Biomedical subjects
Publications and source records attributed to K Fink.
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The work and postulations of Matte-Blanco are explained in some detail, especially regarding the logical functioning of the conscious and unconscious mind, asymmetrical and symmetrical logic, and bi-logical thought structures. A case serves as an example for the clinical application of Matte-Blanco's ideas to theoretical conceptualization and to the technique of interpretation.
In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mumol/l or 0.032 mumol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine and the selective H2 receptor agonist dimaprit (each up to 10 mumol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.
Human cerebral cortical slices preincubated with [3H]GABA, [3H]noradrenaline, or 5-[3H]hydroxytryptamine and superfused with Krebs solution or Mg(2+)-free Krebs solution were used to investigate the influence of increased D-glucose concentrations on the release of these [3H]-neurotransmitters evoked by high K+ content or NMDA receptor activation, respectively. An increase in level of D-glucose (normal content, 11.1 mM) by 32, 60, and/or 100 mM (a range characteristic for hyperosmolar diabetic coma) increased the [3H]GABA release and inhibited the [3H]noradrenaline release evoked by both methods of stimulation. The K(+)-induced 5-[3H]hydroxytryptamine release was also inhibited by high D-glucose content. Blockade of GABAB receptors by p-(3-aminopropyl)-p-diethoxymethylphosphinic acid (CGP 35348) attenuated the inhibitory effect of high D-glucose content on the K(+)-evoked release of [3H]noradrenaline and 5-[3H]hydroxytryptamine, suggesting that the effect on monoamine release is, at least to a major part, the result of the increased GABA release and, as a consequence, of an increased GABA concentration at inhibitory GABAB receptors. The membrane-impermeable sorbitol mimicked the increasing effect of D-glucose on [3H]GABA release and its inhibitory effect on 5-[3H]hydroxytryptamine release. However, dimethyl sulfoxide, which is known to permeate rapidly through biological membranes, had no effect at concentrations equiosmolar to D-glucose. It is concluded that a reduction in brain cell volume caused by increased extracellular, compared with cytoplasmic, osmolarity is crucial for the changes in neuronal function observed at high D-glucose and sorbitol content.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effect of high D-glucose concentrations on the K+ (15-25 mM)-evoked release of [3H]GABA, [3H]norepinephrine ([3H]NE), [3H]5-hydroxy- tryptamine ([3H]5-HT) and [3H]acetylcholine ([3H]ACh) was investigated in rat cerebral cortical slices and synaptosomes superfused with Krebs' solution which normally contains 11.1 mM glucose. In slices, the release of [3H]GABA was enhanced by increasing D-glucose by 32-320 mM, the release of [3H]NE and [3H]5-HT was inhibited when D-glucose was increased by 60-320 mM but the release of [3H]ACh was not affected. The increase of [3H]GABA release and the inhibition of [3H]NE release were mimicked by D-fructose and NaCl at similar osmolarities, whereas dimethylsulfoxide (DMSO; a freely membrane-permeable drug) at equimolar concentrations failed to affect the release of [3H]GABA and [3H]NE. The GABAB receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl- phosphinic acid (CGP 35348) abolished the inhibitory effect of an increase in D-glucose by 60 and 100 mM on [3H]NE release but only tended to diminish the inhibition caused by an increase by 320 mM. In synaptosomes, the K(+)-evoked release of 3H-GABA was enhanced by increasing D-glucose by 60-320 mM. The K(+)-evoked release of [3H]NE was only inhibited when D-glucose was increased by 320 mM, whereas it was not affected by an increase by 100 mM. In conclusion, high D-glucose differentially influences neurotransmitter release in the brain cortex. Hyperosmolarity in the extracellular fluid together with an osmotic gradient extra- versus intracellular probably plays a role in the mechanism(s) underlying the changes observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Imidazolines bind with high affinity not only to alpha-adrenoceptors but also to specific