Iontophoretic studies of neurones in the mammalian cerebral cortex

Krnjević, K.; Phillis, John W.

doi:10.1113/jphysiol.1963.sp007057

Cited by 624 publications

(130 citation statements)

References 57 publications

(65 reference statements)

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“…Since the demonstration of the effects of amino acids on motoneurons nearly 20 years ago (1,2), much attention has been given to the possibility that L-glutamate, L-aspartate, and other structurally similar acidic amino acids may function as synaptic transmitters in the vertebrate central nervous system. Exogenously applied L-glutamate has been shown to produce a depolarization or increase in spike firing in neurons from a variety of structures, including the cortex, hippocampus, cochlear nucleus, and thalamus (3).…”

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confidence: 99%

“…Part of the reason for this is that these substances produce effects only at rather high concentrations and are usually nonspecific (6). Neurons depolarized by L-glutamate or by L-aspartate are usually also affected (and at similar concentrations) by D isomers of amino acids and by a large number of structurally similar analogues (2,7). It seems possible that these compounds are not all reacting with the same membrane receptor (7,8), but this notion has been difficult to test critically.…”

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confidence: 99%

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D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

Ishida

Fain

1981

Proc. Natl. Acad. Sci. U.S.A.

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The amino acids L-glutamate and L-aspartate depolarize HI horizontal cells in the perfused goldfish retina but only at millimolar concentrations. The effects of L-glutamate (but not of L-aspartate) are potentiated approximately 15-fold by exposure to D-aspartate. D-Aspartate blocks acidic amino acid uptake in goldfish retina, so that the potentiation ofL-glutamate may be produced by an increase in its effective concentration at the horizontal cell membrane. Because D-aspartate also augments the light responses of horizontal cells, our results are consistent with the possibility that L-glutamate is a neurotransmitter of cone photoreceptors in goldfish.Since the demonstration of the effects of amino acids on motoneurons nearly 20 years ago (1, 2), much attention has been given to the possibility that L-glutamate, L-aspartate, and other structurally similar acidic amino acids may function as synaptic transmitters in the vertebrate central nervous system. Exogenously applied L-glutamate has been shown to produce a depolarization or increase in spike firing in neurons from a variety of structures, including the cortex, hippocampus, cochlear nucleus, and thalamus (3). A Ca2+-dependent release of L-glutamate or L-aspartate has been demonstrated in several preparations, and there is evidence for a Na+-dependent, highaffinity uptake system for acidic amino acids in glia and some neurons (3)(4)(5).In spite of these findings, there is still considerable uncertainty whether L-glutamate or L-aspartate actually functions as a synaptic transmitter in vertebrates. Part of the reason for this is that these substances produce effects only at rather high concentrations and are usually nonspecific (6). Neurons depolarized by L-glutamate or by L-aspartate are usually also affected (and at similar concentrations) by D isomers of amino acids and by a large number of structurally similar analogues (2, 7). It seems possible that these compounds are not all reacting with the same membrane receptor (7,8) The retina offers several advantages for the study of synaptic transmitter mechanisms. Because it is possible in certain poikilotherms to remove the retina from its surrounding tissue and to maintain it in artificial media, it is possible to add amino acids and other drugs directly to the Ringer's solution. This reduces the uncertainty in estimates of drug concentration at the postsynaptic membrane. Furthermore, the retina is considerably simpler in structure than most of the rest of the central nervous system and has been extensively studied, both anatomically and physiologically (9). This is especially true for the outer plexiform layer, where photoreceptors synapse onto two kinds of secondorder cells, the horizontal cell and the bipolar cell (10).In this study we describe the effects of amino acids on one of the types of horizontal cells in the goldfish retina. This cell, called the H1 (or luminosity-type) cell, receives most of its synaptic input from the cone photoreceptors, predominantly those containing the red-sensitive p...

