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K Fuxe

Publications and source records attributed to K Fuxe.

At least 667 records · Page 37Linked to original sources
PubMed1976

Aporphines. 14 Dopaminergic and antinociceptive activity of aporphine derivatives. Synthesis of 10-hydroxyaporphines and 10-hydroxy-N-n-propylnoraporphine.

The synthesis of racemic 10-hydroxyaporphine [(+/-)-2a] and 10-hydroxy-N-n-propylnoraporphine [(+/)-2b] is described. The method involved a Reissert alkylation-Pschorr cyclization route. The dopaminergic activity of (+/-)-2b was evaluated in comparison with L-Dopa, (-)-apomorphine (1a), (+/-)-N-n-propylnorapomorphine (NPA) (1b), and (+/-)-11-hydroxy-N-n-propylnoraporphine [(+/-)-11-OH-PNA] by the behavioral model of rotational behavior in animals after unilateral lesion of the ascending DA pathways. The dopaminergic activity of NPA and 11-OH-PNA is essentially equivalent to L-Dopa and (-)-apomorphine, and both are more active than (+/-)-2b. Furthermore, (+/-)-NPA (threshold doses, 5 mug/kg) appears to be even more potent that (-)-apomorphine (threshold doses, 25 mug/kg). The duration of action of NPA and 11-OH-PNA is considerably longer than that obtained with L-Dopa. The antinociceptive activity of (+/-)-2b was evaluated by the tail-flick procedure and compared with 1a, 2b, morphine, and L-Dopa. Weak but significant antinociceptive activity was shown by (+/-)-2b and by (+/-)-1b but not by (-)-apomorphine. This effect was not antagonized by naloxone. The finding that (+/-)-2b and particularly (+/-)-11-OH-PNA are active in doses from 500 to 50 mug/kg, respectively, in causing rotational behavior further supports previous studies indicating that N-n-propyl derivatives of monohydroxylated aporphines were more active than the corresponding parent N-methyl derivatives as DA receptor agonists and that a catechol system is not an absolute requirement for dopaminergic activity in such aporphines.

Analgesics↗
PubMed1976

Microfluorimetric quantitation of catecholamine fluorescence in rat median eminence. I. Aspects on the distribution of dopamine and noradrenaline nerve terminals.

Using the fluorescence histochemical technique of Falck and Hillarp, a quantitative microfluorimetric study of the catecholamine fluorescence in the median eminence has been performed. On the basis of morphologic criteria, the median eminence was subdivided into various areas from which the microfluorimetric measurements were made; the subependymal layer, the medial and lateral palisade zone of the rostral and the central and caudal region of the median eminence (for definitions of the various areas and regions, see Anatomical Subdivision). The highest fluorescence intensities were recorded from the lateral palisade zone, indicating that this area has the most dense catecholamine innervation, whereas the lowest fluorescence intensities were recorded from the subependymal layer. Dopamine-beta-hydroxylase inhibition produced by FLA-63, fusaric acid or diethyldithiocarbamate resulted in all cases in a 50-70% reduction of the catecholamine fluorescence in the subependymal layer, whereas only minute effects were observed in the lateral palisade zone. In the medial palisade zone, these treatments generally led to a substantial reduction (30-50%) of the catecholamine fluorescence. Basal hypothalamic deafferentation according to Halasz, or lesioning of the ventral catecholamine bundle, produced an almost complete disappearance of the fluorescence in the subependymal layer, while both procedures were largely ineffective in affecting the catecholamine fluorescence in the lateral palisade zone. On basal hypothalamic deafferentation the catecholamine fluorescence in the medial palisade zone was markedly reduced (40-60%), while the ventral bundle lesions were less efficient in this respect. From the present results it is suggested that the subependymal layer is mainly innervated by noradrenaline nerve terminals and the lateral palisade zone is mainly innervated by dopamine nerve terminals, whereas the medial palisade zone receives a mixed innervation of dopamine and noradrenaline terminals, the dopamine proportion being in the order of 50-75% of total catecholamine content.

Animals↗
PubMed1976

Microfluorimetric quantitation of catecholamine fluorescence in rat median eminence. II. Turnover changes in hormonal states.

