24 and 36 months (N = 56). Although both knowledge and sex-typed behaviour increased significantly between 2 and 3 years, there was no systematic pattern of cross-lagged correlations between the two, although some concurrent relationships were present at 24 months. Future longitudinal work might profitably focus on younger children using reliable preverbal measures of gender knowledge and employing a shorter lag between measurement times.

Age Factors↗
PubMed1998

Locus of frequency-dependent depression identified with multiple-probability fluctuation analysis at rat climbing fibre-Purkinje cell synapses.

1. EPSCs were recorded under whole-cell voltage clamp at room temperature from Purkinje cells in slices of cerebellum from 12- to 14-day-old rats. EPSCs from individual climbing fibre (CF) inputs were identified on the basis of their large size, paired-pulse depression and all-or-none appearance in response to a graded stimulus. 2. Synaptic transmission was investigated over a wide range of experimentally imposed release probabilities by analysing fluctuations in the peak of the EPSC. Release probability was manipulated by altering the extracellular [Ca2+] and [Mg2+]. Quantal parameters were estimated from plots of coefficient of variation (CV) or variance against mean conductance by fitting a multinomial model that incorporated both spatial variation in quantal size and non-uniform release probability. This 'multiple-probability fluctuation' (MPF) analysis gave an estimate of 510 +/- 50 for the number of functional release sites (N) and a quantal size (q) of 0.5 +/- 0.03 nS (n = 6). 3. Control experiments, and simulations examining the effects of non-uniform release probability, indicate that MPF analysis provides a reliable estimate of quantal parameters. Direct measurement of quantal amplitudes in the presence of 5 mM Sr2+, which gave asynchronous release, yielded distributions with a mean quantal size of 0.55 +/- 0.01 nS and a CV of 0.37 +/- 0.01 (n = 4). Similar estimates of q were obtained in 2 mM Ca2+ when release probability was lowered with the calcium channel blocker Cd2+. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1 microM) reduced both the evoked current and the quantal size (estimated with MPF analysis) to a similar degree, but did not affect the estimate of N. 4. We used MPF analysis to identify those quantal parameters that change during frequency-dependent depression at climbing fibre-Purkinje cell synaptic connections. At low stimulation frequencies, the mean release probability (pr) was unusually high (0.90 +/- 0.03 at 0.033 Hz, n = 5), but as the frequency of stimulation was increased, pr fell dramatically (0.02 +/- 0.01 at 10 Hz, n = 4) with no apparent change in either q or N. This indicates that the observed 50-fold depression in EPSC amplitude is presynaptic in origin. 5. Presynaptic frequency-dependent depression was investigated with double-pulse and multiple-pulse protocols. EPSC recovery, following simultaneous release at practically all sites, was slow, being well fitted by the sum of two exponential functions (time constants of 0.35 +/- 0.09 and 3.2 +/- 0.4 s, n = 5). EPSC recovery following sustained stimulation was even slower. We propose that presynaptic depression at CF synapses reflects a slow recovery of release probability following release of each quantum of transmitter. 6. The large number of functional release sites, relatively large quantal size, and unusual dynamics of transmitter release at the CF synapse appear specialized to ensure highly reliable olivocerebellar transmission at low frequencies but to limit transmission at higher frequencies.

Animals↗
PubMed2000

Identification of subunits contributing to synaptic and extrasynaptic NMDA receptors in Golgi cells of the rat cerebellum.

