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Biomedical subjects

D R Curtis

Publications and source records attributed to D R Curtis.

At least 55 records · Page 3Linked to original sources
PubMed1984

The effect of GABA on the terminations of vestibulospinal neurons in the cat spinal cord.

Although GABA and piperidine-4-sulphonate depolarize Ia afferent terminations in the lumbar spinal cord by activation of bicuculline-sensitive GABA receptors, no evidence was obtained for a bicuculline-sensitive alteration by either GABAmimetic of the excitability of vestibulospinal terminations. This suggests that the terminal arborizations of vestibulospinal fibers, unlike their cell bodies, are devoid of GABA receptors having properties similar to those on either central neuron cell bodies, primary afferent cell bodies or their central terminations.

Animals↗
PubMed1984

Ibotenic acid analogues. Synthesis and biological and in vitro activity of conformationally restricted agonists at central excitatory amino acid receptors.

A number of analogues of ibotenic acid [(RS)-3-hydroxy-5- isoxazoleglycine ] were synthesized; they were tested as excitants on neurons in the cat spinal cord, by using microelectrophoretic techniques, and as inhibitors of the binding of kainic acid (KA) in vitro, by using synaptic membranes prepared from rat brains. The excitatory effects of the 3- isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5, 4-c]pyridine-7-carboxylic acid (4, 7- HPCA ), (RS)-alpha-amino-3-hydroxy-5,6-dihydro-4H- cyclohept [1,2-d] isoxa zole - 8-propionic acid (8, 8- AHCP ), (RS)-alpha-amino-3- hydroxy-7,8-dihydro-6H- cyclohept [1,2-d] isoxazole -4-propionic acid (12, 4- AHCP ), and (RS)-alpha-(methylamino)-3-hydroxy-5-methyl- 4- isoxazolepropionic acid (15, N-Me-AMPA) were shown to be sensitive to (S)-glutamic acid diethyl ester (GDEE), an antagonist at quisqualic acid ( QUIS ) receptors, and insensitive to (RS)-2-amino-5-phosphonovaleric acid ( 2APV ), an antagonist at N-methyl-(R)-aspartic acid (NMDA) receptors. The compounds 4 and 12 proved to be particularly potent agonists at the former class of receptor, assumed to represent physiological glutamic acid receptors. The amino acids (RS)-beta-(2-carboxyphenyl)alanine (19), an analogue of 12, and (RS)-2-(3-carboxyphenyl) glycine were weak GDEE-sensitive excitants with potencies comparable with that of 8. All of the compounds were tested as inhibitors of KA binding. With the exception of 12 and 19, which showed very low affinity for the KA binding sites, the compounds studied were inactive in this in vitro test system.

Animals↗
PubMed1984

Depolarization of feline primary afferent fibres by acidic amino acids.

When administered micro-electrophoretically into the spinal grey matter of cats anaesthetized with pentobarbitone, acidic amino acids known to be neuronal excitants lower the threshold of electrically stimulated muscle and cutaneous primary afferent fibres and terminations. This depolarizing effect was not observed with fibres stimulated in the white matter. Depolarization by micro-electrophoretic potassium and excitant amino acids appeared not be be associated with an alteration in terminal membrane conductance since there was no change in synaptically evoked primary afferent depolarization. Excitant amino acid depolarization was not blocked by the gamma-aminobutyric acid antagonist bicuculline methochloride, but was reduced by selective excitant amino acid antagonists. The results are discussed in relation to the probable absence of specific excitant amino acid receptors on afferent terminals, the depolarizing effect of the amino acids on myelinated fibres and non-myelinated terminals being more likely a consequence of changes in the extracellular medium associated with the depolarization and firing of neurones.

Action Potentials↗
PubMed1983

Antagonists of synaptic and amino acid excitation of neurones in the cat spinal cord.

In the spinal cord of the anaesthetized cat microelectrophoretically administered (+/-)-cis-2,3-piperidine dicarboxylate (2,3-PDA), (+/-)-cis-2,5-piperidine dicarboxylate (2,5-PDA), gamma-D-glutamylglycine (gamma DGG), beta-D-aspartyl-beta-alanine (beta DAA), (+/-)-2-amino-4-phosphonobutyrate (2-APB), (+/-)-2-amino-5-phosphonovalerate (2-APV) and (+/-)-2-amino-7-phosphonoheptanoate (2-APH) were assessed as antagonists of chemical excitation of dorsal horn interneurones and Renshaw cells by N-methyl-D-aspartate (NMDA), L-aspartate, quisqualate (QUIS), kainate and L-glutamate, and of monosynaptic and polysynaptic excitation by impulses in primary afferent fibres of muscle and cutaneous origin. Whereas polysynaptic excitation of interneurones was readily and reversibly depressed by 2-APV, 2-APH, beta DAA, gamma DGG and 2,3-PDA, all of which also reduced excitation by NMDA (and L-aspartate) more than that by QUIS (and L-glutamate), no selective antagonism of monosynaptic excitation could be demonstrated. In particular, 2,3-PDA, which depressed excitation by kainate to a greater extent than that by either QUIS or NMDA, appeared to have no effect on monosynaptic excitation. The results support the involvement of L-aspartate as the transmitter of some spinal excitatory interneurones, but none of the antagonists tested were considered suitable for assessing the role of L-glutamate as the transmitter of some spinal primary afferent fibres.