imidazoline binding sites (IBS) labelled by either [3H]clonidine or [3H]idazoxan and termed I1- and I2-IBS, respectively. Since bovine adrenal chromaffin cells lack alpha 2-adrenoceptors, we investigated the pharmacological characteristics of [3H]clonidine binding sites in the bovine adrenal medulla. The binding of [3H]clonidine was rapid, reversible, partly specific (as defined by naphazoline 0.1 mmol/l; 55% specific binding at [3H]clonidine 10 nmol/l), saturable and of high affinity. The specific binding of [3H]clonidine to bovine adrenal medullary membranes was concentration-dependently inhibited by various imidazolines, guanidines and an oxazoline derivative but not, or with negligible affinity, by rauwolscine and (-)-adrenaline. In most cases, the competition curves were best fitted to a two-site model. The rank order of affinity for the high affinity site (in a few cases the single detectable site) was as follows: naphazoline > or = BDF 7579 (4-chloro-2-isoindolinyl guanidine) > or = clonidine > or = cirazoline > or = BDF 6143 (4-chloro-2-(2-imidazoline-2-ylamino)-isoindoline hydrochloride) > BDF 7572 (4,7-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) > moxonidine = rilmenidine > BDF 6100 (2-(2-imidazoline-2-ylamino)-isoindoline) = idazoxan > phentolamine > aganodine = guanabenz > amiloride > histamine. This rank order is compatible with the pharmacological properties of the I1-IBS. The non-hydrolysable GTP-analogue Gpp(NH)p (5'guanylylimidodiphosphate; 100 mumol/l) inhibited specific [3H]clonidine binding by about 50%. Equilibrium [3H]clonidine binding was also significantly reduced by K+ and Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of local and general anaesthetics on cation influx through the fast, voltage-dependent sodium channel and the 5-HT3 receptor cation channel was studied in N1E-115 mouse neuroblastoma cells by measuring 2-min influx of the organic cation 14C-guanidinium induced by either veratridine (1 mmol/l) or 5-HT (100 mumol/l). The veratridine-induced influx of 14C-guanidinium was potentiated by scorpion toxin and inhibited by tetrodotoxin. The 5-HT-induced 14C-guanidinium influx was not affected by tetrodotoxin but it was inhibited by nanomolar concentrations of the selective 5-HT3 receptor antagonists ondansetron and ICS 205-930; at high micromolar concentrations these compounds also inhibited the veratridine-induced influx of 14C-guanidinium. The 14C-guanidinium influx through both channels was inhibited by local and general anaesthetics. The rank order of potency for inhibition of veratridine-induced influx by local anaesthetics was tetracaine > bupivacaine > cocaine > lidocaine > procaine and that for inhibition of the 5-HT3 receptor channel was tetracaine > bupivacaine > cocaine > procaine > lidocaine. With the exception of procaine and cocaine, which were equipotent at both channels, the local anaesthetics were 4.4-fold (lidocaine) to 25-fold (tetracaine) more potent at the fast sodium channel than at the 5-HT3 receptor channel. The rank order of potency for general anaesthetics was propofol > etomidate = alfaxalone = ketamine > thiopental = methohexital at the fast sodium channel, and propofol > or = etomidate > alfaxalone = methohexital > thiopental > ketamine at the 5-HT3 receptor channel.(ABSTRACT TRUNCATED AT 250 WORDS)
Rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline were used to investigate whether the NMDA-evoked noradrenaline release is modulated by agonists or antagonists at presynaptic alpha 2-adrenoceptors. In experiments on slices, noradrenaline and the preferential alpha-adrenoceptor agonists talipexole (former B-HT 920) and clonidine inhibited the NMDA-evoked tritium overflow whereas the selective alpha 1-adrenoceptor agonists cirazoline and methoxamine were ineffective. The alpha 2-adrenoceptor antagonists rauwolscine and idazoxan facilitated the NMDA-evoked tritium overflow whereas the preferential alpha 1-adrenoceptor antagonist prazosin was ineffective. The concentration-response curve of talipexole for its inhibitory effect on NMDA-evoked overflow was shifted to the right by idazoxan (apparent pA2 = 7.5). The EC50 of NMDA (97 mumol/l) for its stimulating effect on tritium overflow was not substantially changed