1. To investigate the properties of N-methyl-D-aspartate receptors (NMDARs) in cerebellar Golgi cells, patch-clamp recordings were made in cerebellar slices from postnatal day 14 (P14) rats. To verify cell identity, cells were filled with Neurobiotin and examined using confocal microscopy. 2. The NR2B subunit-selective NMDAR antagonist ifenprodil (10 microM) reduced whole-cell NMDA-evoked currents by approximately 80 %. The NMDA-evoked currents were unaffected by the Zn2+ chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN; 1 microM) suggesting the absence of NMDARs containing NR2A subunits. 3. Outside-out patches from Golgi cells exhibited a population of 'high-conductance' 50 pS NMDAR openings. These were inhibited by ifenprodil, with an IC50 of 19 nM. 4. Patches from these cells also contained 'low-conductance' NMDAR channels, with features characteristic of NR2D subunit-containing receptors. These exhibited a main conductance of 39 pS, with a sub-conductance level of 19 pS, with clear asymmetry of transitions between the two levels. As expected of NR2D-containing receptors, these events were not affected by ifenprodil. 5. The NMDAR-mediated component of EPSCs, evoked by parallel fibre stimulation or occurring spontaneously, was not affected by 1 microM TPEN. However, it was reduced (by approximately 60 %) in the presence of 10 microM ifenprodil, to leave a residual NMDAR-mediated current that exhibited fast decay kinetics. This is, therefore, unlikely to have arisen from receptors composed of NR1/NR2D subunits. 6. We conclude that in cerebellar Golgi cells, the high- and low-conductance NMDAR channels arise from NR2B- and NR2D-containing receptors, respectively. We found no evidence for NR2A-containing receptors in these cells. While NR2B-containing receptors are present in both the synaptic and extrasynaptic membrane, our results indicate that NR1/NR2D receptors do not contribute to the EPSC and appear to be restricted to the extrasynaptic membrane.

2-Amino-5-phosphonovalerate↗
PubMed2000

Slow deactivation kinetics of NMDA receptors containing NR1 and NR2D subunits in rat cerebellar Purkinje cells.

We have examined the deactivation kinetics of native N-methyl-D-aspartate receptors (NMDARs) containing NR1 and NR2D subunits by patch-clamp recording from Purkinje cells in cerebellar slices from young rats. NMDAR-mediated whole-cell currents were elicited in response to bath application of 20 microM NMDA and 50 microM glycine. The NMDAR-mediated currents were small, with an average whole-cell conductance of approximately 750 pS. Following the rapid application of brief pulses (1-10 ms) of 1 mM glutamate to outside-out membrane patches, we observed a low-conductance type of single-channel activity which lasted up to 30 s after the removal of agonist. Analysis of individual channel openings revealed asymmetry of transitions between the main- and subconductance states - a characteristic of NR1/NR2D-containing NMDARs. The averaged macroscopic current exhibited a decay time course which was well described by a single exponential function with a time constant of approximately 3 s. We conclude that native NR1/NR2D-containing NMDARs, like their recombinant counterparts, display very slow deactivation kinetics. This feature should provide a means for identification of these receptors at synapses, and indicates that they do not contribute to the synaptic NMDAR currents so far described.

Animals↗
PubMed1999

Does reducing the frequency of routine antenatal visits have long term effects? Follow up of participants in a randomised controlled trial.

1117 low risk women, who had been randomly allocated to either the traditional schedule of 13 antenatal visits or a reduced schedule of six to seven visits, were followed up 2.7 years after their delivery. Follow up was by means of a postal questionnaire (assessing the mother-child relationship, maternal psychological wellbeing, health service use, health-related behaviour and health beliefs), and patient record data on the frequency of contacts in general practice. There was no evidence of differences between the two groups for any of the outcomes examined. Offering a reduced schedule of routine antenatal visits to low risk women does not appear to have any long term effects.

Appointments and Schedules↗
PubMed1986

Neocortical cholinergic enzyme and receptor activities in the human fetal brain.

In the human fetus, obtained postmortem at estimated gestational ages of 8-22 weeks, biochemical activities of cortical choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) were comparable to those of adult brain tissue. In contrast cholinergic receptor binding, including muscarinic M1 and M2 subtypes (measured by displacement of [3H]N-methylscopolamine with, respectively, pirenzepine and carbachol) and [3H]nicotine (putative nicotinic) binding were undetectable before 13-14 weeks and even at 22 weeks were substantially (three- to fourfold) below the respective adult values. Cortical ChAT activity decreased significantly with gestational age whereas binding to the three receptors, including the proportion M1/M2, increased significantly. AChE was present at all ages investigated as the two molecular monomeric (G1) and tetrameric (G4) forms. The proportion of G4, which was much more soluble in fetal compared with adult cortex, increased approximately threefold. Histochemically AChE, although intense in the nucleus of Meynert, was generally confined to subcortical white matter at early fetal developmental periods, appearing later in the cortex localized to nerve fibres and occasional cell bodies. These observations suggest that during the second trimester of human fetal development, cortical cholinergic function may be preceded by relatively high ChAT activity and paralleled not only by increasing receptor binding but also by a proportional increase in the tetrameric form and histochemical reactivity of AChE.

