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Biomedical subjects

J T Coyle

Publications and source records attributed to J T Coyle.

At least 235 records · Page 13Linked to original sources
PubMed1984

Characterization of the interactions of N-acetyl-aspartyl-glutamate with [3H]L-glutamate receptors.

The specific binding of [3H]L-glutamate and its displacement by N-acetyl-aspartyl glutamate, a peptide endogenous to brain, has been examined in nine regions of the central nervous system. N-acetyl-aspartyl-glutamate caused only a partial displacement of [3H]L-glutamate specific binding with an uneven regional distribution of maximal inhibition, ranging from 61% in the thalamus to 40% in the cerebral cortex and the hippocampus. The maximal displacement of specifically bound [3H]L-glutamate by N-acetyl-aspartyl-glutamate was not significantly affected by calcium added to chloride containing buffer; however, in the absence of chloride or calcium, no significant displacement of [3H]L-glutamate by N-acetyl-aspartyl-glutamate was observed. N-Acetyl-aspartyl-glutamate displayed the highest affinity for the chloride-dependent sites labeled by [3H]L-glutamate among all peptide analogues examined. These results suggest that N-acetyl-aspartyl-glutamate may play a role as an endogenous excitatory peptide in the mammalian central nervous system and raise the question whether endogenous brain peptides enriched in acidic amino acids may serve as excitatory transmitters.

Animals↗
PubMed1984

Selective cholinergic neurotoxin: AF64A's effects in rat striatum.

The selective neurotoxic effects of the aziridinium ion of ethylcholine (AF64A) have been examined after stereotaxic injection into the rat striatum. In a dose-response study (2-26 nmol), 8 nmol caused a 46% decrease in striatal choline acetyltransferase (CAT) activity with minimal effects on the activities of glutamate decarboxylase (GAD) and tyrosine hydroxylase (TH) at 7 days. Maximal CAT reductions of 78-82% occurred with doses of 16-26 nmol which also caused dose-related decreases in GAD and TH activities that paralleled the progressive decrements in CAT. A time course study with 8 nmol indicated a rapid 20% reduction of CAT activity by 12 h and an additional gradual fall of 20% over the next week; TH and GAD activities were not significantly reduced. The selective inhibition of CAT activity persisted for at least 3 months. Histological examination of Nissl stained sections revealed an area of nonspecific damage at the injection site with an abrupt border surrounded by apparently normal striatal neuropil; however; neuronal perikarya staining intensely for acetylcholinesterase were not reduced. These preliminary findings strongly suggest that AF64A has selective neurotoxic effects against striatal cholinergic neurons while relatively sparing striatal GABAergic intrinsic neurons or dopaminergic afferents.

Animals↗
PubMed1984

CSF cholinesterase activity in Gilles de la Tourette's syndrome.

Cerebrospinal fluid acetylcholinesterase (AChE) activity was studied as a possible marker for central cholinergic neuronal function in seven patients with Gilles de la Tourette's syndrome. No significant differences were found between CSF AChE activity in untreated or haloperidol-treated patients and control populations. These data do not appear to support a pathophysiologic association between the cholinergic system and Gilles de la Tourette's syndrome.

Adolescent↗
PubMed1984

Excitatory amino acid receptor interactions of a novel alpha-phosphinic acid analogue of alpha-methylaspartic acid.

An alpha-phosphino analogue of alpha-methylaspartate has been synthesized. The compound may not interact with excitatory amino acid receptors directly, as assessed by direct in vitro radioreceptor binding methods; however, it possesses weak anticonvulsant activity and exhibits an excitant action in vitro that is apparently not mediated by a N-methyl-D-aspartate receptor.

Acetylcholine↗
PubMed1984

Parametric influences on catalepsy.

Normal haloperidol-injected rats were tested on a standard catalepsy bar test, using varying bar heights, diameters, and descent latency measurement criteria. The results demonstrated that all these small procedural differences can markedly influence the duration of catalepsy exhibited by rats and should be standardized in catalepsy experiments.

Animals↗
PubMed1984

The dissociation of evoked release of [3H]-GABA and of endogenous GABA from chick retina in vitro.

