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Biomedical subjects

R A Nicoll

Publications and source records attributed to R A Nicoll.

At least 19 recordsLinked to original sources
PubMed1992

Postsynaptic action of endogenous GABA released by nipecotic acid in the hippocampus.

Intracellular and whole-cell recording from CA1 pyramidal cells and dentate granule cells was used to study the release of endogenous GABA by nipecotic acid. Local application of nipecotic acid produced responses that could be entirely blocked by a combination of the GABAA receptor antagonist picrotoxin and the GABAB receptor antagonist CGP 35348. These responses were due to the heteroexchange release of endogenous GABA because they were blocked by low Na+ which blocks the GABA transporter and by SKF 89976 which is a competitive antagonist of the GABA transporter. Local application of nipecotic acid could, depending on the location, evoke pure GABAA or pure GABAB responses supporting proposals that GABAA and GABAB receptors can be segregated at separate inhibitory synapses.

Animals↗
PubMed1992

Long-term potentiation is associated with increases in quantal content and quantal amplitude.

Long-term potentiation (LTP) of synaptic transmission in CA1 neurons of the hippocampus, elicited by the conjunction of presynaptic firing and postsynaptic depolarization, is an important model of plasticity, which may underlie memory storage. Although induction of LTP takes place in the postsynaptic cell, it is not clear whether it is expressed through an enhancement of transmitter release or through an increased postsynaptic response to the same amount of transmitter. Analysis of the trial-to-trial amplitude fluctuations of synaptic signals, that is quantal analysis, gives an important insight into the probabilistic mechanisms of transmission, although attempts to apply it to the mode of expression of LTP have so far yielded inconsistent results, at least in part because they have relied on models of transmitter release that have not been confirmed experimentally. Here we report clear evidence for quantal fluctuation in a subset of cells. Induction of LTP in these cells causes abrupt increases in either quantal content or quantal amplitude, or both. This shows that two different mechanisms can underlie the maintenance of LTP.

Animals↗
PubMed1992

Mossy fiber long-term potentiation shows specificity but no apparent cooperativity.

Specificity in long-term potentiation (LTP) means that synapses onto a postsynaptic cell can potentiate independently of one another. Cooperativity refers to a requirement that some threshold number of afferents be co-activated to evoke LTP with a high-frequency stimulus. The induction of long-term potentiation (LTP) at the associational/commissural synapses onto hippocampal CA3 pyramidal cells shows clear cooperativity. LTP of mossy fiber inputs to these cells does not. Mossy fiber LTP does show synapse specificity. These results bear on the cellular mechanisms and the functions of mossy fiber LTP.

2-Amino-5-phosphonovalerate↗
PubMed1992

Postsynaptic contribution to long-term potentiation revealed by the analysis of miniature synaptic currents.

Miniature excitatory synaptic currents were recorded from CA1 pyramidal cells in hippocampal slices to study the site of the persistent change in synaptic efficacy during long-term potentiation. Induction of long-term potentiation produced a large increase in the amplitude of these currents. Such a change in amplitude suggests an increase in postsynaptic transmitter sensitivity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Pharmacological characterization of GABAB-mediated responses in the CA1 region of the rat hippocampal slice.

It is generally accepted that the bicuculline-resistant responses to GABA are mediated through the activation of GABAB receptors that mediate a slow IPSP. However, a number of reported observations are difficult to reconcile with this model. Specifically, GABAB antagonists only partially block bicuculline-resistant GABA responses, and both 4-aminopyridine (4-AP) and carbachol have been reported to block responses to the selective GABAB agonist baclofen, but not GABA itself. Thus, it has been argued that baclofen and GABA increase potassium conductance through separate receptor mechanisms. This suggestion is not easily reconcilable with the postulated physiological role of GABAB receptors in mediating the slow IPSP. We have addressed these discrepancies by using the new GABAB antagonists 2-hydroxy-saclofen (2-OH-SAC) and CGP 35348 in the presence of the GABA uptake inhibitor SKF 89976A. The weak antagonism of 2-OH-SAC against the bicuculline-resistant GABA response was improved when the GABA uptake was inhibited with SKF 89976A, allowing for the application of lower GABA concentrations. Under these circumstances, 2-OH-SAC and CGP 35348 strongly antagonized GABA and baclofen responses, but did not have any effect on outward currents evoked by 5-HT. The slow IPSP evoked in the presence of glutamate antagonists was reversibly inhibited by CGP 35348 (IC50 = 14 microM), without affecting the fast IPSP. Carbachol (0.3-20 microM) had no effect on outward currents evoked by either baclofen or GABA. 4-AP (5 microM to 1 mM), despite causing a large increase in cell excitability, did not change baclofen responses. Higher concentrations of 4-AP (5 mM) induced inward current, and reduced both baclofen and GABA outward currents to a similar extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Dorsal root potentials and changes in extracellular potassium in the spinal cord of the frog.

