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K Fuxe

Publications and source records attributed to K Fuxe.

At least 199 records · Page 11Linked to original sources
PubMed1995

Additivity and non-additivity between dopamine-, norepinephrine-, carbachol- and GABA-stimulated GTPase activity.

The mode of coupling between neurotransmitter receptors and G proteins was investigated by agonist-induced high-affinity GTPase activity in rat striatal membranes. There was a simple additive relationship among dopamine-, carbachol-, and gamma-aminobutyric acid (GABA)-sensitive high-affinity GTPase activity in any combination, indicating that the respective receptors stimulated by these agonists (i.e., dopamine D2, pirenzepine-insensitive muscarinic, and GABAB receptors) interact independently with distinct pools of G proteins. Unexpectedly non-additivity was observed between dopamine- and norepinephrine-stimulation. This lack of additivity was apparently due to stimulation of the same dopamine D2 receptors by both dopamine and norepinephrine, since norepinephrine-stimulated high-affinity GTPase activity could be inhibited by dopaminergic but not adrenergic antagonists. The same non-additivity as seen in rat striatum was confirmed in the membranes prepared from cultured mouse fibroblast cells co-transfected with dopamine D2 and adenosine A2A receptors. The implication of the (non-)additivity between receptor-mediated high-affinity GTPase activity was discussed with a consideration of the possible underlying molecular mechanism.

Adrenergic Agonists↗
PubMed1995

Neurotensin-like immunoreactivity in odontoblasts and their processes in rat maxillary molar teeth and the effect of pulpotomy.

A strong neurotensin-like immunoreactivity (NT-like IR) was detected in the odontoblast cells of the rat teeth. 4 h after a partial pulpotomy performed in two maxillary molar teeth a decreased NT-like IR was observed in the odontoblast layer located at the vicinity of the lesion together with edema and nuclear pyknosis. NT-like IR became further decreased after 24 h. After 7 days NT-like IR had almost fully disappeared with signs of necrosis of the dental pulp and infiltration of polymorphonuclear lymphocytes. It seems possible that NT like peptides in the odontoblast cell layer may play a role, e.g., in dentinogenesis and/or nociception.

Animals↗
PubMed1995

5-HT1A, GABAB, and pirenzepine-insensitive muscarinic receptors are functionally coupled to distinct pools of the same kind of G proteins in rat hippocampus.

In order to probe the interaction between the neurotransmitter receptors and guanine nucleotide-binding regulatory (G) proteins in rat hippocampus, the high-affinity GTPase activity stimulated by 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), carbachol (CCh), and dopamine (DA) has been investigated, focusing on the additivity among the effects of these agonists at their maximally effective concentrations. There were simple additive relationships among 5-HT-, GABA-, and CCh-stimulated activities. As 5-HT, GABA-, and CCh-stimulated high-affinity GTPase activities are mediated by the 5-HT1A, GABAB, and pirenzepine-insensitive muscarinic receptors, respectively, the additive effects indicate that these three receptors are independently coupled to distinct pools of G proteins. In contrast, an apparent lack of additivity was seen between 5-HT- and DA-stimulated activities. This phenomenon was likely due to an activation of the common 5-HT1A receptor-mediated signalling by DA as well as 5-HT, since the DA-sensitive increment of the activity was potently inhibited by the 5-HT1 receptor antagonist methiothepin, but not by the DA D2 receptor antagonist raclopride.

Animals↗
PubMed1995

Functional coupling of dopamine D2 and muscarinic cholinergic receptors to their respective G proteins assessed by agonist-induced activation of high-affinity GTPase activity in rat striatal membranes.

Agonist-induced high-affinity GTPase activity was investigated using the crude membrane preparation from rat striatum. High-affinity GTPase activity was stimulated by dopamine and carbachol in a Mg(2+)-dependent manner and with possible optimum NaCl concentrations of 50-100 mM to detect the percent increase induced by each agonist. Dopamine and selective (as well as non-selective) D2 receptor agonists, but not selective D1 receptor agonists, stimulated activity in a concentration-dependent manner, with affinities which were significantly correlated with those for adenylate cyclase inhibition as previously reported in the literature. Maximal percent stimulation above basal high-affinity GTPase activity was 9.8 +/- 0.6% and 4.4-7.6% for dopamine and other synthetic dopamine D2 receptor agonists, respectively. Dopamine-stimulated activity was inhibited by several dopamine receptor antagonists with the following rank order of potency: (+)-butaclamol > spiperone > raclopride > S(-)-sulpiride; but not by (-)-butaclamol or SCH 23390. High-affinity GTPase activity was also stimulated by carbachol and acetylcholine through the pirenzepine-insensitive muscarinic receptors. Preincubation of the membranes with AS/7, a specific antiserum to Gi1 and Gi2, appeared to attenuate dopamine-sensitive activity, suggesting that Gi1 and/or Gi2 may be at least partially involved. These results indicate that high-affinity GTPase activity in rat striatal membranes is activated through dopamine D2-like receptors and pirenzepine-insensitive muscarinic receptors, both of which are negatively coupled to adenylate cyclase via Gi proteins.

