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J T Coyle

Publications and source records attributed to J T Coyle.

396 records · Page 22Linked to original sources
PubMed1969

Antiparkinsonian drugs: inhibition of dopamine uptake in the corpus striatum as a possible mechanism of action.

A variety of antiparkinsonian drugs are potent, noncompetitive inhibitors of dopamine uptake into synaptosomes in homogenates of rat corpus striatum. Inhibition of dopamine uptake may potentiate the synaptic actions of dopamine in the striatum and could explain the antiparkinsonian effects of these drugs. This hypothesis accounts for several clinical features of Parkinson's disease and predicts compounds which may be new therapeutic agents.

Animals↗
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Noradrenergic innervation patterns in three regions of medial cortex: an immunofluorescence characterization.

A homologous antiserum directed against rat dopamine beta-hydroxylase (DBH was used for the immunohistofluorescent visualization of the noradrenergic (NA) innervation of medial cortex in the albino rat. Three cytoarchitectonic divisions of the medial cortex were studied: prelimbic (PL), anterior cingulate (AC), and granular retrosplenial (RSg). Each division of medial cortex possesses a characteristic and distinct pattern and density of NA fibers. The branching patterns and density of the fibers in PL cortex are similar to those of lateral cortex. AC cortex has the lowest density of NA innervation found in the neocortex; there is minimal arborization in layer I, and a very low density of fibers in layers II and III. In contrast RSg is the most densely innervated region, and NA fibers arborize extensively throughout all layers. The dopaminergic (DA) fibers in medial cortex were studied with glyoxylic acid-induced histofluorescence following midbrain lesions of the dorsal noradrenergic bundle (DNB). A laminar complementarity exists in AC cortex such that the DA fibers terminate in layers I-III, while the NA fibers are largely confined to the deep layers. The distinctive patterns of termination of coeruleocortical fibers indicate that in different cortical areas NA axons contact different elements of neuronal circuitry and that there is some degree of specificity in the distribution of NA terminals within the cortex.

Afferent Pathways↗
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Immunocytochemical distribution of N-acetylaspartylglutamate in the rat forebrain and glutamatergic pathways.

N-acetylaspartylglutamate (NAAG) is an acidic dipeptide found in high concentration throughout the rat central nervous system. NAAG has been proposed as a neurotransmitter/modulator in some excitatory glutamatergic pathways where it is released by a Ca(2+)-dependent process with neuronal activity. Previous immunocytochemical studies have revealed few neurons exhibiting NAAG-like immunoreactivity (LI) in the forebrain, especially in putative glutamatergic neurons. In this study, we present a detailed map of NAAG-LI in rat forebrain utilizing a modified fixation technique that markedly enhances sensitivity. NAAG-LI is located in most of the putative glutamatergic pathways in the forebrain including pyramidal neurons in motor and sensory cortices and the hippocampal formation. Co-localization of NAAG-LI to cholinergic systems of the forebrain was quite extensive with the exception of the striatal local circuit neurons. A noteworthy feature of NAAG-LI-positive neuronal groups is that they were often configured in hierarchical relationships. For example, the pyramidal neurons of the motor cortex and the motor neurons of the brainstem and and spinal cord expressed NAAG-LI; also, several inter-related components of the limbic system stained for NAAG-LI. Taken together, these findings indicate that NAAG is a neuropeptide localized to subpopulations of neurons throughout forebrain as well as in brainstem and spinal cord.

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Newborn basal forebrain lesions disrupt cortical cytodifferentiation as visualized by rapid Golgi staining.

We have previously shown that neonatal lesions of the basal forebrain cholinergic afferents result in transient cholinergic depletion concomitant with abnormal morphogenesis of cerebral cortex in Balb/CByJ mice (Höhmann et al., 1988). Here, we have utilized the rapid Golgi method to further characterize these previously observed abnormalities. We compared layer V pyramidal neurons in somatomotor cortex ipsi- and contralateral to the lesion at postnatal days (PND) 7 and 14. Quantitative evaluations showed a significant reduction in all aspects of the dendritic tree as well as in cell body size in ipsilateral cortex at PND 7. Differences between ipsi- and contralateral pyramidal cells had attenuated by PND 14, but significant somatic size differences persisted, as did changes in the apical branching pattern. Qualitative differences between ipsilateral and contralateral hemispheres included the relatively more immature appearance of ipsilateral neurons at both ages, in addition to unusual dendritic morphology, particularly at PND 14. A close correlation was apparent between the magnitude of cholinergic depletion in cortex (larger at PND 7 than at PND 14) and the severity of abnormalities in pyramidal cell morphogenesis. We conclude that a normal cholinergic innervation to neocortex is instrumental in the timely differentiation of cortical neurons, because neonatal nBM lesions disrupted the time schedule of differentiation, but did not preclude the pyramidal neurons from further differentiation at a later time.

Animals↗
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Efferent and afferent connections of mouse sensory-motor cortex following cholinergic deafferentation at birth.

The present study investigates the effect of cholinergic basal forebrain lesions at birth on cortical connectivity in adulthood. We have previously shown that such neonatal lesions result in extensive cortical cholinergic deafferentation during early postnatal development, which is accompanied by abnormal morphogenesis of cortical cytoarchitecture (Höhmann at al., 1988). Here, we have used WGA-HRP to label anterogradely and retrogradely afferent and efferent projections of dorsal neocortex. Our results show an altered projection pattern from dorsal thalamus to layer IV of sensory-motor cortex following lesions among the cholinergic basal forebrain neurons (nBM), while corticothalamic projections from layer VI appear normal. In addition, corticofugal projections from layer V, labeled by striatal injection, appear to be expanded following the lesion. This indicates that cortical layers undergoing differentiation after the newborn nBM lesion present with long-term abnormalities in connectivity. The present results are compatible with the hypothesis that cholinergic afferents are instrumental in the regulation of cortical morphogenesis. Furthermore, our data show that ontogenetic disturbances can lead to structural abnormalities that persist long after the initial deficiency has abated. We discuss the significance of these results in relationship to human neurological disorders.

