Biomedical subjects
Publications and source records attributed to K Fuxe.
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The noradrenaline (NA) neurotoxin, DSP4, caused a marked impairment of two-way active avoidance acquisition. Pretreatment with desipramine, which inhibits the degeneration of NA neurons by DSP4, consistently blocked the avoidance deficit. Daily treatment with corticosterone (2 X 1 mg/kg, s.c.) also blocked the impaired acquisition of avoidance induced by DSP4 but failed to affect the increase in cortical beta-noradrenergic receptors induced by DSP4. The present findings give further evidence for the important role interactions between the pituitary-adrenal axis and the locus coeruleus NA system play in aversive learning.
Rat prolactin produces in a dose of 100 micrograms/kg a rapid and marked increase of dopamine turnover in the medial palisade zone of the median eminence and of noradrenaline turnover in the posterior periventricular hypothalamic region as well as a possible minor increase of noradrenaline turnover in the magnocellular part of the paraventricular hypothalamic nucleus of the hypophysectomized male rat. The rat prolactin serum levels measured 2 h following injection were within the upper physiological range of lactating rats. The findings suggest that dopamine in the medial palisade zone may be released as a prolactin inhibitory factor and respond rapidly to increases in serum prolactin levels. Furthermore, rat prolactin can acutely modify noradrenergic mechanisms in discrete areas of the hypothalamus indicating that prolactin can participate in the regulation of types of hypothalamic functions other than regulation of its own secretion.
Nine days after medial septal lesion a 20% increase in the number of muscarinic antagonist binding sites in rat hippocampus was observed without any change in the affinity for agonist or antagonist. Chronic atropine treatment (s.c. 5 mg/kg, twice a day for 14 days, 20 mg/kg once a day for 14 days or 100 mg/kg for 4 days and 20 mg/kg for 10 days, once daily) led to an increase in the number of muscarinic antagonist binding sites in rat hippocampus with 35, 80 and 80% respectively and also lowered the affinity for 3H-antagonists in a dose dependent manner. Agonist binding studies also indicated an increase in receptor number and a decrease in affinity. The latter change can possibly be explained by the presence of residual atropine 24 h after the last injection. If this is taken into account we may conclude that muscarinic supersensitivity evoked either by severing the input or by chronic pharmacologic blockade both produced "new receptors' with ligand binding properties similar to the original receptors.
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Tail vein injections of [3H]N-propylnorapomorphine ([3H]NPA) in male mice resulted in a dose-related accumulaton of radioactivity in the following brain regions: striatum (max), olfactory tubercle and cerebellum (min). The specific binding was saturable with increasing concentrations of the drug and stereospecifically displaced by (+) butaclamol. Dopamine agonist (apomorphine, NPA and bromocriptine) and antagonists (spiperone, haloperidol, (+) butaclamol and I-sulpiride) all caused dose-dependent prevention of [3H]NPA binding. Mianserin, phenoxybenzamine and propranolol did not prevent the in vivo [3H]NPA binding suggesting that [3H]NPA binds specifically to dopamine receptors in the striatum and the olfactory tubercle of the mouse.
Acute sino-aortic denervation produces an acute reduction of adrenaline stores in the anterior and posterior hypothalamus and a reduction of noradrenaline stores in the dorsal midline area of the caudal medulla oblongata. Furthermore, removal of baroreflex afferents results in an increase of adrenaline turnover in the DCMO but not in the hypothalamus. The present findings give evidence for participation of adrenergic mechanisms in central baroreflex regulation. The findings can be interpreted according to the adrenaline vasodepressor hypothesis of hypertension.
Male rats and mice received a 14 day peroral treatment with zimelidine, a novel antidepressant drug. Zimelidine produced a 70 and 60% reduction in the number of high affinity [3H]5-hydroxytryptamine (5-HT) and [3H]D-lysergic acid diethylamide (LSD) binding sites, respectively, and induced low affinity binding sites for [3H]5-HT and for [3H]D-LSD. The head twitch behaviour induced by 5-hydroxytryptophan and 5-methoxydimethyltryptamine was attenuated and reductions of prolactin and growth hormone were observed. These findings give further evidence that long-term treatment with zimelidine can produce a reduction of 5-HT neurotransmission in several brain regions.