Adenylyl Cyclase Inhibitors↗
PubMed1995

Increased vasopressor actions of intraventricular neuropeptide Y-(13-36) in spontaneously hypertensive versus normotensive Wistar-Kyoto rats. Possible relationship to increases in Y2 receptor binding in the nucleus tractus solitarius.

The C-terminal NPY fragment (13-36)[NPY-(13-36)], a Y2 receptor agonist, elicits vasopressor responses upon central administration. The cardiovascular responses of NPY-(13-36) together with the distribution of NPY receptor subtypes within the nucleus tractus solitarius (nTS) have therefore been studied in spontaneously hypertensive rats (SHR). NPY-(13-36) was injected intracerebro-ventricularly in different doses (7.5 to 3000 pmol) in awake, unrestrained rats to evaluate the cardiovascular effects. NPY receptor subtypes were studied by autoradiography using [125I]peptide YY ([125I]PYY) as a radioligand and by masking the NPY Y1 and Y2 receptor subtypes with unlabelled [Leu31,Pro43]NPY and NPY-(13-36) respectively. In both male SHR and age-matched male normotensive Wistar-Kyoto rats (WKY) NPY-(13-36) injections elicited vasopressor effects. In WKY this effect was dose-dependent and became significant at doses from 75 pmol, whereas in the SHR the vasopressor effect had a longer duration than in the WKY and became significant at lower doses (25 pmol) but associated with the development of an early ceiling effect. The heart rate was unaffected in both groups of rats. Total specific [125I]PYY binding in the nTS was 25% higher in SHR than in WKY rats. By masking the Y1 and Y2 receptor subtypes respectively it could be shown that this difference was due to an increase in Y2 receptor binding within the nTS. The present results give evidence for an increased potency but not an increased efficacy of NPY-(13-36) in inducing a pressor response in the SHR associated with a longer duration as compared with the WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Cholecystokinin octapeptide and the D2 antagonist raclopride induce Fos-like immunoreactivity in the shell part of the rat nucleus accumbens via different mechanisms.

Induction of neuronal Fos-like immunoreactivity (IR) in the rat brain by cholecystokinin octapeptide (CCK-8) and the dopamine (DA) D2 receptor antagonist raclopride was demonstrated. In vivo treatment with the CCK-8 (0.01, 0.1 and 1 nmol/rat, i.c.v.) or the D2 antagonist raclopride (0.1, 0.5 and 1 mg/kg, i.p.) alone increased in a dose-dependent way the Fos-like ir profiles in the shell part of the rat nucleus accumbens (AcbSh). Combined treatment with CCK-8 (0.1 nmol/rat) and raclopride (0.5 mg/kg) caused significant additive increases in the Fos-like ir profiles in the AcbSh. In the central caudate-putamen, the medial olfactory tubercle, and the frontal cerebral cortex where either compound alone was weakly active or inactive, the combined treatment with both compounds led to a significant induction of neuronal Fos-like ir profiles. These results suggest that the blockade of D2 and activation of CCK transduction lines can induce Fos-like IR via different mechanisms. They may produce additive effects in AcbSh and synergistic effects in the caudate-putamen and the olfactory tubercle on the induction of neuronal Fos-like IR and thus on long-term regulation of gene expression in the striatum.

Animals↗
PubMed1995

Receptor-receptor interactions and their relevance for receptor diversity. Focus on neuropeptide/dopamine interactions.