Catecholamine nerve terminals in the rat median eminence have been studied using the fluorescence histochemical technique of Falck and Hillarp in combination with quantitative microfluorimetry. The catecholamine fluorescence intensities recorded from various parts of the median eminence were all found to be within the linear part of the dopamine or noradrenaline concentration-fluorescence relationship as studied in an agar-albumin model system. The catecholamine fluorescence was also found to disappear with time in an exponential manner following tyrosine hydroxylase inhibition produced by alpha-methyl-p-tyrosine methylester (H44/68). Similar results were obtained when measuring the dopamine decline by mass fragmentography in the median eminence after H44/68 treatment. These results and analysis of fluorescence frequency histograms strongly indicate that the catecholamine fluorescence values recorded are proportional to the catecholamine concentration. It is concluded that the microfluorimetric technique used is a reliable method for catecholamine quantitation in discrete nerve terminal areas of the median eminence. The main advantages of the technique are that a high sensitivity and quantitative data on the transmitter content can be obtained in strict relation to the neuroanatomy. Measurement of the catecholamine fluorescence disappearance after H44/68 was used to evaluate catecholamine turnover during various endocrine states. The results showed that two dopamine systems with different transmitter turnover may be distinguished. Tuberinfundibular dopamine neurons projecting to the lateral palisade zone were thus shown to have a slower turnover than those projecting medially to the capillary loops. No definite changes in catecholamine turnover were observed after adrenalectomy and castration in the male, although there was a tendency toward increased noradrenaline turnover in both states. During pregnancy an increase in noradrenaline as well as dopamine turnover was noted. The present results therefore give further evidence for the view that catecholamine nerve terminals in the median eminence may participate in the regulation of gonadotrophin secretion.

Adrenalectomy↗
PubMed1976

The antiparkinsonian efficacy of bromocriptine.

The antiparkinsonian activity of bromocriptine, a presumed dopaminergic receptor agonist, was investigated in monkeys with surgically induced tremor and in a group of parkinsonian patients. A single administration of bromocriptine resulted in a dose-dependent relief of tremor in monkeys. Repeated administration enhanced this effect. Only mild abnormal involuntary movements were observed and only after repeated administration. Eleven patients with Parkinson's disease were treated with bromocriptine (mean dose, 26.4 mg a day). Clinically obvious improvement was noted in one or more of the cardinal signs of the disease in six patients (responders). No obvious improvement in any of the cardinal signs was noted in the remaining five patients (nonresponders). Clinically, the responders were older and more severely affected and had been on a higher dose of levodopa. However, they had had the disease for a shorter period. It is suggested that failure to respond to bromocriptine may be related to a decrease in the sensitivity of postsynaptic dopaminergic receptors.

Age Factors↗
PubMed1976

Resistance of central phenylethanolamine-n-methyl transferase containing neurons to 6-hydroxydopamine.

The effects of the catecholamine neurotoxin 6-hydroxydopamine on phenylethanolamine-N-methyl transferase (PNMT) in rat brain has been investigated by biochemical and immunohistochemical analysis. 6-Hydroxydopamine was administerered either intracisternally to adult rats or systemically to newborn rats, treatments known to affect markedly central noradrenaline neurons. None of these treatments had any significant effect on the PNMT activity in the hypothalamus, pons-medulla and the spinal cord, as measured in vitro using a radiometric assay. The neonatal 6-hydroxydopamine treatment, which produced an almost complete noradrenaline denervation in the spinal cord, had no notable effect on the specific PNMT immunofluorescence localized in nerve terminals in the spinal cord. Transection of the spinal cord led to an almost complete disappearance of the PNMT activity and the specific immunofluorescence below the transection, pointing to the existence of a descending PNMT containing pathyway in the spinal cord. The present results show that the PNMT neurons are resistant to the neurotoxic action of 6-hydroxydopamine, possibly due to lack of catecholamine uptake mechanism or due to these neurons having an uptake mechanism with a low affinity for 6-OH-DA. Furthermore, the data support the view that the noradrenaline and PNMT containing neurons constitute separate neuron systems.

Adrenergic Fibers↗
PubMed1976

Immunohistochemical studies on the localization and distribution of monoamine neuron systems in the rat brain. I. Tyrosine hydroxylase in the mes- and diencephalon.