Acetylcholinesterase↗
PubMed1986

Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system.

The distribution of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) molecular forms and their solubility characteristics were examined, using density gradient centrifugation, in various regions of the postmortem human CNS. Total AChE activity varied extensively (50-fold) among the regions investigated, being highest in the telencephalic subcortical structures (caudate nucleus and nucleus of Meynert); intermediate in the substantia nigra, cerebellum, and spinal cord; and least in the fornix and cortical regions (hippocampus and temporal and parietal cortex). Total BChE activity was, in contrast, much more evenly distributed, with only a threefold variation between the regions studied. Although the patterns of molecular forms of each enzyme were broadly similar among the different areas, regional variations in the distribution and abundance of the various forms of AChE were much greater than those of BChE. Thus, although the tetrameric G4 form of AChE constituted the majority of the total AChE activity in all regions examined, the ratio of the G4 form to the monomeric G1 form, the latter of which constituted the majority of the remaining activity, varied markedly, ranging from 21 in the caudate nucleus to 1.7 in the temporal cortex. In addition to the G4 and G1 forms of AChE, the dimeric G2 form was observed in the nucleus of Meynert and a fast-sedimenting (16S) species was found in samples of both the parietal cortex and spinal cord. In contrast, the G4 and G1 forms of BChE were the only molecular species observed in the different areas and the G4:G1 ratio varied from 3.3 in the substantia nigra to 0.9 in the temporal cortex. Regarding the solubility characteristics of the individual AChE and BChE molecular forms, the majority of the G4 form of AChE was extractable only in the presence of detergent, indicating a predominantly membrane-bound localization of this species. The smaller AChE forms (G1 and G2) and both the G1 and G4 forms of BChE were all relatively evenly distributed between soluble and membrane-bound species. These findings are discussed in relation to neurochemical and neuroanatomical, particularly cholinergic, features of the regions examined.

Acetylcholinesterase↗
PubMed1987

Molecular forms of butyrylcholinesterase in the human neocortex during development and degeneration of the cortical cholinergic system.

The total levels of butyrylcholinesterase (BChE) activity and, more specifically, the distribution of BChE molecular forms were measured in the human neocortex during fetal development. Both the amount of total activity and the abundance of the different molecular forms (G1 and G4) remained relatively constant between gestational ages of 8-22 weeks and were similar to those observed in samples of cortex from aged brain. In addition, in both Alzheimer-type and parkinsonian dementia, the levels of total BChE activity as well as the relative abundance of the G1 and G4 molecular forms were similar to those observed in control tissue. Hence, both the levels of total activity and the distribution of molecular forms did not change significantly either during fetal development or in the neurodegenerative disorders of Alzheimer-type and parkinsonian dementias. Because these situations are accompanied by changes in the cortical cholinergic system (including an increase and decrease in levels of the G4 form of acetylcholinesterase, respectively), it is concluded that, at least in the human neocortex, BChE is unrelated to cholinergic neurotransmission associated with subcortical cholinergic projection fibres.

Aged↗
PubMed1988

Muscarinic cholinergic receptor subtypes in hippocampus in human cognitive disorders.