Receptor diversity in combination with receptor-receptor subtype specific interactions, which can be antagonistic or synergistic in character, markedly increase plasticity in WT and VT in the nervous system. In this way switching among transmission lines for the various DA receptor subtypes becomes possible. Some of these aspects are supported by our work on selective modulation of D2 receptors by CCK and NT. Selective regulation of D2 receptors via CCK-8 receptor subtypes and NT receptors may underlie CCK/DA interactions and NT/DA interactions in the basal ganglia. These studies underline the importance of receptor-receptor interactions exerted at the membrane level between neuropeptide receptors and D2 receptors, which are determined at least in part by the ongoing activity at D1 receptors. In the case of both CCK/D2 and NT/D2 receptor interactions, it has been possible, by means of intrastriatal and intraaccumbens microdialysis, to obtain a functional correlate to the receptor interactions found in the membrane preparations from the striatum. Schizophrenia may be in part related to reduced release of CCK and/or NT peptides or to alterations in their receptor interactions with the D2 receptor. This view may lead to new therapeutic approaches.

Animals↗
PubMed1995

Long distance pathways of diffusion for dextran along fibre bundles in brain. Relevance for volume transmission.

Texas Red-labelled dextran with a mol. wt of 3000 g mol-1, a marker for the extracellular space, was injected unilaterally into the neostriatum of adult rats (0.3-30 micrograms microliter-1) and its distribution evaluated 1 min to 5 h later. Diffusion in the neuropil was observed with clearance starting after 30 min. After 10-15 min strong labelling along the myelinated fibre bundles was observed in the entire neostriatum. After about 20 min the labelling along the fibres reached into the corpus callosum and the overlaying deep layers of the cerebral cortex. A marked cellular uptake and accumulation of labelled dextran was found in putative perivascular pericytes. Thus, in the living brain preferential extracellular fluid pathways for diffusion exist, especially along fibre bundles, which allow the exchange of chemical signals between two distant regions. These may represent extracellular fluid pathways for volume transmission.

Animals↗
PubMed1995

Evidence for a differential modulation of the alpha-2 adrenoceptors by angiotensin II in the nucleus tractus solitarii of the spontaneously hypertensive and the Wistar-Kyoto normotensive rats.

An interaction between angiotensin II (Ang II) receptors and alpha 2-adrenoceptors was evaluated in the nucleus tractus solitarii (NTS) of the normotensive Wistar-Kyoto rat (WKY) and of the spontaneously hypertensive rat (SHR) using quantitative receptor autoradiography and cardiovascular analysis. In the WKY rat, Ang II promoted a dose-dependent increase in the IC50 value of l-noradrenaline when competing for ([3H]p-aminoclonidine ([3H]PAC) binding sites, which reached a maximum of 400% with 10 nM of Ang II and was associated with a small decrease in the B0 value (20%). In the SHR Ang II (0.1 nM) had an opposite effect leading to a decrease in the IC50 value of about 57%, and no change was observed in the B0 value. Saturation analysis also showed that Ang II (0.1 nM) increased the KD value of [3H]PAC in the WKY strain but in contrast decreased the KD value of [3H]PAC in the SHR. The Bmax value was not significantly changed neither in the WKY rat nor in the SHR. The cardiovascular analysis showed that a threshold dose of Ang II (0.05 pmol) counteracted the vasodepressor effect produced by l-noradrenaline coinjected in the NTS of the WKY rat. No effect was observed in heart rate. In the SHR no counteraction of the l-noradrenaline-induced vasodepressor effect was found, and in contrast a slight increase of the vasodepressor effect associated with a significant increase in the bradycardiac response was observed. The results give evidence for an antagonistic Ang II/alpha 2 receptor interaction in the cardiovascular part of the NTS of the WKY rat as previously observed in the Sprague-Dawley rat. However, this interaction is altered in the SHR, so that in this strain the Ang II/alpha 2 receptor interaction enhances alpha 2 affinity and possibly alpha 2 receptor function. This opposite effect observed in the SHR may represent one compensatory mechanism to counteract the development of high blood pressure in the SHR.

Angiotensin II↗
PubMed1995

A single (-)-nicotine injection causes change with a time delay in the affinity of striatal D2 receptors for antagonist, but not for agonist, nor in the D2 receptor mRNA levels in the rat substantia nigra.

