Guanylate cyclase activity increases after kainic acid lesion of rat striatum.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
K Fuxe
Publications and source records attributed to K Fuxe.
Rotational behaviour in rats with unilateral striatal kainic acid lesions: a behavioural model for studies on intact dopamine receptors.
Rotational behaviour can be induced in rats with unilateral kainic acid induced degeneration of the neostriatum and adjacent regions by means of dopaminergic drugs. Kainic acid lesioned rats, when challenged with apomorphine or the ergot compounds elymoclavine, lergotrile and bromocriptine, perform dose-related turning towards the lesioned side. Blockade of the rotations by a number of dopamine receptor antagonists indicates dopaminergic involvement. Since kainic acid treatment had previously been shown to reduce the number of dopamine receptors in the injected brain regions, ipsilateral turning behaviour elicited by dopaminergic drugs after these lesions seems to be due to intact receptors on the contralateral hemisphere. Comparison of rotation data from experiments at intact dopamine receptors with those from experiments at supersensitive dopamine receptors revealed: (1) A marked decrease of the threshold dose for induction of rotational behaviour in the 6-OHDA lesioned rats. This decrease is particularly pronounced for lergotrile and bromocriptine. (2) A higher peak activity of rotations in rats with supersensitive dopamine receptors. (3) A considerable increase in the slope values of logits plots following denervation of dopamine receptors. Thus, the present report suggests: (a) that a behavioural model for studies of drugs acting at intact dopamine receptors can be obtained by unilateral neostriatal kainate injections and (b) that development of dopaminergic supersensitivity involves increased affinity of the receptors for dopamine receptor agonists and an increase in the coupling to its biological effector mechanism.
Animals↗
3H-kainic acid binding: relevance for evaluating the neurotoxicity of kainic acid.
Explore the source record for details and available documents.
Animals↗
Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study.
Possible neurotoxic actions of intracerebral injections of ibotenic acid, a conformationally restricted analogue of glutamic acid, have been evaluated in rat brain and compared with those of kainic acid. Light microscopical analysis revealed that ibotenic acid produced a marked disappearance of nerve cells in all areas studied, namely striatum, the hippocampal formation, substantia nigra and piriform cortex. Lesions in areas distant to the injection site were not seen. Axons of passage and nerve terminals of extrinsic origin did not seem to be damaged, since, e.g., no apparent degeneration of the dopaminergic terminals in the neostriatum was observed except for a small area surrounding the cannula. In the neostriatum, enkephalin immunoreactive neuronal cell bodies as well as nerve terminals disappeared after injection of ibotenic acid into this nucleus. After injection into the substantia nigra tyrosine hydroxylase immunoreactive cell bodies in the zona compacta disappeared, whereas no certain effect could be seen on the enkephalin immunoreactive nerve fibers. In vitro experiments, conducted with striatal synaptosomal and membrane preparations, showed that ibotenic acid differed from kainic acid by being devoid of a significant inhibitory effect on high affinity glutamate uptake and by having a low affinity for 3H-kainic acid binding sites. Furthermore, ibotenic acid did not interfere with the binding of a number of radioligands for other transmitter receptors. As compared to kainic acid, ibotenic acid has the advantage of being less toxic to the animals and of producing more discrete lesions, possibly due to faster metabolism and/or other fundamental biochemical differences. Because of these special features, ibotenic acid seems to represent a valuable new tool in the morphological and functional analysis of central neuronal systems.
Animals↗
Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs.
The effects of antidepressant drugs on central 5-HT receptor activity were studied in rats and mice. Antidepressant drugs were evaluated for their ability to displace 3H-5-HT and 3H-d-LSD from membrane binding sites in the dorsal neocortex of rats in vitro and for their ability to block 5-HTP and d-LSD induced behavioral effects in mice. The degree of blockade of head-twitches in mice produced by the antidepressants was highly correlated with their affinity for 3H-d-LSD binding sites. A number of antidepressant drugs such as amitriptyline, nortriptyline, mianserine, doxepine, nomifensine and dibenzepine appear to possess marked 5-HT receptor blocking activity at some type of 5-HT receptors in brain. New antidepressant drugs such as zimelidine, which specifically inhibit 5-HT reuptake and do not block 5-HT receptor sites, may after chronic treatment also reduce the functional activity of 5-HT systems by producing adaptive changes in postsynaptic 5-HT mechanisms. Thus, a new indoleamine hypothesis of depression is presented: the therapeutic action of antidepressant drugs may in part be due to a reduced functional acitivity of some central 5-HT systems.