The release of prelabeled [3H]-GABA and endogenous GABA evoked by KCl and excitatory amino acid analogs was compared in intact chick retina and retina previously lesioned by the neurotoxins, kainic acid and N-methyl-D,L-aspartic acid. Significant discrepancies were found in the results obtained by the two techniques; and while changes in endogenous GABA release after neurotoxin lesions correlated with retinal glutamate decarboxylase activity, a marker for GABAergic neurons, the release of [3H]-GABA did not. These results call into question the validity of the prelabeling technique for studying GABA release from retina.

Animals↗
PubMed1984

Neurotransmitter specific alterations in dementing disorders: insights from animal models.

Recent years have witnessed considerable change in the conceptualization of the pathophysiology of the cognitive impairments in dementing disorders, as a result of synaptic neurochemical analyses. Profound reductions in the forebrain cholinergic projections occur in Alzheimer's disease. In GM1 gangliosidosis, variable alterations in neurotransmitter related processes that are located in synaptic membranes have been described. Exploitation of animal models of human disorders resulting in dementia may further clarify the dynamic alterations in the biochemical processes required for effective neurotransmission in cortex.

Alzheimer Disease↗
PubMed1984

The differential effects of excitatory amino acids on uptake of 45CaCl2 by slices from mouse striatum.

Exposure to L-glutamate (10 mM) or 60 mM K+ for 1 min significantly stimulated the uptake of 45Ca2+ in slices from mouse striatum. Glutamate-induced stimulation was antagonized by 30 mM Mg2+ and by 5 or 10 mM L-glutamic acid diethyl ester, but not by 5 microM tetrodotoxin. Under these 1-min incubation conditions, neither kainate nor N-methyl-D,L-aspartate significantly affected the uptake of 45Ca2+ ion. By contrast, following preincubation for 10 min, glutamate and the conformationally restricted analogues, ibotenate, quisqualate, and kainate significantly inhibited the 60 mM K+-induced stimulation of the uptake of 45Ca2+. These effects of glutamate and kainate were not significantly affected by the presence of 1 mM Ca2+ in the preincubation medium. These results suggest that glutamate may activate a receptor directly linked to Ca2+ channels, whereas kainate may indirectly modulate the intracellular disposition of Ca2+.

Absorption↗
PubMed1984

Morphologic and neurochemical studies of embryonic brain development in murine trisomy 16.

Telencephalic and diencephalic/brainstem regions from embryonic trisomy-16 mice (Ts16) between gestational days 15-18 were analyzed for alterations of morphologic and neurochemical parameters and compared to phenotypically normal littermates. Mean trisomic wet weights from both regions were significantly diminished (greater than 20%) and total protein content was reduced. Ratios of the thickness of the ventricular (germinal) zone to the thickness of the whole cortex were increased, suggesting a delay in neuronal differentiation. Pre- and postsynaptic markers for GABAergic, cholinergic, catecholaminergic and serotonergic transmitter systems were compared. A significant impairment of the trisomic brain catecholaminergic and serotonergic system development was observed, based upon regional reductions in norepinephrine, dopamine and serotonin content. Choline acetyltransferase activity in the diencephalon/brainstem was reduced by 21-26% in contrast to normal levels within the cerebral hemispheres. Presynaptic GABAergic markers were not affected in the Ts16 embryos. It is concluded that although a genetic imbalance involving chromosome 16 in the mouse embryo produces a delay in neurogenesis, it has a more selective effect on the catecholaminergic, serotonergic and cholinergic systems than on GABAergic neurons.

Amino Acids↗
PubMed1984

Ontogenesis of N-acetyl-aspartate and N-acetyl-aspartyl-glutamate in rat brain.

The levels of N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG) were measured in several regions and in whole brain of rats from 15 days of gestation (DG) to adulthood by means of an isocratic HPLC method. The levels of NAAG in whole brain increased 3-fold between 15 DG and birth, which was 90% of the adult level. Whereas the levels of NAAG in spinal cord increased from 2 days to 4 weeks after birth, in forebrain regions the levels increased 2-3-fold between 2 and 8 days after birth and then declined substantially to adult levels. In contrast, in whole brain and in the several regions examined after birth, the levels of NAA rose steadily from 15 DG to adulthood with a 30-fold increase in whole brain concentration. The results of this study demonstrate the lack of correlation in the development of NAA and NAAG levels and suggest that NAAG is localized in a cell system that matures early.