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confidence: 99%

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confidence: 99%

D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

Ishida

Fain

1981

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast to other hypotheses such as the ammonia [2,7,8,11], the synergistic neurotoxins [7,8], and the false neurotransmitter [12][13][14] hypotheses, in which the neural mechanisms responsible for inducing encephalopathy have not been precisely defined, an attractive feature of the GABA hypothesis is that the neural mechanisms responsible for mediating neural inhibition when the GABA neurotransmitter system is stimulated are well characterized [18][19][20][21][22][23][24]29]. Furthermore, some recent experimental data provide no support for the ammonia, the synergistic neurotoxins, and the false.neurotransmitter hypotheses.…”

Section: Concluding Perspectives and Speculationsmentioning

confidence: 99%

“…It induces acute liver failure, followed by hepatic encephalopathy, hepatic coma, and death. The model fulfills the requirements of an appropriate animal model of hepatic encephalopathy [27] [29], but, in a potentially important study conducted by Smialowski [30], it was shown that GABA can probably induce coma as well. Within ten seconds of the instillation of less than 1 itmole of GABA into the hippocampal region of conscious rabbits the animals "became quiet; the spontaneous locomotor activity declined and the animals mostly lay on the cage floor."…”

Section: Introductionmentioning

confidence: 99%

The GABA Hypothesis of the Pathogenesis of Hepatic Encephalopathy: Current Status

Jones

Schafer

Ferenci

et al. 1987

Assessment and Management of Hepatobiliary Disease

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Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian brain, can induce coma. Outside the central nervous system it is synthesized by gut bacteria and catabolized largely in the liver. GABA and its agonists, as well as benzodiazepines and barbiturates, induce neural inhibition as a consequence of their interaction with specific binding sites for each of these classes of neuroactive substances on the GABA receptor complex of postsynaptic neurons. In a rabbit model of acute liver failure: (i) the pattern of postsynaptic neuronal activity in hepatic coma, as assessed by visual evoked potentials, is identical to that associated with coma induced by drugs which activate the GABA neurotransmitter system (benzodiazepines, barbiturates, and GABA agonists); (ii) the levels of GABA-like activity in peripheral blood plasma increase appreciably before the onset of hepatic encephalopathy, due at least in part to impaired hepatic extraction of gut-derived GABA from portal venous blood;(iii) the blood-brain barrier becomes abnormally permeable to an isomer of GABA, a-aminoisobutyric acid, before the onset of hepatic encephalopathy; and (iv) hepatic coma is associated with an increase in the density of receptors for GABA and benzodiazepines in the brain. These findings are the bases of the following hypotheses: (i) when the liver fails, gut-derived GABA in plasma crosses an abnormally permeable blood-brain barrier and by mediating neural inhibition contributes to hepatic encephalopathy; (ii) an increased number of GABA receptors in the brain found in liver failure increases the sensitivity of the brain to GABA-ergic neural inhibition; and (iii) an increased number of drug binding sites mediates the increased sensitivity to benzodiazepines and barbiturates observed in liver failure by permitting increased drug effect. INTRODUCTIONHepatocellular failure, whether acute or chronic, is characterized by jaundice, fluid retention, a hemorrhagic diathesis, and hepatic encephalopathy [1]. Of these four complications of liver disease the pathogenesis of hepatic encephalopathy is least well understood. It has not even been established whether hepatic encephalopathy occurs as a result of failure of the liver to synthesize a substance that is necessary for the maintenance of normal brain function or failure of the liver to metabolize adequately neuroactive substances that are capable of inducing encephalopathy.

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“…The release of acetylcholine from the surface of the brain was first demonstrated by Macintosh and Oborin (2) and later Collier and Mitchell (3,4) and Mitchell (5) showed that afferent stimulation increases the output of acetylcholine from the somatosensory cortex. Recent experiments have proved that some nerve cells in the mammalian cortex can be excited by acetylcholine applied directly from micropipettes (6)(7)(8)(9).<BR> Another approach to the cortical cholinergic mechanism has been made by studying the effect of topically applied cholinomimetic drugs on the somatosensory evoked potentials (10). Cortical application of cerebro-spinal fluid (CSF) containing various concentrations of acetylcholine or eserine has been shown to increase the amplitude of the repetitive after discharges of the somatosensory evoked potentials.…”

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Effect of Carbachol on the Somatosensory Evoked Potentials in the Rat

Bhargava

1971

Jpn.J.Pharmacol

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Iontophoretic studies of neurones in the mammalian cerebral cortex

Cited by 624 publications

References 57 publications

D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

D-aspartate potentiates the effects of L-glutamate on horizontal cells in goldfish retina.

The GABA Hypothesis of the Pathogenesis of Hepatic Encephalopathy: Current Status

Effect of Carbachol on the Somatosensory Evoked Potentials in the Rat

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