The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate
TL;DR: The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.
Abstract: 1The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone-anaesthetized cats and rats.
2Both ketamine and phencyclidine selectively blocked excitation by N-methyl-aspartate (NMA) with little effect on excitation by quisqualate and kainate.
3Ketamine reduced responses to L-aspartate somewhat more than those of l-glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other.
4On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root-evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation.
5Intravenous ketamine, 2.5–20 mg/kg, and phencyclidine, 0.2–0.5 mg/kg, also selectively blocked excitation of neurones by NMA.
6Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or γ-aminobutyricacid (GABA).
7The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.
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TL;DR: It is now clear that anaesthetics act directly on proteins rather than on lipids, with potentiation of postsynaptic inhibitory channel activity best fitting the pharmacological profile observed in general anaesthesia.
Abstract: General anaesthetics are much more selective than is usually appreciated and may act by binding to only a small number of targets in the central nervous system. At surgical concentrations their principal effects are on ligand-gated (rather than voltage-gated) ion channels, with potentiation of postsynaptic inhibitory channel activity best fitting the pharmacological profile observed in general anaesthesia. Although the role of second messengers remains uncertain, it is now clear that anaesthetics act directly on proteins rather than on lipids.
1,736 citations
TL;DR: In this article, the authors propose a method to solve the problem of unstructured data.Abbreviations 198 and 198.3.1.5.1].
1,691 citations
TL;DR: Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate, providing an explanation for the mechanism of action ofMK-801 as an anticonvulsant.
Abstract: The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.
1,660 citations
TL;DR: It is shown that neurons have a number of different types of calcium channels, each with their own unique properties and pharmacology, and these calcium channels may be important in the control of different aspects of nerve activity.
Abstract: Recent investigations have demonstrated that neurons have a number of different types of calcium channels, each with their own unique properties and pharmacology. These calcium channels may be important in the control of different aspects of nerve activity. Some of the possibilities can now be discussed.
1,364 citations
TL;DR: Quinoxalinediones have been found to be potent and competitive antagonists at non-NMDA glutamate receptors and will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.
Abstract: The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the "non-NMDA" glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.
1,221 citations
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2,465 citations
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01 Jan 1974TL;DR: Evidence for A m i n o Acids as T ransmi t t e r s as well as evidence for Synthesis and Storage are presented.
Abstract: 2. Evidence for A m i n o Acids as T ransmi t t e r s . . . . . . . . . . . . . . . . . . . . 99 2.1. Synthesis and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.2. Synapt ic Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3. Postsynapt ic Act ion . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.4. Postsynapt ic An tagon i s t s . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.5. Inac t iva t ion and R e m o v a l . . . . . . . . . . . . . . . . . . . . . . . . . 104
1,090 citations
TL;DR: There is a definite need for safe and T potent intravenously administered anesthetics of short duration which combine analgesic and sleep-producing effects without significant cardiovascular and respiratory depression.
Abstract: HERE IS A definite need for safe and T potent intravenously administered anesthetics of short duration which combine analgesic and sleep-producing effects without significant cardiovascular and respiratory depression. Recently, a number of compounds related to phenylcyclohexylamine have aroused clinical interest because they appear to approach such requirements. Phencyclidine hydrochloride was the prototype of this group of agents. After preliminary laboratory studies1 its clinical usefulness as an anesthetic was investigated by Greifenstein and associates.2
437 citations
TL;DR: [3H]PCP binding was most enriched in crude synaptosomal subcellular fractions, and was about three times higher in hippocampus than in cervical spinal cord, suggesting that PCP may exert its effects on the central nervous system via binding to specific brain receptor sites.
Abstract: [3H]Phencyclidine (PCP) bound specifically and with high affinity (Kd = 0.15 microM at pH 7.4) to a single saturable class of binding sites in rat brain membrane preparations. Specific binding constituted approximately 70% of total binding at 0 degrees C and 33% of total binding at 37 degrees C (at 10 nM [3H]PCP). Bound [3H]PCP could be displaced by nonradioactive PCP, a series of its derivatives, and the psychotomimetic opiate N-allylnorcyclazocine (SKF 10,047) with relative potencies that closely paralleled those determined in animal behavioral tests. Muscarinic cholinergic ligands inhibited [3H]PCP binding, but only at 0.1 mM and in rank order at variance with that for binding to muscarinic sites or for pharmacological potencies. Other drugs, including opiates other than SKF 10,047, were unable to displace specifically bound [3H]PCP at 0.1 mM. [3H]PCP binding was most enriched in crude synaptosomal subcellular fractions, and was about three times higher in hippocampus (region of highest density) than in cervical spinal cord (region of lowest density). Trypsin and Pronase reduced specific [3H]PCP binding. Thus, PCP may exert its effects on the central nervous system via binding to specific brain receptor sites.
350 citations
TL;DR: A new class of Glu agonist obtained by structural manipulation of Ibo is described, which is likely to be converted by decarboxylation into muscimol20 during microelectrophoretic ejection near CNS neurones.
Abstract: L-Glutamic acid (Glu) and L-aspartic acid (Asp) are putative excitatory transmitters in the mammalian central nervous system (CNS)1–3. Receptors at Glu- and Asp-mediated synapses are presumably different4,5, and a prerequisite for the identification and characterisation of such sites is the availability of specific antagonists and agonists. Among various potential Glu and Asp antagonists3–6 Glu diethyl ester (GDEE)7–9 and (D)-α-aminoadipic acid (α-AA)9–13 show some selectivity, the latter particularly towards excitation by N-methyl-Asp. Kainic acid (KA), a structural analogue of Glu, is a powerful excitant of CNS neurones14–16 that seems to interact with only a small proportion of Glu receptors5. Ibotenic acid (Ibo) is a powerful neuronal excitant9,17,18 also structurally related to Glu. Excitation by Ibo, however, is readily antagonised by α-AA, whereas GDEE has little or no effect13, suggesting that Ibo preferentially activates Asp rather than Glu receptors. Furthermore, excitation of neurones by Ibo is followed by a prolonged depression of excitability18,19 which is sensitive to bicuculline methochloride19, indicating that Ibo is probably converted by decarboxylation into muscimol20 during microelectrophoretic ejection near CNS neurones. Thus, neither KA nor Ibo seem to have sufficient specificity to be useful compounds with which to study central Glu or Asp receptors. We describe here a new class of Glu agonist obtained by structural manipulation of Ibo (Table 1). Elongation of the side chain of Ibo by an additional methylene group and introduction of different ring substituents have led to isoxazole amino acids with carboxyl groups resistant to decarboxylation. A further aim of this homologation was to convert the apparent Asp agonist Ibo into a Glu agonist.
313 citations