by blockade of alpha 2-autoreceptors with 1 mumol/l rauwolscine (EC50 of NMDA in the presence of the alpha 2-adrenoceptor antagonist, 155 mumol/l), but the maximal overflow of tritium was increased 2.5 fold by this rauwolscine concentration. In experiments on synaptosomes, talipexole and noradrenaline inhibited the NMDA-evoked tritium overflow. The inhibitory effect of talipexole was abolished by idazoxan which, given alone, was ineffective, as was prazosin. Talipexole did also not produce an inhibition when tritium overflow was evoked by NMDA in the presence of omega-conotoxin GVIA 0.1 mumol/l; the latter, by itself, decreased the response to NMDA by about 55%.(ABSTRACT TRUNCATED AT 250 WORDS)
In superfused mouse striatal slices preincubated with [3H]dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 mumol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [3H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H3 agonist R-(-)-alpha-methylhistamine; it was not affected by the H1 antagonist dimetindene and the H2 antagonist ranitidine but abolished by the H3 antagonist thioperamide. Tritium overflow evoked by Ca2+ ions (introduced into Ca(2+)-free, K(+)-rich medium containing tetrodotoxin) was not affected by histamine 10 mumol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H3 receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H3 receptor-mediated inhibition of dopamine release.
The problem of perception and conceptualisation of time in the unconscious and the conscious is seen in terms of Matte-Blanco's theories. In a short outline of his ideas, symmetrical and asymmetrical logic and his newer concept of 'bi-logic structures' are discussed. Clinical examples from the psychoanalysis of a patient with a time problem are presented to illustrate the hypothesis that a misperception and misconception of time lead in this case to obsessive-compulsive pathology. The clinical application of Matte-Blanco's postulations not only explains the psychopathology of the patient but also allows the formulation of a treatment strategy leading to a positive solution of the problem.
Rat brain cortex synaptosomes pre-incubated with [3H]norepinephrine were used (1) to provide evidence that part of the NMDA receptors mediating stimulation of norepinephrine (NE) release are located on the noradrenergic varicosities themselves, (2) to characterize these receptors and (3) to examine whether ethanol specifically inhibits the NMDA-evoked NE release via a presynaptic site of action. In synaptosomes superfused with Mg(2+)-free Krebs-Henseleit solution, NMDA (2-min exposure) stimulated tritium overflow in a concentration- and glycine-dependent manner. The stimulatory effect of NMDA was not altered by tetrodotoxin but was abolished by omission of Ca2+ from the superfusion fluid and was considerably reduced in the presence of 1.2 mM Mg2+. DL-(E)-2-Amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849; a competitive NMDA receptor antagonist) produced a parallel shift of the concentration-response curve for NMDA to the right, whereas dizocilpine (MK-801; an antagonist at the phencyclidine, PCP, recognition site of the NMDA-gated ion channel) reduced the maximum effect of NMDA. Ethanol inhibited the NMDA-evoked tritium overflow in a concentration-dependent manner. In contrast, in synaptosomes superfused with Ca(2+)-free Krebs-Henseleit solution containing 15 mM K+ throughout, ethanol did not affect the tritium overflow evoked by 2 min introduction of 75 microM Ca2+ into the superfusion fluid. This Ca(2+)-evoked overflow was also not altered by tetrodotoxin and dizocilpine, but was inhibited by the inorganic Ca2+ channel antagonist Cd2+.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of DSP4-induced destruction of noradrenergic neurones on 3H-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (3H-CPP) binding to N-methyl-D-aspartate (NMDA) receptors and on 3H-desipramine (3H-DMI) binding to the neuronal noradrenaline carrier was investigated in rat brain cortex buffy coat membranes. 