Animals↗
On the role of ascending dopamine systems in the control of voluntary ethanol intake and ethanol intoxication.
Selective lesions of the ascending dopamine pathways were made by bilateral injection of the neurotoxin 6-OHDA (8 micrograms/4 microliters). Catecholamine fluorescence histochemistry revealed a marked degeneration of the ascending mesostriatal and mesolimbic dopamine systems, while the hypothalamic dopamine and noradrenaline nerve terminals were unaffected. After recovery of feeding and drinking behaviors the voluntary ethanol intake was not different from that of the controls. The time of ethanol-induced narcosis and the extent of ethanol-induced hypothermia were not affected. In contrast, in a tilting-plane test conducted two months after the operation, ethanol impaired the performance of the 6-OHDA-treated rats significantly less than that of the controls. This finding suggests a role for the ascending dopamine neurons to the forebrain in the intoxicating effect of ethanol.
Alcohol Drinking↗
On the action of nicotine and cotinine on central 5-hydroxytryptamine neurons.
The actions of nicotine, and its main metabolite cotinine, on 5-hydroxytryptamine (5-HT) neurons in the brain of the rat have been assessed biochemically (on turnover, uptake, release, overflow and binding of 5-HT in brain) and functionally (on extensor reflex activity, which is 5-HT dependent). Nicotine and cotinine in repeated doses of 2 mg/kg caused a reduction of brain 5-HT turnover, which was not blocked by pretreatment with mecamylamine, and nicotine sifnificantly inhibited the effects of norfenfluramine and 5-methoxydimethyltryptamine on extensor reflex activity, effects counteracted by mecamylamine. In low concentrations cotinine weakly inhibits the uptake and retention of 5-HT and also increases its spontaneous release in vitro. The biochemical findings suggest that the reduction of 5-HT and also increases its spontaneous release in vitro. The biochemical findings suggest that the reduction of 5-HT turnover caused by high doses of nicotine are mediated, at least in part, by its main metabolite cotinine. The experiments on extensor reflexes indicate that nicotine can block the functional expression of 5-HT receptor activity in the spinal cord by an action beyond the 5-HT receptor at nicotine-like cholinergic receptors whose location is also discussed.
Amides↗
A method to determine dopamine levels and turnover rate in discrete dopamine nerve terminal systems by quantitative use of dopamine fluorescence obtained by Falck--Hillarp methodology.
In tissue sections of regions with evenly distributed dopamine (DA) nerve terminals such as the nucleus caudatus, it is possible to obtain absolute amounts (nmol/g) of DA by means of quantitative microfluorimetrical measurements of catecholamine (CA) fluorescence intensity in the tissue and in DA-containing albumin-agar standards. The values agree well with mass-fragmentographical determinations of DA. The steady-state DA levels of heterogenously innervated areas such as the tuberculum olfactorium determined by quantitative microfluorimetry can be made comparable to the steady-state levels of DA obtained by biochemistry in the entire tuberculum olfactorium by means of a conversion factor which considers the dilution of the DA-containing structures by non-DA-containing nerve cells in the biochemical analysis. This factor is obtained by making biochemical determinations in such regions of untreated animals (e.g. the tuberculum olfactorium). The results of this paper have demonstrated that the histochemical approach not only has a high power of resolution and makes it possible to perform studies on an intact morphological substrate but also allows the determination of DA steady-state (nmol/g) and DA turnover rate (nmol/g x min-1) in discrete DA nerve terminal systems of the brain in absolute amounts.
Analysis of Variance↗
The effects of chronic treatment with the 5-hydroxytryptamine uptake blocker zimelidine on central 5-hydroxytryptamine mechanisms. Evidence for the induction of a low affinity binding site for 5-hydroxytryptamine.
Male rats were treated with saline or the 5-hydroxytryptamine (5-HT) uptake inhibitor zimelidine (10 mumol/kg postoperatively) twice daily for a period of 14 days. The effects of this treatment on [5-3H]HT binding in the cerebral cortex and hypothalamus and on 5-HT synthesis were examined. Long-term treatment with zimelidine induced a low affinity site for 5-HT (Kd approximately 20 nM) in both areas and a reduced number of high affinity binding sites in the hypothalamus. Long-term zimelidine treatment did not attenuate the feed-back mediated inhibition of 5-HT synthesis. These findings suggest that chronic zimelidine treatment could result in a reduced activity at postsynaptic 5-HT receptor sites.
