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J T Coyle

Publications and source records attributed to J T Coyle.

At least 127 records · Page 7Linked to original sources
PubMed1990

Striosomal organization of cholinergic and dopaminergic uptake sites and cholinergic M1 receptors in the adult human striatum: a quantitative receptor autoradiographic study.

The distribution of cholinergic pre- and postsynaptic markers and dopaminergic presynaptic markers was analyzed in the adult human striatum, using quantitative receptor autoradiography. The distribution of the different binding sites indicates that cholinergic and dopaminergic uptake sites display a striosomal organization, with a higher binding site density in the striatal matrix. M1 muscarinic cholinergic receptor distribution parallels the distribution of cholinergic presynaptic markers. Our data show that cholinergic and dopaminergic terminals, and M1 receptors are enriched in the matrix of the adult human striatum.

Aged↗
PubMed1990

Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis.

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of a variety of chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). The concentration of the excitatory amino acids glutamate and aspartate in the cerebrospinal fluid were increased significantly (p less than 0.01) by 100 to 200% in patients with ALS. Similarly, the concentrations of the excitatory neuropeptide N-acetyl-aspartyl glutamate and its metabolite, N-acetyl-aspartate, were elevated twofold to threefold in the cerebrospinal fluid from the patients. There was no relationship between amino acid concentrations and duration of disease, clinical impairment, or patient age. In the ventral horns of the cervical region of the spinal cord, the level of N-acetyl-aspartyl glutamate and N-acetyl-aspartate was decreased by 60% (p less than 0.05) and 40% (p less than 0.05), respectively, in 8 patients with ALS. Choline acetyltransferase activity was also diminished by 35% in the ventral horn consistent with motor neuron loss. We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.

Adult↗
PubMed1990

Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice.

The effects of galanthamine, a long-acting acetylcholinesterase inhibitor, on passive avoidance and a modified Morris swim task were studied in mice. Lesions of the nucleus basalis magnocellularis (nBM) produced significant decreases in cortical choline acetyltransferase (ChAT) activity and profound deficits on the 24-h retention of a passive avoidance response and the reversal phase of the swim task. Galanthamine, administered 4 h before testing, improved performance of the two tasks in a dose-dependent fashion. In both tasks, galanthamine produced a U-shaped dose-response curve: the optimal dose was 3.0 mg/kg, IP on passive avoidance and 2.0 mg/kg on the swim task. The improvements in performance were not due to differences in motor activity or sensitivity to electric footshock. Behavioral tolerance did not occur from repeated doses of galanthamine; in fact, prior doses of galanthamine appeared to have a priming effect on later performance. In contrast to the effects in nBM-lesioned mice, galanthamine impaired performance of control mice on both tasks. Several characteristics of galanthamine suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease: 1) its ability to attenuate cognitive deficits in nBM-lesioned mice, 2) its relatively long half-life, and 3) its lack of tolerance effects in mice during 2 weeks of repeated dosing.

Animals↗
PubMed1990

Idebenone attenuates neuronal degeneration induced by intrastriatal injection of excitotoxins.

Previous studies with the N18-RE-105 neuronal-like cell line and primary cortical cultures demonstrate that glutamate can produce a calcium-dependent, delayed form of neuronal degeneration that results from its competitive inhibition of cystine transport, which leads to cellular glutathione depletion and death by oxidative stress. Idebenone, a centrally active antioxidant used to treat multiinfarct dementia, protects cells from this form of glutamate-induced cytotoxicity in vitro. In the present study, we have examined the effects of systemic treatment with idebenone on the neurotoxic consequences of intrastriatal injection of kainic acid, quisqualic acid, or quinolinic acid, an NMDA receptor agonist, on neuronal degeneration. Striatal damage was assessed by quantitative neurochemistry with measurement of choline acetyltransferase activity and glutamate decarboxylase activity, by histochemical analysis for acetylcholinesterase and NADPH diaphorase staining and by behavioral assessment of circling produced by systemic apomorphine treatment 10 days after the unilateral lesion. The results indicate that treatment with idebenone provides significant protection against the neuronal degeneration induced by intrastriatal injection of kainic acid and quisqualic acid, but not the NMDA receptor agonist, quinolinic acid. The results suggest that oxidative stress may contribute to the proximate cause of neuronal degeneration induced by quisqualate and by kainate receptor agonists and that the mechanisms of neuronal degeneration caused by quisqualate/kainate receptor agonists differ from those associated with NMDA receptor agonists.

