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Biomedical subjects

J T Coyle

Publications and source records attributed to J T Coyle.

At least 325 records · Page 18Linked to original sources
PubMed1979

Rotational behaviour in rats with unilateral striatal kainic acid lesions: a behavioural model for studies on intact dopamine receptors.

Rotational behaviour can be induced in rats with unilateral kainic acid induced degeneration of the neostriatum and adjacent regions by means of dopaminergic drugs. Kainic acid lesioned rats, when challenged with apomorphine or the ergot compounds elymoclavine, lergotrile and bromocriptine, perform dose-related turning towards the lesioned side. Blockade of the rotations by a number of dopamine receptor antagonists indicates dopaminergic involvement. Since kainic acid treatment had previously been shown to reduce the number of dopamine receptors in the injected brain regions, ipsilateral turning behaviour elicited by dopaminergic drugs after these lesions seems to be due to intact receptors on the contralateral hemisphere. Comparison of rotation data from experiments at intact dopamine receptors with those from experiments at supersensitive dopamine receptors revealed: (1) A marked decrease of the threshold dose for induction of rotational behaviour in the 6-OHDA lesioned rats. This decrease is particularly pronounced for lergotrile and bromocriptine. (2) A higher peak activity of rotations in rats with supersensitive dopamine receptors. (3) A considerable increase in the slope values of logits plots following denervation of dopamine receptors. Thus, the present report suggests: (a) that a behavioural model for studies of drugs acting at intact dopamine receptors can be obtained by unilateral neostriatal kainate injections and (b) that development of dopaminergic supersensitivity involves increased affinity of the receptors for dopamine receptor agonists and an increase in the coupling to its biological effector mechanism.

Animals↗
PubMed1979

Histological and neurochemical effects of fetal treatment with methylazoxymethanol on rat neocortex in adulthood.

Forebrain microencephaly results when developing rats are exposed to methylazoxymethanol acetate (MAM) at 15 days of gestation (DG). This potent alkylating agent is selectively cytotoxic for dividing cells. Since distinct neuronal populations in neocortex vary greatly with respect to timing of mitotic activity during gestation, it was predicted that some groups would be differentially reduced by treatment. Histological examination of neocortex from treated rats grown to adulthood revealed major losses of laminae II--IV with relative preservation of deeper layers. The atrophic adult neocortex was further characterized by assay of several defined pre- and postsynaptic neurochemical markers. Total markers for GABAergic neurons were greatly reduced (glutamate decarboxylase -71%, [3H]GABA synaptosomal uptake -63% and endogenous GABA -59%). Total [3H]GABA binding to cortical membranes was reduced 67%. Total [3H]glutamate synaptosomal uptake and endogenous glutamate were reduced 71% and 65% respectively. In contrast, total presynaptic markers for noradrenergic innervation were minimally altered but concentration of tyrosine hydroxylase, [3H]norepinephrine synaptosomal uptake and endogenous norepinephrine were increased by 275%, 130% and 133%, respectively. Concentration of cholinergic presynaptic markers was also increased (choline acetyltransferase +97%, endogenous acetylcholine +64%) in atrophic cortex, but to a lesser degree than for noradrenergic innervation. Specific binding of muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate and the beta-adrenergic receptor antagonist [3H]dihydroalprenolol was reduced 25% and 29% respectively in treated cortex. Thus, MAM treatment at 15 DG severely reduces intrinsic neuronal populations including GABAergic and glutamatergic neurons, and produces a shrunken cortex relatively hyperinnervated by noradrenergic and cholinergic neurons. MAM-induced microencephaly is a useful model system for producing relatively selective lesions of telencephalic neurons and for study of altered neurochemical relationships following developmentally incurred brain damage.

Acetylcholine↗
PubMed1979

Cooperative interactions at [3H]kainic acid binding sites in rat and human cerebellum.

Inhibition of the specific binding of [3H]kainic acid was studied in membranes isolated from rat and human cerebellum; the sequence of potencies in both species were: kainic acid greater than L-glutamic acid greater than dihydrokainic acid greater than D-glutamic acid. Whereas the Hill coefficient for unlabelled Kainate was 1.0, dihydrokainic acid and D- and L-glutamic acids exhibited negative cooperativity with Hill coefficients of near 0.5. This allosteric interaction of glutamic acid at the kainic acid recognition site suggests a biochemical correlate for the synergistic effects of these compounds in vivo.

Animals↗
PubMed1979

Methylazoxymethanol treatment of fetal rats results in abnormally dense noradrenergic innervation of neocortex.