The in vitro and in vivo effects of (-)-nicotine on dopamine D2 receptors in the rat neostriatum have been studied using biochemical binding, in situ hybridization and immunocytochemistry. A single i.p. injection (1 mg/kg) of (-)-nicotine resulted in a reduction of the KD value of the D2 antagonist [3H]raclopride binding sites in rat neostriatal membrane preparations at 12 h without any significant change in the Bmax value. This action of (-)-nicotine was counteracted by pretreatment 15 min earlier with the nicotine antagonist mecamylamine (1 mg/kg, i.p.). However, the KD and the Bmax values of the D2 agonist [3H]NPA binding sites in the rat neostriatal membrane preparations were not significantly affected 0.5-48 h after a single i.p. injection with 1 mg/kg of (-)-nicotine. No significant change in neostriatal D2 receptor mRNA levels was observed at any time interval after the (-)-nicotine injection. No significant change was observed in tyrosine hydroxylase (TH) immunoreactivity in either the substantia nigra or the neostriatum, nor in nigral TH mRNA levels during the time interval studied (4-24 h posttreatment). Furthermore, addition of low (10 nM) or high (1 microM) concentrations of (-)-nicotine in vitro to rat neostriatal membranes did not alter the characteristics of [3H]raclopride or [3H]NPA binding. These results indicate that a single (-)-nicotine injection can produce a selective and delayed increase in the affinity of D2 receptors for the antagonist, but not for the agonist without modifying the levels of D2 receptor mRNA, probably via the activation of central nicotinic receptors.

Animals↗
PubMed1995

Cholecystokinin octapeptide in vitro and ex vivo strongly modulates striatal dopamine D2 receptors in rat forebrain sections.

Receptor autoradiographic experiments together with the filter wipe-off technique were performed to investigate the effects of cholecystokinin octapeptide (CCK-8) on dopamine D2 receptors. In vitro studies showed that 1 nM CCK-8 significantly increased the KD value of binding sites for the D2 agonist [3H]N-propylnorapomorphine (NPA) in the rostral and caudal parts of the nucleus accumbens by 48 and 148% respectively. In contrast, 1 nM CCK-8 significantly decreased the IC50 value of dopamine for binding sites for the D2 antagonist [125I]iodosulpride in the rostral and caudal parts of the caudate-putamen by 46 and 56% respectively, and in the rostral and caudal parts of the nucleus accumbens (areas of CCK-dopamine coexistence) by 57 and 75% respectively. Ex vivo studies demonstrated that 30 min after an intraventricular injection of 1 nmol/rat CCK-8 the KD value of [3H]NPA binding sites in the caudal part of the forebrain and the IC50 value of dopamine for [125I]iodosulpride binding sites in the caudal part of the nucleus accumbens were significantly increased by 160% and decreased by 77% respectively. These results indicate for the first time that in sections CCK-8 in vitro and ex vivo can strongly regulate D2 receptor affinity in the striatum. The present studies also provide evidence for stronger modulation of D2 receptors by CCK-8 in the area of CCK/dopamine coexistence in the nucleus accumbens than in other basal ganglion areas, supporting the existence of CCK/D2 receptor interactions in cotransmission. The stronger interactions found in sections than in membrane preparations may indicate the requirement of intracellular mechanisms and/or a more intact membrane structure for optimal receptor-receptor interactions.

Animals↗
PubMed1995

On the cellular localization and distribution of carbonic anhydrase II immunoreactivity in the rat brain.

Evidence is provided that carbonic anhydrase-II is localized in the central nervous system to wide spread systems of oligodendrocytes and restricted astroglia populations, involving both fiber bundles and neuropil. It is suggested that CO2 formed in activated axons may, via carbonic anhydrase-II, give rise to protons controlling the excitability of surrounding neuropil. Thus, CO2 may represent an important, highly diffusible, signal in brain, involved in the tonic control of neuronal activity.

Animals↗
PubMed1995

Presynaptic A2-adrenoceptors and neuropeptide Y Y2 receptors inhibit [3H]noradrenaline release from rat hypothalamic synaptosomes via different mechanisms.

Presynaptic receptors may reduce transmitter release with different mechanisms. Both the alpha 2-agonist, clonidine and the Y2-agonist, neuropeptide Y fragment 13-36 (NPY 13-36), induce a concentration-dependent inhibition of the 4-aminopyridine (4-AP)-evoked [3H]noradrenaline ([3H]NA) release from hypothalamic synaptosomes. Changes in alpha 2- and Y2-modulation of noradrenaline (NA) release were observed by lowering the calcium influx with the use of omega-conotoxin (omega-CgTx), a calcium-channel blocking agent. In these experimental conditions, clonidine was less active, whereas NPY 13-36 preserved its efficacy. It therefore seems possible that presynaptic alpha 2-adrenoceptors can primarily inhibit NA release by reducing calcium influx via voltage-sensitive calcium channels (VSCC), while Y2-receptors may inhibit the intracellular release process with a mechanism independent of the calcium entry.