Animals↗
PubMed1990

Increased number of somatostatin-immunoreactive neurons in primary cultures of trisomy 16 mouse neocortex.

The gene encoding for pre-prosomatostatin is located on chromosome 16 of the mouse. To determine the effect of an extra copy of this gene on somatostatin expression in neurons, primary disaggregated cultures of neocortex prepared from 15 days gestational Trisomy 16 mice and their littermate euploid controls were subjected to immunocytochemical staining for somatostatin, neuropeptide Y and glutamic acid decarboxylase. The results demonstrate a selective and significant increase in the number of somatostatin-immunoreactive neurons.

Animals↗
PubMed1990

The Johns Hopkins Depression Scale: normative data and validation in child psychiatry patients.

With a newly devised 38-item symptom checklist based upon DSM-III criteria for major affective disorder, normative data were obtained on 1,004 school children, aged 5 to 13 years. The items on the checklist were scored on a severity scale of 0 to 4 with a maximum score of 152. The average raw scores in this population was 31.2, SD +/- 2.4. Of 57 inpatients, 27 met DSM-III criteria for a major affective disorder and obtained mean raw scores of 66.8, SD +/- 13.4. The 30 nondepressed inpatients had scores of 36.4, SD +/- 5.3. The differences in the raw scores between the depressed inpatients and normal controls, and depressed and nondepressed inpatients were found to be statistically significant (p less than 0.01). The new checklist can serve as a potential screening instrument, is not time consuming, and has been standardized on a large normal control population for age and sex.

Adolescent↗
PubMed1990

Production and characterization of monoclonal antibodies to N-acetyl-aspartyl-glutamate.

N-acetyl-aspartyl-glutamate (NAAG) is a putative neuromodulator/neurotransmitter in the mammalian nervous system. Immunohistochemical studies with polyclonal NAAG antisera have revealed immunoreactive neurons and processes in several brain regions. However, these antisera crossreact to some degree with N-acetyl-aspartate (NAA), which is present in mM concentrations in brain, prompting the development of monoclonal antibodies (MAb) more specific for NAAG. By fusing spleen lymphocytes obtained from BALB/c mice pre-immunized with NAAG covalently linked to bovine serum albumin by carbodiimide with SP2/0-Ag 14 mouse myeloma cells, we produced three IgG2a (kappa) MAb which specifically reacted with NAAG. These MAb exhibited negligible crossreactivity with NAA or with structurally similar peptides, as shown by solid-phase radioimmunoassay. Antibody activity was absorbed out selectively by both NAAG-thyroglobulin conjugate and free NAAG. These MAb stained many nuclei of the medulla-pons and midbrain, mitral cells in the olfactory bulb, pyramidal neurons in sensorimotor cortex, locus ceruleus, and several cholinergic cranial nuclei. The staining pattern strongly correlated with NAAG levels determined by HPLC. Monoclonal antibodies significantly enhanced sensitivity of staining, allowing visualization of dorsal horn neurons in spinal cord, which were not readily detectable with polyclonal antiserum. Availability of these MAb now facilitates further clarification of the role of NAAG in the brain.

Animals↗
PubMed1990

Phospholipase A2 and 3H-hemicholinium-3 binding sites in rat brain: a potential second-messenger role for fatty acids in the regulation of high-affinity choline uptake.

