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Biomedical subjects

K Fuxe

Publications and source records attributed to K Fuxe.

At least 523 records · Page 29Linked to original sources

Actions of centrally administered neuropeptide Y on EEG activity in different rat strains and in different phases of their circadian cycle.

The effects of centrally administered neuropeptide Y (NPY) on the sleep-wakefulness cycle have been studied by analyzing its action in different strains of rats with or without spontaneous hypertension and during two different phases of the circadian cycle. Normal adult Sprague-Dawley (SD), Wistar-Kyoto (WKy) and spontaneous hypertensive (SH) rats were used. By means of EEG electrodes the recording of the fronto-parietal electrocorticogram and the electromyogram could be made. Stainless steel cannula were also implanted into the lateral ventricle. The effects of an intraventricular injection of NPY (1.25 nmol/rat) was compared with the effects of the vehicle (saline) alone. The EEG patterns were classified as desynchronized, mixed or synchronized. In the SD rats NPY produced behavioural signs of sedation and a significant reduction of synchronized EEG activity as well as significant increase of synchronized and mixed EEG activities in comparison with the saline treated rats. In the WKy rats NPY administration produced an increase of synchronized EEG activity during evening sessions. In SH rats NPY produced a significant increase of desynchronized EEG activity and a decrease in mixed EEG activity indicating an awakening effect of the peptide. In view of the NPY innervation of the locus ceruleus, it therefore seems possible that the neuronal and hormonal regulation of the locus ceruleus noradrenaline nerve cells is different in the two strains of rats. It also seems possible that the ability of NPY to increase wakefulness in hypertensive animals is related to abnormal changes in the alpha 2-adrenoreceptors taking place in SH rats.

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Effect of GM1 ganglioside treatment on the recovery of dopaminergic nigro-striatal neurons after different types of lesion.

The effect of GM1 ganglioside treatment on the recovery of biochemical and behavioral parameters which define the activity of nigro-striatal dopaminergic systems has been investigated in rats after different types of lesion. GM1 favours the recovery of tyrosine-hydroxylase activity, of the number and affinity of 3H-N-n-propyl-norapomorphine binding sites in the striatum of the lesioned side and reduces the apomorphine-induced rotational behavior after mechanical (i.e. unilateral hemitransection) but not after chemical (i.e. 6-OHDA injected in the substantia nigra) lesion. The source of regrowing dopaminergic nerve terminals in the striatum after hemitransection is mainly a response of intact remaining axons of the ipsilateral side. Moreover the contralateral nigro-striatal systems seems to play, through intrathalamic connections, an important role in regulating the GM1-induced increase of the tyrosine-hydroxylase activity.

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Transmitter and peptide systems in areas involved in the control of blood pressure.

The distribution of catecholamine neurons in the dorsal vagal complex is described on the basis of indirect immunofluorescence histochemistry using antisera to three enzymes in the catecholamine synthesis, tyrosine hydroxylase, dopamine-beta-hydroxylase and phenylethanolamine-N-methyltransferase, allowing differentiation between dopamine, noradrenaline and adrenaline cells. In addition attention was focused on the occurrence of two peptides, neuropeptide Y (NPY) and neurotensin in this region. It could be established that they partly were present in subpopulations of the A2/C2 catecholamine neurons. The significance of this coexistence of a peptide and a catecholamine is discussed.

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Studies on aging processes.

By means of computer assisted morphometry and microdensitometry it has been possible to characterize aging processes in transmitter identified neurons demonstrated at the presynaptic level by immunocytochemistry and at the postsynaptic level by receptor autoradiography. Three-month- and 24-month-old rats were used in the present study. It was discovered that the DA neurons innervating the striatum and nucleus accumbens underwent degeneration in the aging brain both at the pre- and post-synaptic level, while the DA synapses within the tuberculum olfactorium remained intact. In this quantitative receptor autoradiographical analysis 3H-spiperone and 3H-N-propyl-norapomorphine were used as radioligands for DA receptors. In comparison with the aging induced changes in DA receptors in the striatum and in the nucleus accumbens the alpha 2- and the beta-adrenergic receptors appeared to be more resistant to the aging process. In the analysis of the opiate receptors of the aging brain it could be demonstrated by quantitative receptor autoradiography using both radioligands for the mu-type (3H-etorphin) and delta-type (3H-d-ala2-d-leu5-enkephalin) of opiate receptors that there is a marked and widespread disappearance of both types of opiate receptors in the aging brain. It must be emphasized that no correlation exists in the degeneration pattern of the mu- and delta-type of opioid receptors indicating that they may represent two separate entities with separate trophic regulation. In contrast, it was discovered in the quantitative receptor autoradiographical analysis that 3H-flunitrazepam binding was increased in many areas of the aging brain compared with the adult rat brain. These results underline the heterogeneity in the degenerative patterns which take place in transmitter receptors in relation to aging. Thus, these results indicate that the simple replacement therapy in aged patients may not give optimal results. As a matter of fact, such treatments can lead to a further unbalance between the various types of transmitter identified neurons building up the neuronal networks of the brain, which are undergoing degeneration.