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Dopamine receptors have been characterized by the use of radiolabelled dopamine agonists and antagonists. Using ibotenic acid induced lesions of the striatum, evidence was obtained that 3H-N-propylnorapomorphine (3H-NPA) binding sites and 3H-bromocriptine binding sites are located both on intrastriatal nerve cells and on extrinsic nerve terminals probably mainly originating in the cerebral cortex. Development of dopamine receptor supersensitivity as evaluated in 6-hydroxydopamine lesioned rats was associated with an 50% increase in the number of 3H-NPA binding sites in the striatum. Furthermore, one year following the 6-hydroxydopamine induced lesion of the dopamine pathways two binding sites for 3H-NPA could be demonstrated in the striatum. However, at this time interval the total number of 3H-NPA binding sites was not increased. The functional significance of these two binding sites for 3H-NPA in the striatum is unknown, but they are probably coupled to the biological effector in view of the marked behavioural supersensitivity demonstrated in these old animals. The dopamine receptor agonists and especially the dopaminergic ergot derivatives have been characterized by studying their affinities for 3H-bromocriptine, 3H-spiperone, 3H-ADTN and 3H-NPA binding sites in vitro. It is suggested that the Ki ratios for agonist and antagonist radioligands may be one useful way to characterize the agonist-antagonist character of the drug. Another important method is to study the effects of dopamine receptor agonists on the specific in vivo binding of 3H-spiperone and 3H-NPA. The correlation analysis of DA agonist affinities for the four radioligands of DA receptors used in the present study give evidence for the existence of at least 3 types of DA receptors. Actions of dopaminergic ergot drugs have been evaluated at supersensitive dopamine receptors. The findings suggest that the shift to the left of the threshold dose to activate supersensitive dopamine receptors could be due to a lowering of the stereoselectivity of agonist interaction at the dopamine agonist sites of supersensitive dopamine receptors. Such a change may explain the highly preferential action of CF 25-397 at supersensitive dopamine receptors, since its affinity for 3H-NPA binding sites was not increased in the present experiments. In agreement with previous work, evidence have also been presented that prolonged treatment with a potent dopaminergic drug, pergolide, can produce a down regulation of normal dopamine receptors by reducing the density of such receptors. Evidence has also been presented that CCK-8 and the desulphated CCK-8 (10(-6) M) can in vitro reduce the number of 3H-NPA binding sites in the striatum. These results indicate that cholecystokinin peptides via activation of cholecystokinin receptors can regulate the movements of the 3H-NPA binding sites across the plane of the membrane in such a way as to make them less available to the external surface of the membrane...
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The actions of intraventicular injections and intravenous infusions of nicotine were studied on dopamine stores and turnover in discrete areas of the forebrain of normal male rats. This was done by measuring the decline of the dopamine stores after tyrosine hydroxylase inhibition using alpha-methyl-tyrosine methyl ester (H44/68). The dopamine concentrations in the various telencephalic dopamine nerve terminal systems were measured using the Falck-Hillarp methodology involving quantitative microfluorimetry. The catecholamine concentrations in the anteromedial frontal cortex were measured biochemically using high pressure liquid chromatography combined with electrochemical detection. Intraventricular experiments. The dopamine levels in discrete areas of nuc. caudatus and nuc. accumbens were significantly reduced even with the lowest dose of nicotine (1 microgram/rat). Intraventricular injections of nicotine in a dose of 100 microgram/rat produced significant increases of dopamine turnover in various types of dopamine nerve terminal systems in the nuc. caudatus, nuc. accumbens and tuberculum olfactorium, and following a dose of 10 microgram/rat increases of dopamine turnover were observed in the medial part of the nuc. caudatus. Furthermore, nicotine (100 microgram/rat) significantly increased noradrenaline but not dopamine turnover within the anterofrontal cortex. Intravenous experiments. The dopamine levels were selectively reduced by nicotine (1000 microgram/kg) in the cholecystokinin positive and negative dopamine nerve terminal systems of the nuc. accumbens. On the other hand, dopamine levels in the anteromedial frontal cortex were increased after this dose of nicotine. Intravenous infusions of nicotine (10-1000 microgram/kg) produced dose-related increases of dopamine turnover in the various dopamine nerve terminal systems analysed in the telencephalon. These effects became significant with a dose of 1000 microgram/kg/h. The dopamine terminals in the nuc. caudatus showed a higher sensitivity to intravenous infusions of nicotine, being affected by 10-100 microgram/kg of nicotine. These findings suggest that relatively low dose of nicotine via an activation of central nicotine-like cholinergic receptors can reduce dopamine concentration and increase dopamine turnover in discrete limbic and striatal areas. These actions may in part represent the neurochemical basis for the rewarding actions of nicotine and for nicotine dependence in man.
An hypothesis is proposed arguing that local circuits might work as biochemical units involved in synthesis of macromolecules related to the memory processes. Specific sequences in the activation of local circuits should act as a "template" for the synthesis of particular memory molecules, which, in turn, may facilitate the repetition of the original sequences of bioelectrical signals (short-term memory). The resynthesis of the local memory molecules in cell body areas, their flow to terminal areas via axoplasmic transport and their possible passage to other nerve cells via transynaptic transport might be the basis of long term memory. The role of diffuse neuronal systems (e.g. noradrenaline systems) is discussed in the frame of memory recall and consolidation. The suggested hypothesis can be represented in a very effective way by means of the graph theory.
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By means of a new photographic method to quantitate catecholamine fluorescence in tissue sections it has been possible to demonstrate a high dopamine (DA) turnover within the DA cell bodies of the midbrain. The medially located small-sized DA cell bodies of the A10 DA cell group has a very high DA turnover which was significantly different from that found in the laterally located medium-sized DA cell bodies of the A10 cell group. Thus, the mesolimbic DA pathways may be divided into two systems, the medial system having a very high DA turnover in their cell bodies which may reflect a high functional activity in this system.