Allylamine↗
Intrahippocampal injections of ibotenic acid provide histological evidence for a neurotoxic mechanism different from kainic acid.
Stereotaxic injections of ibotenic acid (IBO) and kainic acid (KA) into either the dorsal hippocampus or the lateral cerebroventricle were performed in order to determine the relative potencies of the drugs and the vulnerability of different hippocampal cell types to their neurotoxic action, IBO was found to be approximately five times less potent than KA in causing degeneration of hippocampal neuronal cell bodies. Unlike KA (0.5 and 1.0 microgram), IBO (5.0 micrograms) caused few signs of intrahippocampal bleeding or necrosis of non-neuronal elements. Pyramidal cells of the CA3 and CA4 regions were the most sensitive and dentate granule cells the least sensitive to KA. In contrast, IBO cused degeneration of granule cells and CA3/CA4 pyramids to an equal extent.
Animals↗
Catecholamine turnover changes in hypothalamus and dorsal midline area of the caudal medulla oblongata of spontaneously hypertensive rats.
The central noradrenaline (NA) and adrenaline (A) turnover in 15--16-week-old stroke prone, spontaneously hypertensive (sp-SH) female rats in an advanced stage of hypertension was found to differ from that of normotensive Wistar-Kyoto (WKy) control rats. The catecholamine (CA) levels were measured after inhibition of dopamine-beta-hydroxylase (DBH) or phenylethanolamine-N-methyltransferase (PNMT). in the hypertensive rats the dopamine (DA) and NA levels and the NA turnover were reduced in the hypothalamus, while in the dorsal part of the caudal medulla oblongata NA levels and A turnover were reduced. Changes in hypothalamic DA and NA mechanisms and in A mechanisms in medulla oblongata may therefore be of importance in the blood pressure regulation of sp-SH rats.
Animals↗
Reduction of adrenaline turnover in cardiovascular areas of rat medulla oblongata by clonidine.
Explore the source record for details and available documents.
Animals↗
Evidence for a selective reduction of adrenaline turnover in the dorsal midline area of the caudal medulla oblongata of young spontaneous hypertensive rats.
Explore the source record for details and available documents.
Animals↗
Localization and possible function of peptidergic neurons and their interactions with central catecholamine neurons, and the central actions of gut hormones.
The localization of various neuropeptides is described in the gut and in the hypothalamus in the rat. Evidence is given for the presence of material resembling corticotropin-like intermediate peptide in arcuate and periarcuate neurons, projecting to various hypothalamic nuclei, limbic areas and the thalamus. beta-Endorphin and glucagon decrease dopamine turnover in the median eminence, while secretin increases dopamine turnover and vasoactive intestinal polypeptide (VIP) has no effect. beta-Endorphin, VIP, secretin, and glucagon all produce discrete changes in norepinephrine turnover in various hypothalamic nuclei. Mainly increases of norepinephrine turnover were observed. These catecholamine turnover changes appear to cause changes in the secretion of prolactin and growth hormone. The results therefore indicate that gut hormones and opioid peptides may act directly on the hypothalamus on specific types of receptors to participate in the control of hypothalamic functions such as control of hormone secretion from the anterior pituitary and of food intake. It seems possible that gastrointestinal peptides released from the gastrointestinal tract into the circulation under certain circumstances could reach the hypothalamus and modulate its activity via the above-mentioned mechanisms. It may therefore be speculated that disturbances in gastrointestinal functions could lead to pathological changes in food intake via modulation of hypothalamic activity.
Adrenocorticotropic Hormone↗
Effects of bromocriptine on 3H-spiroperidol binding sites in rat striatum. Evidence for actions of dopamine receptors not linked to adenylate cyclase.
Explore the source record for details and available documents.
Adenylyl Cyclases↗
Studies on dopamine turnover in ovariectomized or hypophysectomized female rats. Effects of 17 beta-estradiol benzoate, ethynodioldiacetate and ovine prolactin.