The involvement of phospholipase A2 (PLA2) and fatty acid release in the regulation of sodium-dependent high-affinity choline uptake in rat brain was assessed in vitro through the use of the specific binding of 3H-hemicholinium-3 (3H-HCh-3). Addition of arachidonic acid and other unsaturated fatty acids to rat striatal membranes in vitro resulted in a dose-dependent, temperature-independent activation of 3H-HCh-3 binding. Scatchard analysis revealed that these changes in binding result from a 2-fold increase in the affinity and capacity of 3H-HCh-3 binding. Saturated fatty acids, lysophospholipids, and phospholipids did not affect specific 3H-HCh-3 binding. Addition of defatted BSA to membranes, which had been treated previously with arachidonic acid, completely reversed the increase in specific 3H-HCh-3 binding. However, several inhibitors of fatty acid metabolism, including nordihydroguaiaretic acid, indomethacin, catalase, and superoxide dismutase, did not alter arachidonic acid-induced changes in 3H-HCh-3 binding, suggesting that unsaturated fatty acids, and not their metabolites, are directly responsible for the observed activation of specific 3H-HCh-3 binding. Additionally, unsaturated fatty acids dose-dependently inhibited high-affinity 3H-choline uptake in rat striatal synaptosomes, apparently due to the disruption of synaptosomal integrity. The phospholipase A2 inhibitors quinacrine hydrochloride, trifluoperazine, and 4-bromophenacylbromide dose-dependently inhibited potassium depolarization-induced activation of specific 3H-HCh-3 binding in slices of rat brain in vitro. Similarly, both quinacrine and trifluoperazine inhibited the metabolism of phospholipids and the release of fatty acids evoked by either elevated KCl or calcium ionophore A23187. These results support the involvement of PLA2 and subsequent fatty acid release in the increase of 3H-HCh-3 binding in cholinergic neurons and suggest that activation of PLA2 may be the penultimate step in regulating the velocity of sodium-dependent choline transport.

Animals↗
PubMed1989

Seizures decrease regional enzymatic hydrolysis of N-acetyl-aspartylglutamate in rat brain.

Previous results have shown that kindled seizures increase N-acetyl-aspartylglutamate (NAAG) levels in the entorhinal cortex, while non-kindled convulsions have no effect. To further explore possible relationships between epilepsy and the physiology of NAAG, the effect of amygdaloid kindling on the activity of a NAAG-hydrolyzing enzyme was examined in specific brain regions associated with limbic seizures. NAAG is hydrolyzed into glutamate (Glu) and N-acetyl-aspartate (NAA) by N-acetylated-alpha-linked acidic dipeptidase (NAALADase), a membrane-bound peptidase. We found that convulsions decreased NAALADase activity and these effects were generalized to several brain regions. While small decreases in the hippocampus were specific to kindling, the decreases in other limbic regions were larger, non-specific, and appear to be aftereffects of convulsions; i.e. not specific to kindling. Although there is evidence that NAAG may be an excitatory neurotransmitter, it could also function as a storage form of Glu. Thus, a reduction in NAALADase activity could reduce the availability of Glu at certain synapses, which might be a homeostatic mechanism for lessening susceptibility to further seizures.

Animals↗
PubMed1989

Lesions of the basal forebrain alter stimulus-evoked metabolic activity in mouse somatosensory cortex.

The role that acetylcholine plays in processing sensory stimuli is beginning to be characterized; however, morphological correlates of cholinergic effects on activity patterns in sensory cortex are not available. To study this problem, unilateral neurotoxic lesions that depleted the necortex of acetylcholine were made in the basal forebrains of mice. The aim of these experiments was to study the effect of cholinergic depletion on stimulus-evoked activity in the barrel field of the mouse somatosensory cortex. One month following the lesion, 2-deoxyglucose (2DG) experiments were conducted on the lesioned and on normal mice while the animal received bilateral stimulation to the C3 whisker. The tissue was processed for acetylcholinesterase and cytochrome oxidase histochemistry and 2DG autoradiography. Evaluation of the column-like 2DG label evoked in the somatosensory cortex revealed that the activity on the lesioned side was significantly reduced in dimension and intensity from that in the normal hemisphere. On the normal side, the activated barrels averaged 641 microns in tangential width, were 76.5% above background in density, and extended from lamina I-V. On the lesioned side, the activated barrels were 485 microns in tangential width, 65.4% above background in density, and extended from lamina II-V. In other cortical regions, outside the stimulus-evoked barrel field, 2DG activity values were similar on the normal and lesioned side. Additionally, both the pattern and intensity of the cytochrome oxidase staining within the barrel field displayed no differences in either hemisphere. These studies suggest that acetylcholine plays a significant role in the processing of somatosensory information. Neurotoxic lesions that diminish cortical cholinergic innervation cause a reduction of stimulus-evoked activity levels, while underlying metabolic activity is either not affected or recovers over time.

Acetylcholine↗
PubMed1989

Compartment-specific changes in the density of choline and dopamine uptake sites and muscarinic and dopaminergic receptors during the development of the baboon striatum: a quantitative receptor autoradiographic study.