Amino Acids↗
PubMed1983

Post-excitatory depression of neuronal firing by acidic amino acids and acetylcholine in the cat spinal cord.

In the spinal cord of cats anaesthetized with pentobarbitone, the excitation of interneurones and Renshaw cells by acidic amino acids or acetylcholine (Renshaw cells) is followed by a period of depressed excitability. This depression appears to be the consequence of prolonged repetitive firing rather than of the enzymic or chemical conversion of the excitants to neuronal depressants.

Acetylcholine↗
PubMed1983

Effects of noradrenaline and 5-hydroxytryptamine on spinal Ia afferent terminations.

When administered microelectrophoretically, noradrenaline (NA) and 5-hydroxytryptamine (5-HT) increased the thresholds of the terminal portions of extensor muscle Ia afferents stimulated extracellularly near lumbar motoneurons of anesthetized cats. This effect, and the concomitant increase in the electrical resistance of the extracellular medium near the orifices of multibarrel micropipettes, could be reversibly altered by ouabain. The results suggest further evidence is required of a direct effect of these amines at transmitter-related receptors on Ia terminations since the observed increase in threshold may be indirect, resulting from the sodium-dependent uptake of the administered amines by neurons and glia.

Afferent Pathways↗
PubMed1983

The structure of bovine rhodopsin.

We have isolated 16 peptides from a cyanogen bromide digest of rhodopsin. These cyanogen bromide peptides account for the complete composition of the protein. Methionine-containing peptides from other chemical and enzymatic digests of rhodopsin have allowed us to place the cyanogen bromide peptides in order, yielding the sequence of the protein. We have completed the sequence of most of the cyanogen bromide peptides. This information, in conjunction with that from other laboratories, forms the basis for our prediction of the secondary structure of the protein and how it may be arranged in the disk membrane.

Amino Acid Sequence↗
PubMed1983

Actions of midazolam in the spinal cord of the cat.

Midazolam, which induces anaesthesia in humans at intravenous doses of 0.3 mg/kg, did not anaesthetize cats at doses of 20 mg/kg. Nevertheless, intravenous doses as small as 0.3 mg/kg enhanced spinal primary afferent depolarization and presynaptic inhibition of spinal monosynaptic reflexes, and both intravenous and microelectrophoretic administration of midazolam enhanced the inhibitory effect of GABA on spinal neurones and the depolarization of Ia afferent terminations by GABA and piperidine-4-sulphonate. Some degree of specificity was demonstrated for the inhibitory effect of GABA in relation to those of glycine and noradrenaline, and the enhancement by midazolam of inhibition by GABA was blocked by R015-1788, which alone was inactive. Although these results are consistent with proposals that depressant benzodiazepines enhance the effectiveness of GABA as a central transmitter, such an effect alone may not fully account for the anaesthesia produced by midazolam in humans.

Afferent Pathways↗
PubMed1983

4,5,6,7-Tetrahydroisothiazolo[5,4-c]pyridin-3-ol and related analogues of THIP. Synthesis and biological activity.

The thio analogues of the GABA (gamma-aminobutyric acid) agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), the GABA uptake inhibitor THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol), and the glycine antagonist THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) have been synthesized and tested biologically on single neurons in the cat spinal cord and in vitro by using synaptic membrane preparations obtained from rat brains. In contrast to THIP, thio-THIP (4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-ol, 5) was only a weak GABA agonist. Thio-THPO (4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol, 10) was slightly weaker than THPO as an inhibitor of GABA uptake in vitro, and these two compounds were approximately equipotent in enhancing the inhibition of the firing of cat spinal neurons by GABA. Like THAZ and structurally related bicyclic isoxazole zwitterions, thio-THAZ (5,6,7,8-tetrahydro-4H-isothiazolo[4,5-d]azepin-3-ol, 15) was an antagonist at glycine receptors on cat spinal neurons. The I/U ratios, which reflect the ability of neutral amino acids to penetrate the blood-brain barrier (BBB), were calculated for 5 (I/U = 16), 10 (63), and 15 (200). These low I/U ratios, compared with the findings that THIP (I/U = 500 or 1500) and THPO (I/U = 2500) enter the brain after systemic administration, suggest that the thio analogues may penetrate the BBB very easily.

Animals↗
PubMed1983

Preparation of peptides containing any desired amino acid: methionyl peptides of bovine rhodopsin.