3H-DMI bound with high affinity to a single site at the neuronal noradrenaline carrier (KD = 5.26 +/- 1.67 nmol/l) whereas the binding of 3H-CPP to the NMDA receptor was of intermediate affinity (KD = 274 +/- 45 nmol/l). Fourteen days after a single-dose treatment with DSP4 (1) the Bmax value for 3H-DMI binding was reduced by 74%, (2) the Bmax value for 3H-CPP binding only tended to be decreased (by 24%; not statistically significant), (3) the endogenous noradrenaline content was reduced by 70% compared to untreated controls and, (4) the absolute amount of the NMDA-evoked 3H-noradrenaline overflow but not the fractional release was reduced by 55%. It is concluded that in the rat cerebral cortex presynaptic NMDA-receptors on noradrenergic nerve endings, which have previously been detected in release experiments with NMDA on cortical synaptosomes preincubated with 3H-noradrenaline, cannot be identified in radioligand binding experiments. Obviously, the cerebral cortical NMDA receptors are predominantly located on postsynaptic neuronal membranes and potentially on non-noradrenergic nerve terminals as well.
The effect of ethanol on the release of noradrenaline evoked by various stimuli was investigated in human cerebral cortical slices from patients undergoing neurosurgery. The slices were preincubated with [3H]noradrenaline and then superfused. Tritium overflow was stimulated by exposure to N-methyl-D-aspartate (NMDA; in slices superfused without Mg2+), kainic acid, veratridine or by increasing the K+ concentration. The NMDA-evoked tritium overflow was concentration-dependently inhibited by ethanol; an inhibition by 37% occurred at 48 mmol/l ethanol. This ethanol concentration was not yet effective when kainic acid was used for stimulation, but ethanol 150 mmol/l strongly inhibited the tritium overflow evoked by kainic acid as well. The tritium overflow evoked by veratridine or high K+ was not affected by ethanol in the concentration range investigated. These findings are compatible with the suggestion that the NMDA receptor and, with less susceptibility, the kainate receptor are sites of action underlying the effect of ethanol in the human brain.
1. Human brain cortical slices from patients undergoing neurosurgery for treatment of epilepsy resistant to antiepileptic drugs were used to identify and characterize N-methyl-D-aspartate (NMDA) and non-NMDA receptors mediating stimulation of noradrenaline release. The slices preincubated with [3H]-noradrenaline were superfused with Krebs-Henseleit solution with or without Mg2+ (1.2 mmol l-1) and were stimulated by 2-min exposure to NMDA, kainic acid or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). 2. In slices superfused without Mg2+, NMDA induced a concentration-dependent tritium overflow. 3. The NMDA-evoked tritium overflow was almost abolished by tetrodotoxin (TTX), Mg2+ or by omission of Ca2+ from the superfusion fluid. 2-Amino-5-phosphonopentanoic acid (AP5; a competitive NMDA receptor antagonist) or dizocilpine (formerly MK-801; an antagonist at the phencyclidine receptor within the NMDA-gated ion channel) inhibited the NMDA-evoked tritium overflow. The stimulatory effect of NMDA was not significantly enhanced by glycine added to the superfusion fluid but was reduced by 7-chlorokynurenic acid (an antagonist at the glycine site coupled to the NMDA receptor). 4. In slices superfused with solution containing Mg2+, kainic acid or AMPA induced a concentration-dependent tritium overflow which was susceptible to blockade by TTX. 5. The kainic acid-evoked tritium overflow was not affected by DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP37849; a competitive NMDA receptor antagonist), but was inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; an antagonist at glutamate receptors of the non-NMDA type). 6. The AMPA-evoked tritium overflow was also inhibited by CNQX.2ń
In rat brain cortex synaptosomes superfused with Mg(2+)-free solution containing glycine, [3H]noradrenaline (3H-NA) release evoked by NMDA was abolished by omission of glycine or Ca2+ and inhibited by Mg2+, the competitive and noncompetitive NMDA receptor antagonists CGP 37849 and dizocilpine (MK-801), respectively, as well as by ethanol, but was not affected by tetrodotoxin. The 3H-NA release evoked by L-glutamate was also competitively inhibited by CGP 37849. In conclusion, presynaptic NMDA receptors mediate stimulation of NA release. Ethanol probably acts at this receptor system.