In the fetal and young primate neostriatum, cholinergic and dopaminergic markers show patches of high density surrounded by a lower-density matrix. In the adult, the same markers display the opposite pattern, a lower density in striosomes, surrounded by a higher-density matrix. In order to understand the developmental sequences leading to the adult compartmental organization of the primate neostriatum, a quantitative technique was used to study the ontogeny of pre- and postsynaptic components of cholinergic and dopaminergic neurons in baboon caudate nucleus and putamen. The development of specific uptake mechanisms for choline and dopamine and receptors was studied by means of quantitative autoradiography of the specific binding of [3H]-hemicholinium-3 [( 3H]-HC3) and [3H]-mazindol [( 3H]-MAZ) to the choline and dopamine uptake systems, respectively. [3H]-pirenzepine [( 3H]-PIR) was used to label M1 muscarinic receptors and [3H]-spiroperidol [( 3H]-SPI) was used to label striatal dopamine D2 receptors. Serial sections were used for each ligand to determine the precise anatomical relationships between the binding patterns of the different markers. Our aim was to determine whether the adult striosomal distribution of the binding sites studied was due to 1) a selective decrease in patch/striosomal binding density or 2) a selective increase in matrix binding density. Our studies show that a postnatal decrease in the density of [3H]-HC3 sites in the patch/striosomes and an increase in the matrix density of [3H]-MAZ sites are the primary, but not the sole, changes in the compartmental distribution of these sites leading to the adult striosomal organization of the striatal cholinergic and dopaminergic innervation. D2 receptors follow the general developmental pattern of [3H]-MAZ and [3H]-HC3, changing their density of distribution in both compartments during the developmental period examined. In addition, M1 muscarinic receptors already display their adult pattern in the newborn baboon striatum, and therefore represent one of the first neurochemical makers to adopt its mature organization.

Animals↗
PubMed1989

The postnatal expression of acetylcholinesterase in somatostatin-positive cells of mouse hippocampus.

The neuroanatomical distributions of acetylcholinesterase (AChE) staining and somatostatin-like immunoreactivity (SOMLI) of neurons intrinsic to the mouse hippocampal formation have been evaluated during postnatal development. Besides the progressive development of neuropil staining for AChE, as a consequence of the septohippocampal innervation, intense AChE staining was also expressed in a subpopulation of neurons intrinsic to the stratum oriens and the hilus of dentate gyrus. In the stratum oriens, the number of AChE-positive cells increased between postnatal day (PND) 3 and PND 10 and declined slightly after PND 21. In the hilus of the dentate gyrus, the number of AChE-stained cell bodies increased progressively until PND 21 when the adult complement was achieved. The AChE-positive neurons of strata radiatum and lacunosum-moleculare, which were few and scattered, increased progressively from PND 7 until adulthood. SOMLI-positive neurons were present in the hippocampal formation by PND 3, and their density showed initial increases followed by decreases in the second to third postnatal week. SOMLI cell distribution on the other hand did not change remarkably during subsequent maturation. Because of the similar developmental time course and localization of AChE and SOMLI neurons, co-localization was assessed by a double-staining method. A large percentage of the neurons staining for one of these markers also stained for the other. In the stratum oriens, from PND 3 to PND 10, the number of SOMLI neurons expressing AChE was increased while a slight decrease from the PND 21 to adulthood was evident. Virtually all SOMLI-positive neurons in the dentate gyrus stained for AChE from PND 7 through adulthood, although the intensity of AChE reactivity declined with maturation.

Acetylcholinesterase↗
PubMed1989

The effects of N-acetylated alpha-linked acidic dipeptidase (NAALADase) inhibitors on [3H]NAAG catabolism in vivo.

N-Acetylated, alpha-linked acidic dipeptidase (NAALADase) is a chloride-activated, membrane bound, metallopeptidase that cleaves the endogenous neuropeptide N-acetyl-aspartyl-glutamate (NAAG) in vitro. To determine whether NAALADase is the catabolic enzyme of NAAG in vivo, we have examined the effects on [3H]NAAG metabolism of intrastriatal co-injections of agents that affect NAALADase activity in vitro. Co-injections of NAALADase inhibitors, such as quisqualate (Quis), phosphate, dithiothreitol and EGTA were found to prolong the t1/2 of [3H]NAAG, whereas cobalt, a NAALADase activity stimulator, accelerated [3H]NAAG catabolism. These results are consistent with a role for NAALADase in the extracellular disposition of endogenous NAAG.

Animals↗
PubMed1989

Galanthamine, an acetylcholinesterase inhibitor: a time course of the effects on performance and neurochemical parameters in mice.