1. In the present study changes in extracellular potassium, ([K]e), were recorded in the isolated spinal cord of the frog with glial cell recordings and K-selective micro-electrodes to test the hypothesis that elevations in [K]e during neuronal activity produce the dorsal root potential (d.r.p.). 2. Sucrose gap recording from the dorsal root (d.r.) was used to record responses to root stimulation and to exogenously applied K+. 3. Stimulation of the ventral root, which elicits a d.r.p. in the frog spinal cord, was not associated with any change in [K]e, suggesting that d.r.p.s produced by ventral root stimulation are not due to changes in [K]e. 4. The largest change in [K]e observed following single stimuli to the dorsal root was 0.4 mM. Such a change in [K]e, if evenly distributed, would depolarize the dorsal root by about 1 mV and yet the simultaneously recorded d.r.p. evoked by stimulating an adjacent dorsal root (d.r.-d.r.p.) was over 10 mV. 5. The time-to-peak of the glidal cell responses was 10 times that of the d.r.-d.r.p. Low frequency (1-10 Hz) d.r. stimulation caused a decremental summation of glial cell responses, while there was no summation in the d.r.-d.r.p. These results suggest that the d.r.p. produced by single d.r. stimulation is generated in large part by a mechanism other than a change in [K]e. 6. During high frequency d.r. stimulation, which evoked 6-8 mM increases in [K]e, the adjacent d.r. was depolarized to a greater extent than that produced by single stimuli. The magnitude of this depolarization was similar to that produced by applying a [K]e equivalent to that observed in the spinal cord during high frequency stimulation. Thus, a substantial component of the sustained d.r. depolarization during high frequency d.r. stimulation may result from changes in [K]e. 7. In the presence of magnesium, high frequency d.r. stimulation evoked a picrotoxin resistant depolarization of an adjacent d.r. whose magnitude correlated well with the changes in [K]e recorded in the spinal cord. 8. In the presence of picrotoxin a slow, long duration depolarization of the d.r. occurred following single stimuli to the adjacent d.r. and the appearance and time course of this response correlated well with the time course of changes in [K]e. 9. Addition of K+ to the Ringer solution in concentrations up to 12 mM had a facilitatory action on reflex activity in the frog spinal cord. 10 The present results suggest that although changes in [K]e play a relatively minor role in generating d.r.p.s. elicited by single d.r. stimulation, the sustained dorsal root depolarization evoked either by high frequency stimulation or by single stimuli in the presence of picrotoxin may be due to a considerable extent to [K]e.

Animals↗
PubMed1978

Pentobarbital: differential postsynaptic actions on sympathetic ganglion cells.

The frog sympathetic ganglion has been used as a model to elucidate the cellular mechanism of barbiturate anesthesia. Anesthetic concentrations of pentobarbital markedly reduced the fast nicotinic excitatory postsynaptic potential while having no effect on the slow excitatory postsynaptic potential or slow inhibitory postsynaptic potential, even though all three synaptic potentials depend on the presynaptic release of acetylcholine. A similar differential effect was seen for nicotinic and muscarinic responses to exogenously applied agonists, while the depolarizing action of gamma-aminobutyric acid (GABA) was enhanced. These results indicate that pentobarbital has remarkably selective actions on the sympathetic ganglion and further indicate that blockade of ganglionic transmission by anesthetic concentrations of pentobarbital can be entirely explained by a postsynaptic action. The present results strengthen the concept that pentobarbital anesthesia results from a postsynaptic blockade of central excitatory synapses which increase sodium conductance coupled with a postsynaptic enhancement of GABA-mediated synaptic inhibition.

Animals↗
PubMed1978

The blockade of GABA mediated responses in the frog spinal cord by ammonium ions and furosemide.

1. A variety of compounds which are known to block chloride transport in a variety of systems have been examined for their effects on amino acid and synaptic responses in the frog spinal cord in vitro. 2. A number of monocarboxylic aromatic acids, copper sulphate, and acetazolamide had no effect on any of the responses. 3. Ammonium ions blocked the motoneurone hyperpolarizing responses to all the neutral amino acids. In addition it selectively blocked dorsal root potentials and the action of GABA and beta-alanine on primary afferents. 5. Intracellular recording from dorsal root ganglion cells demonstrated that furosemide had little effect on the reversal potential for the GABA response. These results suggest that furosemide acts primarily by blocking the conductance increase elicited by GABA. 6. The results with furosemide provide indirect evidence that chloride ions are involved in generating the GABA depolarizations of primary afferent terminals and dorsal root potentials.