Total muscarinic receptor levels, the levels of the subtypes exhibiting high and low affinity for pirenzepine, and the high- and low-affinity agonist states of the receptor were investigated in hippocampal tissue obtained at autopsy from mentally normal individuals and the following pathological groups: Alzheimer's disease, Parkinson's disease, Down's syndrome, alcoholic dementia, Huntington's chorea, and motor-neurone disease. A moderate decrease in the density of both high-affinity pirenzepine and high-affinity agonist subtypes was found in Alzheimer's disease, whereas a trend towards an increase in the overall muscarinic receptor density was apparent in the parkinsonian patients without dementia, mainly due to an increase in the low-affinity agonist state; the differences between the Alzheimer's disease and nondemented parkinsonian cases were highly significant. As previously reported, the levels of both choline acetyltransferase and acetylcholinesterase were markedly reduced in both Alzheimer's disease and Parkinson's disease--with a greater loss of both enzymes in the demented subgroup of parkinsonian patients. Activities of the cholinergic enzymes were also extensively reduced in Down's syndrome, accompanied by a loss of high-affinity pirenzepine binding. There were no significant receptor or enzyme alterations in the other groups studied. These observations suggest that in the human brain, extensive degeneration of cholinergic axons to the hippocampus, as indicated by a loss of cholinergic enzymes, is not necessarily accompanied by extensive muscarinic receptor abnormalities (as might be expected if a major subpopulation were presynaptic). Moreover, the opposite changes in muscarinic binding in Parkinson's and Alzheimer's diseases may be related to the greater severity of dementia in the latter disease.

Acetylcholinesterase↗
PubMed1990

Gallium-67 as a potential marker for aluminium transport in rat brain: implications for Alzheimer's disease.

Evidence of a link between aluminium and Alzheimer's disease, parkinsonism-dementia of Guam, and dialysis encephalopathy raises questions regarding the role of this element in the pathogenesis of these conditions. Therefore, we have investigated the use of gallium-67 (67Ga) as a marker for brain uptake of aluminium. The binding of 67Ga to plasma proteins has been studied, and the blood-brain barrier permeability and autoradiographic distribution of this isotope in rat brain determined in vivo. The autoradiographic distribution of 125I-Fe-transferrin receptors in rat brain has also been determined in vitro. Results show that 67Ga was bound to plasma transferrin, entered the brain with a blood-brain barrier permeability of 2.48 x 10(-6) ml/min/g, and showed a marked regional distribution that was very similar to that of 125I-Fe-transferrin receptors. Our data suggest that the vulnerability of the hippocampus, amygdala, and cerebral cortex in conditions such as those mentioned above may be partly due to an increased uptake and deposition of aluminium in these regions by the iron transport system.

Aluminum↗
PubMed1990

Success rates in testing monocular acuity and stereopsis in infants and young children.

This study demonstrated how success in stereopsis and monocular acuity testing in the under-fives changes with age. Monocular testing was least successful with 1-2-year olds, while success with stereopsis testing increased linearly to 100% by 3 years. The differing patterns mean that a reasonable degree of success with one test or the other is likely whatever a child's age. Since the demonstration of either stereopsis or normal monocular acuities rules out the presence of any gross visual anomaly, the age-appropriate use of the two types of testing will facilitate the early detection of any abnormality.

Age Factors↗
PubMed1970

Iontophoretic release of acetylcholine, noradrenaline, 5-hydroxytryptamine and D-lysergic acid diethylamide from micropipettes.

1. The in vitro iontophoretic release of tritium-labelled acetylcholine and 5-hydroxytryptamine from large and small micropipettes and noradrenaline and D-lysergic acid diethylamide from small micropipettes was determined by liquid scintillation counting.2. The release was directly proportional to the electrical charge passed in the range normally used in the iontophoretic study of these compounds. The transport numbers obtained for the large micropipettes were approximately double those with the small micropipettes. A very low transport number was found for D-lysergic acid diethylamide.3. The spontaneous leakage was small and did not vary appreciably with time.4. The iontophoretic release of acetylcholine in vitro agreed with the in vitro measurements.5. The brain-stem tissue concentration of D-lysergic acid diethylamide after intravenous injection into intact and decerebrate cats was determined.

Acetylcholine↗
PubMed1971

Actions of noradrenaline, other sympathomimetic amines and antagonists on neurones in the brain stem of the cat.