The influence of ethanol, AP5 (DL-2-amino-5-phosphonopentanoic acid) and dizocilpine (MK-801) ((+)-5-methyl-10,11-dihydro-5H-dibenzo (a,b)-cyclo-hept-5,10-imine hydrogen maleate) on the NMDA-induced attenuation of the NMDA-evoked noradrenaline release was examined in rat brain cortex slices preincubated with 3H-noradrenaline. The slices were superfused with Mg(2+)-free Krebs-Henseleit solution. Tritium overflow (corresponding to 3H-noradrenaline release) was stimulated by 300 mumol/l NMDA for 2 min. Presence of 10-100 mumol/l NMDA from 20 to 2 min before stimulation concentration-dependently inhibited the NMDA (300 mumol/l)-evoked 3H overflow, suggesting an agonist-induced desensitization attributable to the modification of events at the NMDA receptor itself and/or distal to this receptor system. The desensitizing effect of 100 mumol/l NMDA was almost complete and was not diminished when the time of preexposure was decreased to 10 min, and when NMDA was removed from the superfusion fluid for up to 5 min before the stimulus; however, the desensitizing effect was reduced after further decrease in the duration of preexposure to NMDA or further prolongation of the interval between preexposure and stimulation. Ethanol inhibited the NMDA-induced 3H overflow (IC50 45 mmol/l); this effect was almost abolished when ethanol was omitted from the superfusion fluid from 2 min before stimulation onward. Ethanol, when simultaneously present with 100 mumol/l NMDA in the superfusion fluid from 20 to 2 min before the NMDA stimulus, concentration-dependently (IC50 112 mmol/l) decreased the inhibitory effect of NMDA.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of neuropeptide Y (NPY), peptide YY (PYY), pancreatic polypeptide and of another four peptides on the electrically evoked 3H overflow were studied in superfused rat brain cortex slices preincubated with 3H-serotonin. In addition, we determined the effect of NPY on the Ca2(+)-induced 3H overflow from rat brain cortex slices and synaptosomes (preincubated with 3H-serotonin) and on the forskolin-stimulated accumulation of cAMP in a membrane fraction from rat brain cortex. The electrically (3 Hz) evoked 3H overflow was inhibited by PYY, NPY and pancreatic polypeptide (decreasing order of potency), but not affected by ACTH1-24, angiotensin II, bradykinin and delta-sleep-inducing peptide. The inhibitory effect of NPY did not change when the stimulation frequency was lowered to 1 Hz, but was markedly reduced at 10 Hz. The inhibitory effect of a presumably maximally active concentration of PYY was not altered in the presence of NPY or pancreatic polypeptide (effects not additive), whereas the inhibition produced by a maximally active concentration of the alpha 2-adrenoceptor agonist clonidine was further increased by NPY. NPY also inhibited (1) the tritium overflow, evoked by introduction of Ca2+, in slices superfused with Ca2(+)-free and K(+)-rich medium containing tetrodotoxin, (2) the tritium overflow, evoked by simultaneously increasing Ca2+ and K+ in the superfusion fluid of synaptosomes previously superfused with Ca2(+)-free medium and (3) the forskolin-stimulated accumulation of cAMP in rat brain cortex membranes. The present results suggest that NPY inhibits serotonin release in the rat brain via presynaptic NPY receptors, which are also activated by PYY and pancreatic polypeptide and may be negatively coupled to an adenylate cyclase.