Aging↗

Computer-assisted morphometry and microdensitometry of transmitter- identified neurons with special reference to the mesostriatal dopamine pathway. Methodological aspects.

New morphometrical and microdensitometrical approaches for evaluation of transmitter-identified neurons in the central nervous system have been developed. These rely at the presynaptic level on the use of immunocytochemistry and at the postsynaptic level on the use of receptor autoradiography. The immunocytochemical analysis involves the indirect immunofluorescence method and the indirect immunoperoxidase method utilizing cryostat and vibratome sections, respectively. In the postsynaptic analysis cryostat sections and tritium-sensitive film were employed. A block diagram representation of the system of the image analyzer used and its connection with its host computer is given. Furthermore, flow charts of the original software developed by our group in presented. The morphometrical analysis has been performed on coronal sections of rat brain resulting in determinations of cell body and cell group parameters. Based on this information, objective criteria have been introduced to assess the existence of a cell group of transmitter-identified neurons in a three-dimensional frame and to give a morphometrical description of this group in the space. Moreover, new quantitative approaches to describe the dendritic and terminal fields have been introduced and for the first time in this type of morphometrical analysis, the Lorenz curves and the Gini index have been utilized in the description of the pattern of dendritic and terminal networks. By means of these morphometrical approaches it became possible to analyze topological and biochemical heterogeneities within cell groups defined in the rostrocaudal frame. In particular, it has been possible to develop a quantitative method for the evaluation of coexistence in nerve cell bodies. This method has been called the overlap method and allows an analysis cell by cell of the possible coexistence of two or more antigens.

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Further studies on the effects of the GM1 ganglioside on the degenerative and regenerative features of mesostriatal dopamine neurons.

By means of computer assisted morphometry and microdensitometry the effects of chronic GM-1 ganglioside treatment have been further evaluated on the degenerative and regenerative features of mesostriatal DA neurons in the rat brain. In this study mainly a rostrocaudal morphometrical analysis was performed in the substantia nigra of the lesioned side. The specificity of the action of the GM-1 ganglioside on the substantia nigra DA cells was evaluated by a comparison with antiinflammatory drugs such as betametazon and acetylsalicylic acid. In the rostrocaudal analysis it was demonstrated that chronic GM-1 treatment preferentially protected the caudally located dopamine nerve cells from degeneration after partial hemitransection, while instead this chronic GM-1 treatment increased tyrosine hydroxylase immunoreactivity mainly within the rostrally located DA nerve cells present close to the site of the lesion. Furthermore, the specificity of the GM-1 action was demonstrated by the absence of protective effects of chronic treatment with betametazon and acetylsalicylic acid on the dopamine nerve cells of the lesioned side. These results open up the possibility that chronic GM-1 treatment, by exerting a stimulatory metabolic action on the DA nerve cells located close to the lesion, can enhance the production of neurotrophic factors in these cells, which in turn can diffuse out to increase the survival of the less severely lesioned DA nerve cells located in the caudal part of the substantia nigra. These results indicate that chronic GM-1 treatment may be beneficial in the treatment of neurons undergoing degeneration, which takes place e.g. in Parkinson's disease and after mechanical injury to the brain due to accidents or neurosurgical operations.

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Morphometrical analysis of the distribution of luteinizing hormone-releasing hormone and tyrosine hydroxylase-immunoreactive nerve terminals within the lateral palisade zone of the median eminence of the male rat.

By means of a semiautomatic image analyzer coupled to an Apple II computer with suitable computer programs it has been possible to demonstrate in a quantitative way the morphological interaction between luteinizing hormone-releasing hormone (LH-RH) and tyrosine hydroxylase (TH)-immunoreactive nerve terminals in the lateral palisade zone (LPZ) at various rostrocaudal levels of the median eminence. The overlap area represented about 50% of the TH- or the LH-RH-immunoreactive area. The dopamine nerve terminals showed a more medial and ventral position than the LH-RH-immunoreactive nerve terminals. The transmitter-identified nerve terminals in the LPZ may be organized in strips extending in the rostrocaudal direction and may have a differential regulation.