A single injection of methylazoxymethanol in pregnant rats at 15 days of gestation results in severe cortical atrophy in the offspring. In the adult offspring, the neurochemical markers for the cortical gamma-aminobutyric acid-containing neurons are severely reduced, whereas the noradrenergic markers are minimally altered. Immunohistofluorescence microscopy demonstrates a marked increase in the density of noradrenergic axons which have an abnormal pattern of distribution in the atrophic cortex. The results suggest that the central noradrenergic neurons determine the number of axons to be formed early in brain development, but local factors in the terminal field regulate the ultimate distribution of the noradrenergic axons.

Adrenergic Fibers↗
PubMed1979

Effects of cortical ablation on the neurotoxicity and receptor binding of kainic acid in striatum.

Lesions of the cerebral cortex alter striatal neuronal vulnerability to locally injected kainic acid. Whereas extensive lesions involving the frontal-parietal-occipital cortex are most effective, lesions limited to the frontal or to the dorsal-lateral parietal cortex offer partial protection. The extensive cortical lesions are associated with selective, marked reductions in the presynaptic markers for glutamatergic afferents in striatum. The protective effects of decortication appear between 6 and 24 hours after the lesion and are maintained up to 30 days after decortication. Whereas decortication results in only a transient reduction of specific receptor binding of [3H]kainic acid to striatal membranes, lesion of striatal intrinsic neurons with kainic acid causes a delayed but marked reduction in specific binding of the ligand. Coadministration of L-glutamic acid (1 mumole) with kainic acid (9 nmoles) partially restores the neurotoxic action of kainic acid in the decorticate striatum; GABA, alanine, and proline (1 mumole) are ineffective with regard to restoring kainate's toxicity for striatal GABAergic neurons. These results suggest that afferent input exerts a permissive effect on the neurotoxic action of kainic acid and that neurotoxicity may involve a cooperative interaction between kainic acid at specific receptors on vulnerable neurons and synaptically released endogenous neurotransmitters, in particular L-glutamic acid.

Animals↗
PubMed1979

Evidence for a cholinergic projection to neocortex from neurons in basal forebrain.

Unilateral stereotaxic injection of 3.5 nmol of kainic acid into the ventral globus pallidus of rats reduced biochemical cholinergic neuronal markers by 45-50% and virtually eliminated histochemical staining for acetylcholinesterase in neocortex ipsilateral to the lesion. At the lesion site, the large, multipolar neurons that stain densely for acetylcholinesterase were absent when compared with the uninjected side. Kainate was as effective as electrocoagulation for reducing cholinergic markers although it did not affect aminergic projections ascending through the lesioned area. The conclusion that the cholinergic projection originated in neuronal perikarya at the lesion site was supported by the failure of kainate or electrolytic lesions in contiguous regions to produce similar effects. These studies provide strong evidence for a cholinergic projection to neocortex from neurons in the forebrain in the nucleus basalis.

Acetylcholinesterase↗
PubMed1979

An animal model for Huntington's disease.

In review is concerned with research done on an animal model for the hereditary neuropsychiatric disorder, Huntington's disease (HD). The neuropathology of HD involves primarily a selective degeneration of neurons with cell bodies in the striatum. Injection of kainic acid, a potent neuroexcitant structurally related to glutamic acid, into the rat striatum causes a selective neuronal degeneration resembling that of HD. Striatal cholinergic and GABAergic neurons, including their terminal projections in the substantia nigra, are affected by kainate; dopaminergic axons innervating the striatum as well as corticofugal fibers passing through the region are spared. The striatal kainate lesion has aided in the characterization of the neuronal circuitry in the nigrostriatal axis including the neuronal localization of dopamine-sensitive adenylate cyclase, neuroleptic binding sites, and GABA receptors. Studies in vivo and in vitro with kainate and its analogues suggest that the potent neurotoxicity of kainate involves a cooperative interaction between synaptically released glutamate and injected kainate on vulnerable neurons; prior destruction of cortico-striatal glutamatergic afferents attenuates kainate's neurotoxicity. The kainate model has been used to test drugs that may be of therapeutic benefit for HD. A better understanding of the mechanism of neurotoxicity of kainate may shed light on the cause of neuronal degeneration in HD.

Animals↗
PubMed1978

Effects of anaesthetics and anticonvulsants on the action of kainic acid in the rat hippocampus.

The effects of anaesthetics and anticonvulsants on the acute behavioral response and neurochemical alterations following intrahippocampal injection of kainic acid were examined. When compared to the effects in animals anaesthetized with a combination of chloral hydrate and pentobarbital (Equithesin), brief anaesthesia with ether or with hexobarbital potentiated whereas prolonged anaesthetia attenuated the action of 0.5 microgram of kainic acid. Of the constituents of Equithesin, chloral hydrate offered less protection than pentobarbital. The anticonvulsants, phenobarbital, diazepam, diphenylhydantoin, and carbamazepine offered partial protection when administered in conjunction with ether anaesthetia.

Anesthetics↗