Alanine↗
PubMed1978

The action of thyrotropin-releasing hormone, substance P and related peptides on frog spinal motoneurons.

The isolated, hemisected spinal cord of the frog has been used to examine the action of peptides on frogs motoneurons. Both sucrose gap recording from the ventral roots and intracellular microelectrode recording were used. Substance P (SP), thyrotropin-releasing hormone (TRH), neurotensin and bombesin all had a depolarizing action. The responses to neurotensin and bombesin were blocked by tetrodotoxin suggesting that their action was indirectly mediated through interneurons. SP and TRH had a direct depolarizing action on motoneurons. SP was slightly more active and TRH slightly less active than glutamate. The responses to both peptides had a slower time course than the responses to glutamate. The maximum depolarizations produced by the peptides rarely surpassed the firing threshold of the motoneurons. However, their excitability was increased, since subthreshold synaptic potentials and responses to current injection surpassed threshold during the peptide responses. In approximately half of the cells tested, a small decrease in membrane resistance could be detected during the peptide responses. These results suggest that if SP and TRH were released from synapses impinging on frog motoneurons they would exert a background excitatory action.

Action Potentials↗
PubMed1977

Neuronal actions of endorphins and enkephalins among brain regions: a comparative microiontophoretic study.

The brain peptides alpha- and beta-endorphin, leucine- and methionine-enkephalin, as well as the opiate normorphine, have been evaluated by microiontophoresis for their effects on neuronal activity in several regions of the rat brain. In cerebral cortex, brainstem, caudate nucleus, and thalamus, most responsive cells were inhibited by the peptides and by normorphine, while in hippocampus all responsive cells were excited. Both inhibitory and excitatory responses were blocked by the narcotic antagonist naloxone. Occurrence of responsive cells encountered in a particular region was loosely correlated with density of stereospecific opiate binding sites as reported by others. These results are consistent with the hypothesis that the endorphins and enkephalins may represent a new class of central neurotransmitters; among other functions, these peptides may play a role in the regulation of behavior and the expression of psychopharmacological agents such as the opiate alkaloids.

Animals↗
PubMed1977

The effect of conformationally restricted amino acid. Analogues on the frog spinal cord in vitro.

1 The isolated spinal cord of the frog (Rana pipiens) was used to examine the structural requirement for the activity of neutral amino acids. The potencies of the aliphatic amino acids, gamma-aminobutyric acid (GABA), beta-alanine and glycine were compared with the potencies of conformationally restricted cyclopentane and cyclohexane amino acid analogues. Both motoneurone hyperpolarizing and primary afferent depolarizing activity were examined in this study. 2 On motoneurones beta-alanine was the most potent aliphatic amino acid and glycine the least potent. Of the substituted aminocyclopentane carboxylic acids, that compound with a separation of amino and carboxylic acid groups closest to that of the extended GABA molecule (4.74 A) had a potency similar to GABA. As the separation decreased the hyperpolarizing activity fell off rapidly. The substituted aminocyclohexane carboxylic acids were generally inactive even at a concentration of 10 mM. 3 Strychnine blocked the motoneurone hyperpolarizing responses to all compounds with a distance between the amino and carboxylic acid groups of 3.66 A or less, but did not block the response of compounds with a distance of 4.08 A or greater. Picrotoxin and bicuculline antagonized all the responses to varying degrees and therefore were of little value in characterizing the responses. 4 On the primary afferents GABA was the most potent aliphatic amino acid and glycine the least potent. The substituted aminocyclohexane carboxylic acids were generally inactive on primary afferents. The response of the substituted aminocyclopentane carboxylic acid whose separation of amino and carboxylic acid groups was closest to that of the extended GABA molecule was most similar to the GABA response. However, (+/-)-cis-3-aminocyclopentane-carboxylic acid (separation=4.08 A),which mimicked the action of GABA on motoneurones, closely mimicked the depolarizing action of beta-alanine on primary afferents. 5 The findings suggest that the hyperpolarizing GABA receptor on motoneurones will accept a molecule whose amino and carboxylic acid groups are separated by a distance of 4.08 A or greater while the glycine receptor will accept a compound with a distance of 3.66 A or less. The depolarizing GABA receptors on primary afferents appear to be more selective since they are not activated by (+/-)-cis-3-aminocyclopentane carboxylic acid (separation = 4.08 A), while the motoneurone receptors are.

Action Potentials↗