The time course of the effects of the long-acting acetylcholinesterase (AChE) inhibitor, galanthamine, on a spatial navigation task and on AChE and acetylcholine (ACh) levels were investigated in mice. Mice received either saline or ibotenic acid injections into the nucleus basalis magnocellularis (nBM). The control and nBM group were than trained to perform a modified Morris swim task and the time to find the hidden platform was recorded. The nBM group took significantly longer to find the platform than the control group in the reversal phase of testing. Galanthamine attenuated the performance deficit in the nBM-lesioned group in a time-dependent manner, with peak performance at four hours after injection of 5.0 mg/kg galanthamine IP. This dose impaired performance of the task in control mice, with the most severe deficits observed at two hours after injections when motor activity was severely reduced. Galanthamine (5.0 mg/kg IP) significantly decreased cortical AChE activity and significantly increased cortical ACh content in control mice in a time-dependent manner. The time courses of the neurochemical effects, however, did not correlate precisely with the behavioral time course. Galanthamine concentrations up to 1 x 10(-5) M did not affect choline acetyltransferase (ChAT) activity, [3H]hemicholinium-3 (HCh-3) binding to the choline carrier, [3H]quinuclidinylbenzilate (QNB) binding to muscarinic receptors, or [3H]acetylcholine binding to nicotinic receptors in cortical homogenates. AChE activity was inhibited by galanthamine in cortical homogenates with an IC50 of 4.1 x 10(-7) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Neurogenesis of the basal forebrain in euploid and trisomy 16 mice: an animal model for developmental disorders in Down syndrome.

The neurogenesis and early histochemical differentiation of the basal forebrain in trisomy 16 fetal mice and their euploid littermates were examined by combining [3H]thymidine autoradiography with acetylcholinesterase histochemistry. Neurons of the basal forebrain were being born between embryonic day 11 and 15 in both chromosomally normal (euploid) and aneuploid mice. In euploid littermate controls, neurogenesis proceeded along a caudal to rostral gradient with the peak on embryonic day 11 for caudal portions and embryonic day 13 for rostral portions of the basal forebrain. In contrast, in trisomy 16 mice, rostral sections exhibited a peak of neurogenesis on embryonic day 11, 2 days earlier than in their euploid littermate controls. Hypocellularity of the basal forebrain region was noted in trisomy 16 mice; particularly dramatic was the reduction of the population of cells that expressed acetylcholinesterase. This reduction in cell number in the trisomics was not accompanied by a reduction in cell size or by a dramatic change in the distribution of residual neurons when compared to that of euploid littermate controls. Since trisomy 16 mice do not survive the perinatal period, we examined the pattern of acetylcholinesterase expression in normal C57B1/6J mice from embryonic day 16 to postnatal day 5 to determine the postnatal disposition of these neurons. Already at embryonic day 16, fibers staining for acetylcholinesterase penetrated the striatal anlage, in their course towards targets in the cerebral cortices. By postnatal day 5, the previously expansive distribution of basal forebrain neurons had become consolidated in a more ventral and rostral position by the extensive outgrowth of the striatal neurons, a pattern resembling that seen in adult animals.

Acetylcholinesterase↗
PubMed1989

Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress.

Glutamate binds to both excitatory neurotransmitter binding sites and a Cl(-)-dependent, quisqualate- and cystine-inhibited transport site on brain neurons. The neuroblastoma-primary retina hybrid cells (N18-RE-105) are susceptible to glutamate-induced cytotoxicity. The Cl(-)-dependent transport site to which glutamate and quisqualate (but not kainate or NMDA) bind has a higher affinity for cystine than for glutamate. Lowering cystine concentrations in the cell culture medium results in cytotoxicity similar to that induced by glutamate addition in its morphology, kinetics, and Ca2+ dependence. Glutamate-induced cytotoxicity is directly proportional to its ability to inhibit cystine uptake. Exposure to glutamate (or lowered cystine) causes a decrease in glutathione levels and an accumulation of intracellular peroxides. Like N18-RE-105 cells, primary rat hippocampal neurons (but not glia) in culture degenerate in medium with lowered cystine concentration. Thus, glutamate-induced cytotoxicity in N18-RE-105 cells is due to inhibition of cystine uptake, resulting in lowered glutathione levels leading to oxidative stress and cell death.

Animals↗