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D R Curtis

Publications and source records attributed to D R Curtis.

At least 73 records · Page 4Linked to original sources
PubMed1982

Glycine antagonists structurally related to muscimol, THIP, or isoguvacine.

Microelectrophoretic methods were used to study the effects on cat spinal neurones of a number of compounds structurally related to the gamma-aminobutyric acid (GABA) agonists muscimol, THIP, and isoguvacine. While N-methylmuscimol was an agonist at bicuculline methochloride-sensitive GABA receptors, somewhat weaker than GABA and THIP, neither N,N-dimethylmuscimol nor N-methyl-THIP interfered significantly with GABA receptors in vivo or binding sites in vitro. Both N,N-dimethylmuscimol and N-methyl-THIP, however, reversibly antagonized the depressant action of glycine. The seven-membered ring analogues of THIP, namely THIA (5,6,7,8-tetrahydro-4H-isoxazolo[5,4-c]azepin-3-ol), THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) and iso-THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol), also blocked neuronal inhibition by glycine, iso-THAZ being the most potent compound. The conformationally mobile isomer of THAZ and iso-THAZ, 3-PYOL (5-(3-pyrrolidinyl)-3-isoxazolol), was a much less selective glycine antagonist, being also an antagonist of GABA, 3,4-TAZA (2,5,6,7-tetrahydro-1H-azepine-4-carboxylic acid) and 4,5-TAZA (2,3,6,7-tetrahydro-1H-azepine-4-carboxylic acid), which are amino acid analogues of THIA and THAZ, respectively, and ring homologues of isoguvacine, were also shown to be glycine antagonists. The mechanism of action of the present class of zwitterionic glycine antagonists is unknown. The compounds are much less potent than strychnine.

Animals↗
PubMed1981

Selective effects of (-)-baclofen on spinal synaptic transmission in the cat.

When ejected microelectrophoretically near spinal interneurones of cats anaesthetised with pentobarbitone and under conditions where postsynaptic excitability was maintained artificially at a constant level, (-), but not (+), -baclofen selectively reduced monosynaptic excitation by impulses in low threshold muscle (Ia and Ib) and cutaneous (Aalpha) afferents. Polysynaptic excitation of interneurones and Renshaw cells by impulses in higher threshold afferents was less affected, and baclofen had little or no effect on the cholinergic monosynaptic excitation of Renshaw cells. Glycinergic and gabergic inhibitions of spinal neurones were relatively insensitive to baclofen. These stereospecific actions of baclofen, produced by either a reduction in the release of excitatory transmitter or postsynaptic antagonism, suggest that Ia, Ib, and Aalpha afferents may release the same excitatory transmitter which differs from that of spinal excitatory interneurones. Microelectrophoretic (-), but not (+), -baclofen also reduced primary afferent depolarization of ventral horn Ia extensor afferent terminations produced by impulses in low threshold flexor afferents, without altering either the electrical excitability of the terminations or their depolarization by electrophoretic GABA or L-glutamate. This stereospecific action of baclofen is interpreted as a reduction in the release of GABA at depolarizing axo-axonic synapses on Ia terminals.

Action Potentials↗
PubMed1980

Cyclobutane analogs of GABA.

Both cis- and trans-3-aminocyclobutane-1-carboxylic acid have been synthesized as conformationally restricted analogs of GABA. The cis isomer displayed weak to moderate GABA-like activity with respect to (1) inhibition of GABA uptake in rat brain minislices, (2) inhibition of sodium-independent binding of GABA to rat brain membranes, (3) activity as a substrate for GABA aminotransferase. and (4) depression of the firing rate of cat spinal neurons in vivo. The trans isomer was less effective on all four assays. The results has been interpreted in terms of the conformational "pinning back" of the polar groups by the cyclobutane ring in the trans GABA analog so that unfavorable steric interactions would occur between one of the methylene groups and a region of steric hindrance at the active sites for particular GABA processes.

4-Aminobutyrate Transaminase↗
PubMed1980

Selective antagonist activity of 5-aminohex-2-enedioic acid on amino acid excitation of cat spinal neurones.

D- and L-5-aminohex-2-enedioic acid (AHED) and the DL-2-bromo derivative, which are conformationally restricted analogues of the excitatory amino acid antagonist D-alpha-aminoadipic acid (D alpha AA), were tested microelectrophoretically on cat spinal neurones. D-AHED reduced the excitatory action of N-methyl-D-aspartate (NMDA) to a greater extent than that of L-glutamate and the potency of this action was a half to a third that of D alpha AA. The DL-2-bromo derivative excited neurons, an effect greater than that of L-glutamate and not blocked by either D alpha AA or L-glutamic acid diethyl ester.

2-Aminoadipic Acid↗
PubMed1979

A method for continuously monitoring the electrical threshold of single intraspinal nerve fibers.

A method is described for the determination and continuous monitoring of the electrical threshold of single primary afferent fibres within the spinal cord of the cat. The centre barrels of multibarrel micropipettes, filled with 3.6 M NaCl, were used as stimulating electrodes, impulses in single afferents were recorded peripherally and a firing index of 50% was maintained by using a feedback circuit to regulate the amplitude of the stimulating pulses (0.2-0.3 msec duration, less than 2 microA).

Animals↗
PubMed1979

Kainate neurotoxicity and glutamate inactivation.

Dihydrokainate, an inhibitor of high affinity L-glutamate as an excitant of cat spinal neurones in vivo. This action of dihydrokainate was selective in that the effects of excitants taken up actively in vitro by CNS tissue (L-aspartate, D- and L-glutamate and L-homocysteate) were enhanced whereas those of other substances not taken up (acetylcholine, D-homocysteate, kainate and N-methyl-D-aspartate) were not. Since kainate and dihydrokainate have similar potencies as inhibitors of L-glutamate uptake, interference with the inactivation of synaptically released L-glutamate may contribute to the neurotoxic effects of kainate.

Amino Acids↗
PubMed1979

The excitation and depression of spinal neurones by ibotenic acid.

1. The firing of spinal interneurones and Renshaw cells by microelectrophoretic (+/-)-ibotenate, which was approximately eight times more active as an excitant than L-glutamate, was followed by prolonged depression of the sensitivity of the neurones to excitant amino acids and acetylcholine. 2. The depression, which lasted for 15--30 min when ibotenate was ejected for 3--6 min, was blocked by the GABA-antagonist bicuculline methochloride, and was independent of prior firing since it occurred with subthreshold concentrations of ibotenate and when ibotenate firing had been blocked by DL-alpha-aminoadipate. 3. When administered electrophoretically for 5 min, muscimol, a potent GABA agonist, reduced neuronal excitability for prolonged periods and this effect was also prevented by bicuculline methochloride. 4. The depression of neuronal excitability produced by GABA, taurine, isoguvacine or 3-aminopropane sulphonate, ejected for periods of 5--6 min, recovered rapidly. 5. It is suggested that ibotenate is converted in vivo to muscimol or a related compound which has a prolonged, bicuculline-sensitive depressant action on the excitability of neurones.

Action Potentials↗