4-Aminopyridine↗
PubMed1995

5-HT1A receptor-mediated activation of high-affinity GTPase in rat hippocampal membranes.

GTP hydrolyzing activity was assayed by measuring the amount of 32P(i) released from 0.3 microM [gamma-32P]GTP in the membranes prepared from rat brain. 5-Hydroxytryptamine (5-HT) stimulated the high-affinity GTPase activity in hippocampus, but not in striatum, in a concentration-dependent manner with an EC50 value of 18 nM and maximal percent stimulation of 13.9%. This response was mimicked by (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin [(+/-)-8-OH-DPAT], but not by (+/-)-1-(2,5-dimethoxy-4-iodophyenyl)-2-aminopropane [(+/-)-DOI]. These results suggest that 5-HT-stimulated high-affinity GTPase activity of the GTP-binding protein(s) is mediated via 5-HT1A receptor subtype in the rat hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Counteraction of NYP-induced c-Fos expression in the nucleus tractus solitarii by alpha 2 receptor agonists.

Neuronal c-Fos protein-like immunoreactivity (c-Fos IR) in parts of the nucleus tractus solitarii (NTS)-dorsal motor nucleus of the vagus nerve (dmnX) complex of the anaesthetized rat was studied 90 min after NTS microinjections of neuropeptide Y (NPY) and/or adrenergic receptor agonists in relevant cardiovascular doses. Microinjections of NPY and l-adrenaline alone into the NTS induced neuronal c-Fos IR in parts of the NTS-dmnX complex, while clonidine had no action. No double-labelled GFAP/c-Fos immunoreactive cells were found in the NTS-dmnX complex after the microinjection of NPY into the NTS. Coinjections of NPY and l-adrenaline or clonidine into the NTS reduced the NPY-induced increase in c-Fos IR. The results emphasize that during cardiovascular regulation NPY receptors can control neuronal gene expression in the NTS-dmnX complex via c-fos and that stimulation of alpha 2-adrenoceptors can attenuate NPY receptor transduction also in terms of induction of c-Fos IR in the NTS-dmnX complex via an antagonistic alpha 2/NPY receptor interaction.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1995

Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins.

The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased gamma-amino-butyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35.8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In vitro experiments, performed in rat cortical slices, showed that modafinil failed to affect [3H]GABA release and uptake as well as glutamic acid decarboxylase activity. In conclusion, our results suggest that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by modafinil of the GABAergic release in the cerebral cortex.

5,7-Dihydroxytryptamine↗
PubMed1995

Volume versus wiring transmission in the brain: a new theoretical frame for neuropsychopharmacology.

A volume transmission mode of communication in brain was implicit already in the early work of Golgi, who postulated the existence of electrical signals in the extracellular fluid (ECF) based on Volta's "wet conductor" made by solutions. The term volume transmission is taken from the term volume conduction describing the flow of ionic currents in the ECF as a basis for the electrocorticogram. The slow VT mode includes also chemical signals and is opposed to the fast synaptic (wiring) transmission. Every neuron may function in a dual mode, the synaptic and the volume transmission mode, when considering the autocrine and synaptic classes of communication. The paracrine- and neuroendocrine-like classes only involve the VT mode in the latter case including the CSF as a route. The chemical signals for VT are the neuropeptides, but also the classical transmitters, the monoamines, acetylcholine, GABA, and glutamate can participate, when they operate via slow, high affinity G protein coupled receptors. Ions such as K+, Ca++, and H+ also function as VT signals. The hypothesis is also introduced that CO2 can act as a multifacit long-distance VT and WT regulator besides being part of the CO2/HCO3 buffer. CO2 via regulating NMDA receptor sensitivity can also regulate NO formation, which represents a paracrine and fast VT signal. The therapy of CNS disorders is also discussed in the frame of the wiring and VT concept. Two therapeutical approaches can therefore be developed, one based on increasing WT and one based on increasing VT. In contrast to the WT therapy, which must preserve the electrotemporal code, the VT therapy can operate also with postsynaptic agonists. Therefore, a therapeutic effect with such a drug indicates that the deficiency in the communication process operates via VT. In view of the lack of very effective negative feedbacks in VT vs. WT, VT therapy may produce less tolerance and drug dependency.

Brain↗