A general method is described which allows the identification and preparation of peptides containing any amino acid of interest. The method has been applied to isolation of the methionyl peptides from a peptic digest of oxidized bovine rhodopsin. The peptide digestion mixture is first partially separated by ion exchange column chromatography. Location of peptides containing the desired amino acid is performed by amino acid analysis of acid hydrolyzed column fractions by high voltage paper electrophoresis. Peptides are further purified and prepared by peptide mapping, elution, and amino acid analysis using inexpensive high capacity techniques. Peptide sequencing is performed by a manual dansyl-Edman method well adapted for rapidly processing large numbers of samples. The methods are particularly well suited for detection and preparation of peptides containing amino acids for which there is no specific detection method.

Amino Acid Sequence↗
PubMed1983

Spinal interneurone depression by DS103-282.

The depressant effect of 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiodiazole (DS103-282) on the polysynaptic excitation of interneurones in the cat spinal cord appears to be related to a postsynaptic reduction in the effectiveness of excitatory transmitters than to interference with their presynaptic release.

Amino Acids↗
PubMed1982

Glutamic acid agonists. Stereochemical and conformational studies of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and related compounds.

Microelectrophoretic techniques were used to study the effects of the optical isomers of the L-glutamic acid (GLUT) agonist AMPA on cat spinal neurones. Both enantiomers excited spinal interneurones, L-AMPA being more potent than D-AMPA, and, like GLUT, this excitation was blocked by L-glutamic acid diethyl ester but not by 2-amino-5-phosphonovaleric acid. ATPA and ABPA, in which the methyl group of AMPA was replaced by more bulky substituents, were also GLUT agonists, although weaker than AMPA. O-methyl-AMPA was inactive, suggesting that a necessary condition for GLUT agonist or antagonist actions of this class of compound is the presence of an acidic group in the position equivalent with the omega-position of GLUT.

2-Amino-5-phosphonovalerate↗
PubMed1982

The depolarization of feline ventral horn group Ia spinal afferent terminations by GABA.

The unmyelinated terminal regions of extensor muscle Ia afferent fibres were stimulated electrically near lumbar motoneurones in anaesthetised cats using 300 microseconds pulses of less than 1 microA passed through the central NaCl barrel of seven barrel micropipettes. Such terminations were identified by anodal blocking factors of less than four and the latency of the antidromic impulse recorded in the appropriate peripheral muscle nerve. Although the effects of microelectrophoretically administered GABA were occasionally complex, the most consistent finding was a reduction in termination threshold followed by an increase. Both this reduction in threshold by GABA, and that produced by tetanic stimulation of low threshold flexor afferents (PAD) were diminished by microelectrophoretic bicuculline methochloride. This GABA antagonist alone elevated the threshold of some terminations but did not reduce the depolarizing action of either potassium or L-glutamate. Furthermore, since reductions in threshold by GABA, but not by either potassium or L-glutamate, were associated with a decrease in PAD, GABA appears to increase terminal membrane conductance. Since neither GABA nor bicuculline methochloride influenced the threshold or afferent depolarization of non-terminal regions of Ia fibres, there results are consistent with the function of GABA as a depolarizing transmitter at gabergic axoaxonic synapses upon the terminals of Ia afferent fibres synapsing with motoneurones.

Afferent Pathways↗
PubMed1982

The dual effects of GABA and related amino acids on the electrical threshold of ventral horn group Ia afferent terminations in the cat.

Amino acids were administered microelectrophoretically near the unmyelinated terminations of extensor muscle Ia afferent terminations stimulated electrically in the vicinity of lumbar motoneurones in anaesthetized cats. The predominant effect of one group (structurally related to GABA, poor substrates for in vitro amino acid uptake systems) was a reduction in the threshold (depolarization). The second group (including GABA and structural analogues which are substrates for GABA transport systems in vitro) had biphasic effects, an initial reduction being followed by an increase in threshold. The third group (structurally unrelated to GABA, substrates for amino acid uptake systems) only increased Ia termination thresholds. Reductions in termination thresholds, but not increases, were associated with diminution of synaptically evoked primary afferent depolarization, and were decreased by bicuculline methochloride. Many amino acids increased the electrical resistance of the intraspinal medium near the orifices of the barrels of seven barrel micropipettes, and for L-histidine, one of the third group of amino acids, both this effect and the increased threshold of terminations were reversibly modified by microelectrophoretic ouabain. These observations suggest that GABA-mimetics depolarize Ia terminations by interacting with bicuculline-sensitive receptors similar to those at hyperpolarizing gabergic synapses upon spinal interneurones. In addition, under the experimental conditions used, these and other amino acids increase termination thresholds, probably in the absence of any change in membrane conductance, an effect resulting from alterations in the ionic constitution of the extracellular medium around the orifices of micropipettes ejecting amino acids consequent upon the ouabain-sensitive co-transport of amino acids and sodium ions into neurones and glia.

Afferent Pathways↗