Afferent Pathways↗
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Dicarboxylic amino acids block epileptiform activity in hippocampal slice.

Effects of prolonged (5-10 min) continuous perfusion of excitatory amino acids on penicillin (PEN)-evoked epileptiform activity in hippocampal slices were examined with extracellular and intracellular recordings. L-glutamate (GLU), L-aspartate (ASP), quisqualate (QUIS), and N-methyl-D,L-aspartate reversibly depressed multiple (epileptiform) population spikes elicited by PEN (1.7 mM). Intracellularly recorded, PEN-evoked paroxysmal depolarization shifts (PDS) were partially blocked by 1 mM GLU and largely eliminated by 2 mM GLU or ASP. In the presence of PEN, perfusion with both GLU and ASP induced a transient 4 to 6-mV depolarization, usually followed by spontaneous return of membrane potential to control levels. During the amino acid (AA)-induced block of epileptiform activity, there was no significant change in resting membrane potential, input resistance, or the ability to fire action potentials in response to depolarization, indicating that the decreased responsiveness is not a consequence of nonspecific pyramidal cell overdepolarization. The observed depression of epileptiform activity by continued exposure to GLU and its analogues may reflect desensitization or another regulatory mechanism to limit overexcitation.

Action Potentials↗
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The glutamatergic dysfunction hypothesis for schizophrenia.

Schizophrenia is a syndrome, undoubtedly with multiple etiologies, that variably exhibits several features including positive and negative symptoms, cognitive deficits, onset in young adulthood, and deterioration from the previous level of function. This review will examine the growing evidence that dysfunction of corticolimbic glutamatergic neurotransmission may contribute to or account for the manifestations of schizophrenia. Glutamatergic neurons represent the primary excitatory afferent and efferent systems innervating the cortex, limbic regions, and striatum. The postsynaptic actions of glutamate are mediated by a family of glutamate-gated ion channels that permit the influx of sodium and calcium, thereby depolarizing (exciting) neurons. One of these receptors, the N-methyl-D-aspartate (NMDA) receptor, is the site of action of psychotomimetics such as phencyclidine and related anesthetics, which can reproduce in normal individuals most of the symptomatic features of schizophrenia. An endogenous antagonist at the NMDA receptor, N-acetyl-aspartyl glutamate, appears to have enhanced activity in the frontal cortex and hippocampal formation in persons with this disorder. Glutamatergic dysfunction may be particularly relevant to those forms of schizophrenia in which negative symptoms, cognitive deficits, and deterioration are prominent features. In support of this inference, clinical studies have shown that drugs that enhance NMDA-receptor function reduce negative symptoms and cognitive deficits in persons with chronic schizophrenia who are receiving neuroleptics. Thus, dysfunction of glutamatergic neurotransmission represents an important organizational focus for research on the complex manifestations of schizophrenia.

Cerebral Cortex↗
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Failure of folic acid derivatives to mimic the actions of kainic acid in brain in vitro or in vivo.

The ability of three derivatives of folic acid, N-5-methyltetrahydrofolic acid (MTHF), tetrahydrofolic acid (THF) and dihydrofolic acid (DHF) to mimic the actions of kainic acid (KA) in a number of in vitro and in vivo systems known to be sensitive to KA was examined. None of the three folate derivatives at 100 microM concentration significantly inhibited the specific binding of [3H]-KA to striatal membranes although 2 microM L-glutamate produced a 40% inhibition. None of the three folate derivatives stimulated the formation of cyclic GMP in cerebellar slices incubated in vitro although KA (0.5 mM) increased cyclic GMP levels by 2.5-fold. Whereas intrahippocampal injection of 2.3 nmoles of KA produces prolonged abnormalities of the EEG, limbic-type seizures and a characteristic pattern of neuronal degeneration in the hippocampal formation and related structures, intrahippocampal injection of a 100-fold greater dose of THF caused only minor and transient EEG abnormalities, no overt seizures and a highly restricted lesion. Whereas intrastriatal injection of 5.6 nmoles of KA caused a profound reduction in the specific activities of choline acetyltransferase and glutamate decarboxylase, markers for striatal intrinsic cholinergic and GABAergic neurons, 50-fold greater doses of MTHF did not affect either enzyme although this high dose of THF did cause a significant 33% reduction in choline acetyltransferase activity. These findings support the suggestion that THF may have weak neurotoxic effects in brain but indicate that the actions of this compound and the related MTHF and DHF are not mediated through KA-specific receptors.

Animals↗
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Kainic acid: insights from a neurotoxin into the pathophysiology of Huntington's disease.

Kainic acid, a conformationally restricted analog of L-glutamic acid, is a potent neuroexcitant. Consistent with the excitotoxin hypothesis of Olney, intrastriatal injection of kainic acid causes degeneration of neurons with perikarya within the striatum but spares axons passing through or terminating in the region. The striatal kainate lesion shares many neurochemical and histopathologic alterations with those observed in the hereditary neurodegenerative disorder of man, Huntington's Disease. Recent studies on the mechanism of neurotoxicity of kainate indicate that its action is complex and indirect; however, ligand binding studies have revealed specific receptors for kainate. Understanding the fundamental mechanisms involved in excitotoxin action may shed light on the pathophysiology of neurodegenerative disorders such as Huntington's Disease.

Animals↗