The effects of 17 beta-estradiol benzoate (EB), ethynodioldiacetate and ovine prolactin on dopamine (DA) turnover have been studied. As an index for a change in turnover, differences in DA depletion following tyrosine hydroxylase inhibition with alpha-methyl-tyrosine methylester were observed. DA was measured by means of mass fragmentographical analysis in the rat median eminence, the olfactory tubercle and the striatum. The actions of ethynodioldiacetate and ovine prolactin on DA turnover in various subregions of the rat median eminence were analysed by quantitative microfluorimetry. Repeated injections of EB to ovariectomized rats resulted in a significant increase of DA turnover in the median eminence. Administration of ethynodioldiacetate to ovariectomized rats almost significantly increased DA turnover in the olfactory tubercle. In the median eminence DA turnover was significantly increased only in the lateral palisade zone. In male hypophysectomized rats ovine prolactin increased DA turnover in both the lateral and the medial palisade zone of the median eminence. The results support the involvement of DA neurons in the control of prolactin and luteinizing hormone secretion. It is suggested that the tubero-infundibular DA neurons are involved in mediating the central inhibitory feedback actions of prolactin and gonadal steroids on prolactin and LH secretion, respectively.
Animals↗
5,7-Dihydroxytryptamine as a tool to study the functional role of central 5-hydroxytryptamine neurons.
Explore the source record for details and available documents.
5,7-Dihydroxytryptamine↗
Dopamine receptors and ergot drugs. Evidence that an ergolene derivative is a differential agonist at subcortical limbic dopamine receptors.
The actions of a new type of ergolene derivative, MPME ((5R, 8R)-8-(4-p-methoxyphenyl-1-piperazinyl methyl)-6-methylergolene), have been evaluated on central catecholamine (CA) neurons in the rat by means of a combined biochemical, histochemical and behavioural analysis. The evidence suggests that this ergolene derivative is a preferential agonist at subcortical limbic dopamine (DA) receptors and at DA receptors belonging to the neostriatal DA islands. (1) MPME does not change the DA and noradrenaline (NA) levels 4 h after the injection in doses ranging from 0.1 to 5 mg/kg. MPME significantly reduced DA turnover in doses from 0.5 to 5 mg/kg, whereas the NA turnover was increased in the same dose range. (2) Histochemically, using quantitative microfluorometry, DA levels were unchanged, except in the islands of the nucleus caudatus following administration of MPME. The drug selectively reduced DA turnover in the subcortical limbic regions (tuberculum olfactorium and nucleus accumbens) and in the DA terminal islands of the nucleus caudatus in doses of 1-5 mg/kg, whereas the large diffuse DA terminal systems of the nucleus caudatus were unaffected. Using this ergolene derivative the islandic small neostriatal DA system can be excellently demonstrated also in the adult rat. The effects of MPME on DA turnover, are blocked by haloperiodol but not by methergoline (which blocks 5-HT receptors). (3) Studies on uptake of tritiated DA in the nucleus caudatus and tuberculum olfactorium reveal a weak inhibition of DA uptake and retention only in high concentrations (10(-5)-10(-6) M). Such actions therefore can probably not explain the changes in DA turnover observed. (4) Behavioural effects of MPME were evaluated in the rotometer model of Ungerstedt25. This model will reveal actions on supersensitive striatal DA receptors. MPME was found to mimic the action of apomorphine and cause a prolonged rotational behaviour towards the nonoperated side in doses of 0.25-0.5 mg/kg. A marked potentiation of the action of MPME was obtained by means of pretreatment with phosphodiesterase inhibitors suggesting that the effect of MPME might be mediated by cyclic AMP. Studies with the DA receptor blocking agent pimozide indicated a high affinity of MPME for the supersensitive striatal DA receptors, since only very high doses of pimozide (15 mg/kg) were capable of blocking the actions of MPME. (5) Studies on the effect of MPME on DA sensitive adenylate cyclase in the nucleus caudatus and the subcortical limbic system (mainly tuberculum olfactorium and nucleus accumbens) suggested that MPME is a partial DA receptor agonist with different intrinsic activity on the DA receptors of the subcortical limbic system and of the nucleus caudatus, the effects in the subcortical limbic system being considerably larger than in the nucleus caudatus. Thus, the present paper gives evidence that the various DA receptor populations in the brain are sufficiently different to allow their preferential activation by drugs.
Animals↗