Age Factors↗
PubMed1984

Cholinergic lesion of the striatum impairs acquisition and retention of a passive avoidance response.

Significant impairments in the acquisition and retention of a step-down passive avoidance task were found in rats with striatal lesions induced by the cholinergic neurotoxin AF64A. No significant differences between control and AF64A-injected rats were found in sensitivity to electric shock or in various measures of spontaneous locomotor activity. Striatal choline acetyltransferase (CAT) activity was significantly decreased in AF64A-treated rats compared with controls, whereas glutamic acid decarboxylase (GAD) activities were not. Furthermore, there were no significant differences between groups in activities of CAT and GAD in either the cortex or the hippocampus, results that support the specificity of the lesion to the striatum. The passive avoidance deficits found in these rats after intrastriatal injection of AF64A support a role for the striatal cholinergic system in complex behavioral processes.

Animals↗
PubMed1984

Automated measurement of rearing behavior in adult and neonatal rats.

Three variables constituting an index of rearing behavior from an animal-activity monitoring system were compared with a standard visual rating at various ages of neonatal and adult rats. All three automated measures correlated significantly with measures rated by visual observation, although only the "number of vertical episodes" was similar in magnitude to the actual number of observed rearings. The height of the vertical sensors was critical in detecting rearings, although reliable results were obtained over a relatively wide range of heights. Analyses in neonatal rats demonstrated developmental progression in rearing behavior, with an onset around Day 15 of age. This automated technique was found to be useful and eliminated confounding variables, such as experimenter bias, commonly associated with visual observation techniques.

Age Factors↗
PubMed1984

Decreased cortical glucose utilization after ibotenate lesion of the rat ventromedial globus pallidus.

Rats received unilateral injections of ibotenic acid (12 micrograms) or vehicle in the ventromedial globus pallidus to lesion the primary source of cortical cholinergic innervation. At 3 or 28-32 days postinjection, the regional cerebral metabolic rate for glucose (rCMRglu) was measured by the 2-deoxy-D-[14C]glucose technique in nine cortical areas, the anterior thalamus, and the dorsal hippocampus. Effects of oxotremorine (0.1 mg/kg i.p.) on rCMRglu in these areas were assessed in ibotenic acid-lesioned and sham-treated rats. Significant effects of ibotenic acid injections and hemispheric asymmetries in rCMRglu were observed in all cortical areas (p less than or equal to 0.05), but not in the anterior thalamus or hippocampus. Cortical rCMRglu generally was lower in the lesioned hemisphere 3 days after ibotenic acid injections, but not after sham treatments. Hemispheric asymmetries were not apparent 28-32 days after pallidal lesions. Oxotremorine produced significant effects in the frontoparietal cortex and anterior thalamic nuclei. In the frontoparietal cortex, rCMRglu was 32% lower in the ibotenate-lesioned hemisphere as compared with the contralateral hemisphere. Oxotremorine did not eliminate hemispheric asymmetry, but increased rCMRglu in the lesioned frontoparietal cortex by 38%. Results support the views that cortical metabolic decrements in Alzheimer's disease are due in part to loss of subcortical cholinergic innervation and that muscarinic agonists may partially reverse these decrements.

Alzheimer Disease↗
PubMed1984

Synaptic neurochemical alterations associated with neuronal degeneration in an inherited cerebellar ataxia of Gordon Setters.