The localization and distribution of tyrosine hydroxylase (TH), the first enzyme in the catecholamine synthesis, in the mes- and diencephalon has been studied with the indirect immunofluorescence technique of Coons and collaborators. Principally, TH was present in neuron systems with a distribution similar to known dopamine, noradrenaline and adrenaline systems. The present data, taken together with published and some unpublished results, indicate that all parts of most central dopamine neurons, i.e. cell body, dendrites, axon and nerve terminals, appear strongly fluorescent. The adrenaline neurons also appeared strongly fluorescent, except for their axons, which only exhibited a weak fluorescence. Only cell bodies of noradrenaline neurons were strongly fluorescent, whereas the nerve terminals and axons showed a weak or moderate fluorescence intensity. The fine noradrenaline nerve terminals in some areas, such as the thalamus, were invisible or, under favourable conditions, weakly fluorescent. Therefore, in the present study we are mainly dealing with the dopamine neurons of the upper brain stem. Our results demonstrate a widespread occurrence of TH-positive neuron systems in the mes- and diencephalon. The different mesencephalic dopamine systems and their ascending projections were visualized. Numerous TH-positive cell bodies were present along the ventricle system extending from the aqueductus cerebri to the most cranial periventricular parts of the third ventricle. The caudal part of these neurons, consisting of very small cell bodies, belong to the dorsal periventricular system described by Lindvall and Björklund. Several TH-positive cell bodies were also observed in the inferior collicle of young animals. In the superficial layers of the inferior collicles TH positive nerve terminals were seen. At the hypothalamic level the A11 to A14 cell groups as well as some additonal cell bodies and extensive nerve terminal plexuses appeared strongly fluorescent. The differences in the intensity of the TH-related immunofluorescence between various brain regions and between various neuron systems may well reflect differences in enzyme levels between the various catacholamine systems rather than be due to the existence of different types of TH.

Adrenergic Fibers↗
PubMed1976

A system for measuring the noradrenaline receptor contribution to the flexor reflex.

A system is described for recording psoas muscle contractions in response to stimuli delivered to the sole of the foot of the acute spinalized unanaesthetized rat. Clonidine, an alpha adrenergic receptor agonist, caused a major increase in this flexor reflex amplitude. The increase was blocked by phenoxybenzamine at a dosage level of 20 mg/kg which did not, of itself, reduce flexor reflex amplitude. Older, larger rats responded significantly more forcefully to clonidine than did younger, smaller rats. However, these differences between rats of different size tended to disappear when the data were expressed in terms of 0/0 of original baseline amplitude. L-dopa, 75 mg/kg, increased the flexor reflex amplitude more so than did L(+)erythro dihydroxyphenylserine (DOPS) at twice the disage in rats pretreated with reserpine and nialamide. Other DOPS isomers were less effective, and L(-)threo DOPS was toxic. These results support the view that spinal noradrenaline receptors exist that increase the psoas flexor reflex. The advantages of the present system are twofold: first, the results may be quantitated; second, small amounts of potential central noradrenaline receptor agonists and antagonists may be tested for their effect on the flexor reflex using relatively few unanaesthetized rats.

Animals↗
PubMed1975

Effect of ergot drugs on central 5-hydroxytryptamine neurons: evidence for 5-hydroxytryptamine release or 5-hydroxytryptamine receptor stimulation.

In combined biochemical and functional studies it has been possible to show that ergocornine (0.5-5 mg/kg) and the ergolene derivative (5R,8R)-8-(4-p-methoxyphenyl-1-piperazinylmethyl)-6-methylergolene (PTR 17402; MPME) (0.25-5 mg/kg) reduce in a dose-dependent way brain 5-hydroxytryptamine (5-HT) turnover in rat as evaluated with the tryptophan hydroxylase inhibitor, alpha-propyl-dopacetamide (H 22/54), whereas 2-Br-alpha-ergocryptine (CB 154; Br-EC) had no effect on brain 5-HT turnover. Effects on 5-HT receptor activity were evaluated using the extensor hindlimb reflex of acutely spinalized rats. It was found that ergocornine increased the 5-HT receptor activity independent of presynaptic 5-HT stores and that it didnot have any effects on uptake, retention and spontaneous overflow of 3-H-5-HT in vitro but reduced the fiedl stimulation-induced release of 3-H-5-HT in vitro. Therefore, it is suggested that ergocornine is a 5-HT recpetor-stimulating agent, an effect which may lead to reduction of nervous impulse flow in the 5-HT neurons and subsequently of 5-HT release and turnover. MPME, on the other hand, seems to increase 5-HT receptor release of 5-HT stores, mainly from extragranular sites. Thus, the increase in extensor reflex activity found after MPME was reduced by reserpine and H 22/54 and enhanced by nialamide and in vitro MPME markedly increased 3-H-5-HT overflow in cortical slices of nialamide-pretreated rats and inhibited uptake and retention of 3-H-5-HT (EC50 equals 1.6 times 10-minus 6 M) in cortical slices of normal rats. Inhibition of the 5-HT membrane pump does not seem to be of any major importance, since chlorimipramine was only weakly active on the extensor reflex in the pharmacological models used and since MPME did not block but rather enhanced the 5-HT depletion caused by 4-methyl-alpha-ethyl-m-tyramine. It is suggested that MPME is a releaser of extragranular 5-HT stores leading to increased 5-HT receptor activity and reduction of 5-HT turnover in the same way as indicated for ergocornine. This new ergolene derivative may represent a new class of antidepressant drugs acting via release of extragranular 5-HT stores.

