Relationship between the kinetics of neuronal responses and the release of drugs from micropipettes: effect of retaining current.
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Biomedical subjects
Publications and source records attributed to M H Roberts.
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The effects of mescaline upon single cortical neurones were studied, using the microiontophoretic technique. Mescaline elicited excitatory and depressant responses similar to those evoked by noradrenaline (NA) and 5-hydroxytryptamine (5-HI). The responses to NA and mescaline were usually in the same direction, the neurone being either excited by both drugs or depressed by both drugs. The correlation between the effects of mescaline and 5-HT, however, was less consistent. The beta-adrenoceptor blocking agent MJ-1999 and the 5-HT antagonist methysergide were both effective in antagonizing mescaline responses.
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1. The effects of strychnine on the degree of depression of neuronal firing induced by glycine, gamma-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) have been examined quantitatively. All drugs were applied by iontophoresis to spontaneously active cerebral cortical neurones in the anaesthetized cat. The application of these drugs was continued until a plateau or equilibrium depression was reached. The time taken to reach this steady state was noted. Dose-response curves were then constructed for those currents giving less than complete depression.2. Glycine was less potent than GABA and about 7-fold larger currents were needed to achieve comparable depression. 5-HT was also a weak depressant compared with GABA and had 0.6 the potency of glycine on a current basis.3. Strychnine in currents up to 25 nA shifted the dose-response curve of glycine to the right at a time when equilibrium depression in the same cells induced by the control agonists GABA or 5-HT was unaffected. These currents of strychnine did, however, prolong the time-course of onset of GABA and 5-HT depression.4. In larger currents strychnine reduced GABA equilibrium depression, but the dose-response curve was not shifted in a parallel fashion.5. It is concluded that strychnine can specifically and competitively antagonize the effect of glycine on cortical neurones.
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1. Noradrenaline, isoprenaline, 5-hydroxytryptamine and acetylcholine have been applied into the environment of single neurones in the cat cerebral cortex by micro-iontophoresis. The influence of anaesthesia on the neuronal responses to these drugs was studied.2. In general, excitation of neurones by noradrenaline occurred commonly in both unanaesthetized encéphale isolé (48%) and N(2)O-halothane anaesthetized preparations (57%) while depressions were less frequent (24 and 20% respectively). The picture differed markedly in barbiturate anaesthetized animals where excitation was uncommon (12%) and the majority of cells (59%) was depressed by noradrenaline. Although fewer cells were studied, similar differences were obtained with isoprenaline and 5-hydroxytryptamine for the three types of preparation. In sharp contrast, the vast majority of cells was excited by acetylcholine in each of the preparations: encéphale isolé 84%; N(2)O-halothane 92%; barbiturate anaesthetized preparations 85%.3. The differing neuronal responses observed in these experimental situations were not the result of variations in the depth of anaesthesia.4. Although the depths at which neurones were encountered within the cortex did not differ in N(2)O-halothane and encéphale isolé preparations, significantly more cells were found in deeper layers of cortex in barbiturate preparations. The proportion of cells excited or depressed by noradrenaline was generally similar at each depth in the three preparations used.5. The distribution of rates of cell firing was strikingly similar in each preparation, and most of the cells studied had frequencies below 10/sec.6. The direction in which a cell responds to noradrenaline is mainly determined by the type of anaesthetic used, and not by the depth of anaesthesia, the rate of cell firing, or cell depth within the cortex. This suggests important differences in the central pharmacology of halothane and barbiturates.
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1. 5-Hydroxytryptamine (5-HT) and various 5-HT antagonists have been applied micro-electrophoretically from multibarrelled micropipettes into the environment of single neurones in the post-sigmoid and suprasylvian gyri of the cat cerebral cortex.2. In unanaesthetized animals (encéphale isolé) a high proportion of neurones (30%) were excited by 5-HT. This excitation usually had a rapid onset and was seen both in spontaneously active neurones and in otherwise quiescent neurones in which firing was induced by L-glutamate. Some neurones were so sensitive that the uncontrolled diffusion from micropipettes was sufficient to excite them. More cells were excited by 5-HT applied as a cation from solutions of the bimaleate salt than when solutions of the creatinine sulphate salt were used.3. In a high proportion of cells (33%) spontaneous firing or amino acid excitation was depressed by 5-HT.4. A mixed effect was seen in a small proportion (6%) of the cells tested; usually 5-HT caused an excitation initially which was followed by a depression. In other cells, desensitization occurred, and the excitatory effect of 5-HT was diminished or lost.5. When glutamate was used to excite otherwise quiescent cells, there was a significant increase in the number of cells excited by 5-HT and a significant decrease in the number of cells unaffected compared with spontaneously active cells.6. The micro-electrophoretic application of D-lysergic diethylamide (LSD 25), 2-brom LSD (BOL 148), methysergide (UML 491), or 2'- (3-dimethylaminopropylthio)cinnamanilide (SQ 10643) temporarily prevented excitation by 5-HT in half the cells tested. LSD and SQ 10643 were particularly potent in this respect. This antagonism of 5-HT excitation could still be seen when excitation of the cell by L-glutamate or acetylcholine (ACh) was unaffected.7. The depression induced by 5-HT was not prevented by the application of known 5-HT antagonists in the majority of the cells tested (93%). In two cells, however, the depression was reversibly prevented by these antagonists.8. Some cells tested with 5-HT were also tested with ACh or (-)-noradrenaline. The response of a cell to ACh was not significantly related to its response to 5-HT. The degree of correlation between the responses to noradrenaline and 5-HT was large, but not statistically significant with the small number of cells studied.9. The effects of 5-HT on cells in animals anaesthetized with alpha-chloralose did not differ significantly from its effects in unanaesthetized preparations. It is suggested that the use of this anaesthetic may prove a useful alternative to unanaesthetized preparations.10. The systemic injection of small quantities of thiopentone sodium selectively and reversibly reduced the sensitivity of some units to excitation by 5-HT at a time when the response to glutamate was unaffected. On other occasions, the 5-HT excitation was unaffected, though the response to glutamate was reduced.11. These results are discussed in relation to the possible nature of the 5-HT receptors in the cerebral cortex, and the interfering effects of anaesthesia on the response of brain cells to potential transmitter substances.
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