Canine Inherited Ataxia (CIA) is an autosomal recessive cerebellar disease of Gordon Setters associated with degeneration of Purkinje and granule cells. To define specific biochemical correlates of neuronal loss, synaptic neurochemical parameters were measured in three cerebellar regions (vermis, "pars intermedia," and hemisphere) at early and late stages of this disease. At one and a half years of age, affected dogs showed the most severe lesions in the "pars intermedia," with a 39% decrease in the number of Purkinje cells and a 29% decrease in granule cells. Neurochemical measurements demonstrated decreased [3H]muscimol binding and elevations in norepinephrine concentration (248% above control) and [3H]glutamate receptor binding (118% above control). At five years of age, reduction of Purkinje cells in the three cerebellar regions ranged from 65 to 91% while loss of granule cells was between 13 and 53%. [3H]Muscimol binding remained low throughout the cerebellum (38 to 59% of control) and norepinephrine concentration and [3H]glutamate binding were markedly reduced from the levels observed at one and a half years. Glutamate decarboxylase activity, [3H]QNB binding and GABA concentration were relatively unaffected. Our results indicate that neurochemical parameters associated with cerebellar neuronal systems demonstrate specific alterations in a chronic degenerative disorder. This study also indicates the importance of evaluating neurochemical measurements with regard to both spared and degenerating neuronal systems and emphasizes the role of compensatory neurochemical alterations in cerebellar degenerative disorders.

Animals↗
PubMed1984

N-acetyl-aspartyl-glutamate: regional levels in rat brain and the effects of brain lesions as determined by a new HPLC method.

An isocratic HPLC method to measure endogenous N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) is described. After removal of primary amines by passage of tissue extracts over AG-50 resin, the eluate was subject to HPLC anion-exchange analysis and eluted with phosphate buffer with absorbance monitored at 214 nm. The retention time for NAA was 5.6 min and for NAAG 11.4 min with a limit sensitivity of 0.1 nmol. The levels of NAA and NAAG were measured in 16 regions of rat brain and in heart and liver. NAAG was undetectable in heart and liver and exhibited 10-fold variation in concentration among brain regions; the highest levels were found in spinal cord. In contrast, low concentrations of NAA were detectable in heart and liver, and the regional distribution of NAA in brain varied only twofold. The regional distribution of NAA and NAAG correlated poorly. To assess the neuronal localization of these two compounds, the effects of selective brain lesions on their levels were examined. Decortication caused a 28% decrease in NAAG levels in the ipsilateral striatum while NAA decreased 38%. Kainate lesion of the striatum resulted in a 31% decrease in NAAG in the ipsilateral striatum, whereas NAA fell by 58%. Kainate lesion of the hippocampus resulted in significant decrements in NAAG and NAA in the hippocampus and septum. Transection of the spinal cord at midthorax resulted in a 51% decrease in NAAG levels immediately caudal and a 40% decrease immediately rostral to the lesion; however, NAA decreased only 30% in these areas. These results are consistent with a neuronal localization of NAAG in brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Development of central neurotransmitter-specified neuronal systems: implications for pediatric neuro-psychiatric disorders.

An increasing focus on the mechanism of synaptic neurochemistry in pediatric neurology, may lead to a better understanding of the pathophysiology of many disorders and result in a more rational approach to their pharmacotherapy. With the burgeoning list of putative neurotransmitters in brain, and the growing evidence of co-localization of many of these neurotransmitters, chemical neurotransmission likely involves a higher degree of complexity than appreciated heretofore. The potential role of neurotransmitter dysfunction in the pathophysiology of neurologic and behavior disorders of children, should not be considered as restricted to those disorders that involve selective neuronal loss, but may encompass a much wider spectrum of syndromes due to metabolic abnormalities, as well as disturbances of the finer features of chemical neurotransmission.

Afferent Pathways↗
PubMed1984

Anatomic localization of cholecystokinin receptors to the pyloric sphincter.

In an effort to identify target sites within the gastrointestinal (GI) tract through which cholecystokinin (CCK) may exert its gastric inhibitory and satiety effects, the distribution of CCK receptors was mapped in the stomach and small bowel by in vitro radiography utilizing 125I-labeled Bolton-Hunter CCK-33. Specific receptor binding was localized to the circular smooth muscle layer of the pyloric sphincter. Negligible binding was observed in the oblique, circular, or longitudinal muscle layers of other GI levels. Moderate nonspecific binding was associated with mucosal tissue in all gastric sections. The restriction of CCK receptors to the circular smooth muscle of the pyloric sphincter suggests this location as the site through which CCK inhibits gastric emptying. Gastric distension secondary to this inhibition may be the mechanism for CCK-induced satiety.

Animals↗