1. The effects of (-)-noradrenaline ((-)-NA) and related compounds on brain stem neurones in decerebrate unanaesthetized cats have been investigated using the technique of iontophoretic application from micropipettes.2. Four types of response to (-)-NA have been described. These were short lasting inhibition, long lasting inhibition, excitation, and a biphasic response consisting of short lasting inhibition followed by excitation. A variable amount of desensitization of the excitatory response, but not of inhibitory responses, was observed.3. Experiments in which small currents were used to pass (-)-NA from pipettes with smaller tips did not lead to any appreciable change in the proportions of neurones excited or inhibited.4. A variety of sympathomimetic agonists was tested. Short lasting inhibition was less sensitive than excitation to changes in molecular structure. Long lasting inhibition was more sensitive to molecular change and was not mimicked by some of the agonists which mimicked short lasting inhibition.5. Although agonists without one ring hydroxyl had weaker effects than those with both, compounds in which both ring hydroxyl groups were absent (beta-hydroxyphenylethylamine, ephedrine and amphetamine) mimicked excitation strongly. It is possible that the compounds without both ring hydroxyl groups had some effect other than simple agonistic activity.6. A dissociation was observed between responses to dopamine and (-)-NA. p-Tyramine mimicked dopamine, rather than (-)-NA.7. Neither the alpha-agonist, phenylephrine nor the beta-agonist, isoprenaline mimicked neuronal responses to (-)-NA. The alpha-antagonists phentolamine and phenoxybenzamine and the beta-antagonists dichloroisoprenaline, propranolol and D(-)-INPEA and combinations of propranolol with phentolamine or phenoxybenzamine were ineffective in blocking either excitation or inhibition. Thus, the central receptors appear to be different from peripheral alpha- and beta-receptors.8. The most effective antagonist of excitation was (-)-alpha-methylnoradrenaline. Metaraminol and dihydroergotamine also had some antagonistic activity. None of the compounds tested blocked inhibition. The effects of (-)-alpha-methylnoradrenaline have been discussed in relation to the hypotensive action of alpha-methyldopa.

Amphetamine↗
PubMed1972

A neuronal basis for the alerting action of (+)-amphetamine.

1. (+)-Amphetamine mimicked the excitatory and inhibitory actions of (-)-noradrenaline on single neurones in the brain stem of acute halothaneanaesthetized rats when these compounds were applied by iontophoresis. (+)-Amphetamine had no actions on neurones unaffected by (-)-noradrenaline.2. These mimicking actions of (+)-amphetamine could not be observed 20 h after treatment of the animals with reserpine 5 mg/kg.3. The enzyme inhibitors alpha-methyl-p-tyrosine and FLA 63 also greatly reduced the number of (-)-noradrenaline-mimicking responses to (+)-amphetamine.4. In animals pretreated with alpha-methyl-p-tyrosine, but not in those pretreated with FLA 63, excitatory actions of (+)-amphetamine on neurones excited by (-)-noradrenaline could be elicited 45-90 min after systemic injection of L-DOPA.5. These results indicate that (+)-amphetamine can release noradrenaline from presynaptic sites in the brain stem, which may be a basis for its alerting actions.

Action Potentials↗
PubMed1977

A presynaptic site of action within the mesencephalic reticular formation for (+)-amphetamine-induced electrocortical desynchronization.

1. Changes induced in the electrocorticogram by the bilateral perfusion of (+)-amphetamine into the mesencephalic reticular formation (MRF) have been studied in cat encéphale isolé preparations. 2. (+)-Amphetamine, applied for 5 min in the MRF, mimicked the electrocortical desynchronization induced by the perfusion of (-)-noradrenaline (NA) or (-)-alpha-methylnoradrenaline (AMNA) into the same sites. 3. Perfusion of 6-hydroxydopamine (6-OHDA) also induced desynchronization but, over the 1 h perfusion period, slow wave activity gradually returned to the electrical record. 4. Following the application of 6-OHDA the effect of (+)-amphetamine was abolished or significantly attenuated, whereas the effect of NA or AMNA was not affected. 5. The electrocortical desynchronization induced by (+)-amphetamine could be restored if its application was preceded by perfusion with NA or AMNA. 6. Fluorescence studies using AMNA indicated that 6-OHDA depleted noradrenergic nerve terminals near the cannulae tips. However, the terminals were still capable of taking up exogenously applied AMNA. 7. These results suggest that (+)-amphetamine has a presynaptic action on noradrenergic nerve terminals within the MRF.

Animals↗