Animals↗
PubMed1975

Distribution of thyrotropin-releasing hormone (TRH) in the central nervous system as revealed with immunohistochemistry.

With the indirect immunofluorescence technique TRH-containing nerve terminals were found in the medial part of the external layer of the median eminence, the dorsomedial nucleus and the perifornical area, in extrahypothalmic nuclei such as nucleus accumbens, the lateral septal nucleus and in several motor nuclei of the brain stem and spinal cord. These findings suggest that TRH may act both as a hormone, released into the portal vessels, as well as a neurotransmitter or modulator, released at synapses in discrete regions of the brain and spinal cord.

Animals↗
PubMed1975

Role of monoamines in the control by hormones of sexual receptivity in the female rat.

The involvement of indole- and catecholamines in the hormonal regulation of sexual receptivity has been investigated in ovariectomized female rats. Drugs that reduce 5-hydroxytryptamine, dopamine, and adrenaline or increase noradrenaline neurotransmission tended to facilitate the occurrence of estrous behavior in estrogen-treated females, and drugs having opposite effects tended to inhibit receptivity induced by estrogen and progesterone. Estrogen decreased noradrenaline turnover in cortex and brain stem; progesterone enhanced this effect in brain stem but prevented it in cortex. Both hormones tended to block noradrenaline uptake in hypothalamus in vitro. In a schedule used to induce receptivity, estrogen accelerated serotonin turnover, an effect prevented by progesterone. Thus a number of monoamines may be involved in the control by hormones of estrous behavior. Furthermore, hormones affect both amine turnover and uptake mechanisms.

Adrenalectomy↗
PubMed1975

Action of dopamine receptor agonists in forebrain and hypothalamus: rotational behavior, ovulation, and dopamine turnover.

An ergolene derivative having a piperazine-phenyl side chain instead of a peptide side chain causes rotational behavior in experimental rats and appears to activate mainly limbic DA receptors when given in vivo, in contrast to amino acid ergot alkaloids, which appear to activate all DA receptors when given systemically. Theophyllamine and caffeine were found to cause considerable enhancement of the action of DA formed from DOPAP AND DA receptor agonists such as apomorphine, piribedil, and amino acid alkaloids on supersensitive DA receptors. Many DA receptor agonists such as apomorphine, piribedil, and CB 154 have in common the property to induce hypothermia in mice, an effect that may be related to actions on limbic DA receptors. Many DA receptors agonists such as apomorphine, piribedil, ergocornine, and CB 154 are able to block ovulation in immature rats treated with PMS. It is likely that this blockade is related to activation of a DA receptor in the median eminence controlling LRF secretion. DA receptor agonists antagonize sexual activity in the female rat, whereas DA receptor blocking agents enhance it. DA neurons may therefore subserve an inhibitory role in the control by hormones of sexual behavior. It is of considerable interest that there appear to exist inhibitory DA receptors with regard to both LRF secretion and sexual behavior.

Animals↗
PubMed1975

Evidence for an inhibitory gabergic control of the meso-limbic dopamine neurons: possibility of improving treatment of schizophrenia by combined treatment with neuroleptics and gabergic drugs.

Changes in dopamine (DA) turnover have been studied in rats after treatment with pimozide and/or gabergic drugs such as beta-(p-chlorophenyl)-GABA and aminooxyacetic acid using the tyrosine-hydroxylase inhibitor alpha-methyltyrosine and methylester (H44/68). The changes in DA levels were determined by quantitative microfluorimetrical analysis of the fluorescence in various DA terminal systems. Beta-(p-chlorophenyl)-GABA (5--20 mg/kg) and aminooxyacetic acid (25 mg/kg) counteracted the pimozide (1 mg/kg) induced increase in DA turnover in subcortical and cortical limbic regions but not in the caput of the caudatus. These findings indicate the existence of a strong and preferential inhibitory gabergic control of the mesolimbic DA neurons and offer the possibility of improving the treatment of schizophrenia provided that limbic DA receptors are involved in this disease. If so, lesions of gabergic pathways may exist in the schizophrenic brain.

Aminobutyrates↗