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Evidence for the existence of a dopamine receptor of the D-1 type in the rat median eminence.

By means of receptor autoradiography using the dopamine (DA) receptor radioligands [3H]cis(z)-flupenthixol ([3H]FLU), [3H]spiperone, [3H]N-propyl-norapomorphine and amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphtalene-2-(5,8[3H]) in combination with a microdensitometrical analysis indications have been obtained for the existence of a DA receptor of the D-1 type in the median eminence of the male rat. Thus, only [3H]FLU (10-20 nM) strongly labeled both the nuc. caudatus putamen and the median eminence and the labeling was markedly prevented by (+)-butaclamol in both regions. Furthermore, a DA receptor agonist of the D-1 type preferentially displaced [3H]FLU from the median eminence. Thus, a DA receptor of the low affinity type may regulate the secretion of hypothalamic hormones from the median eminence.

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Rat growth hormone and hypothalamic catecholamine nerve terminal systems. Evidence for rapid and discrete reductions in dopamine and noradrenaline levels and turnover in the median eminence of the hypophysectomized male rat.

Rat growth hormone (rGH) (100 micrograms/kg) produced 2-4 h after its i.v. injection a rapid reduction of catecholamine stores and turnover in the subependymal layer and in the medial and lateral palisade zone of the median eminence. It is suggested that rGH may inhibit its own secretion partly via reduction of DA synthesis and release in the median eminence leading to increased somatostatin release and partly via reduced noradrenaline synthesis and turnover in the median eminence leading to reduced secretion of a growth hormone releasing factor.

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Chronic ganglioside treatment counteracts the biochemical signs of dopamine receptor supersensitivity induced by chronic haloperidol treatment.

Chronic ganglioside treatment (10 mg/kg, i.p.) using the molecular species with only one neuroaminic acid residue (GM1) given together with haloperidol (0.3 and 5 mg/kg, i.p.) once daily in male rats, counteracted the haloperidol-induced increase in the number of [3H]spiperone binding sites in striatal membranes when the low dose of haloperidol, but not the high dose, was administered. The present results therefore indicate that chronic GM1 treatment can partially counteract the increase in the number of dopamine receptors having a high affinity for neuroleptics (D2 type) induced by chronic haloperidol treatment in striatal membranes, and therefore may also partially counteract the development of neuroleptic-induced dopamine receptor supersensitivity.

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Rapid and discrete changes in hypothalamic catecholamine nerve terminal systems induced by audiogenic stress, and their modulation by nicotine-relationship to neuroendocrine function.

The effects of acute audiogenic stress, with or without simultaneous nicotine treatment (0.3 mg/kg i.v.), on catecholamine levels in discrete dopamine and noradrenaline nerve terminal systems of the hypothalamus, and on the secretion of adenohypophyseal hormones and of corticosterone, were studied using quantitative microfluorometric evaluations of catecholamine stores and radioimmunoassays for the determination of serum hormone levels. Audiogenic stress and nicotine induced very rapid and discrete decreases in noradrenaline levels in the subependymal layer (SEL), in the parvocellular part of nuc. paraventricularis hypothalamic (PA FP) and in the posterior periventricular hypothalamic systems, (PV II); the decreases were apparent 2 min following the onset of treatment. Increases of arterial blood pressure were observed after nicotine treatment but could not have been a major factor in producing the changes in catecholamine levels. These changes in NA levels may be related to the nicotine- and stress-induced increases of ACTH (SEL and PA FP) and prolactin secretion (PV II) found in the present experiments. Stress enhanced the rapid but variable increase in vasopressin secretion induced by nicotine, suggesting one possible mechanism by which stress combined with smoking can contribute to the development of increased arterial blood pressure and finally to sustained hypertension.

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Immunohistochemical indications of gastrin releasing peptide--bombesin-like immunoreactivity in the nervous system of the rat. Codistribution with substance P-like immunoreactive nerve terminal systems and coexistence with substance P-like immunoreactivity in dorsal root ganglion cell bodies.

Weak to strong gastrin releasing peptide--bombesin (GRP-Bn)-like immunoreactivity was found in fine varicose nerve terminal systems of low to high densities in several parts of the CNS. The highest densities of strongly immunoreactive terminals were found in the marginal layer and in the substantia gelatinosa of the spinal cord, and in parts of the nuc. tractus spinalis nervi trigemini. Morphometrical analysis in the spinal cord demonstrates that GRP-BN-like-immunoreactive and substance P (SP), but not somatostatin (SS)-immunoreactive nerve terminals strikingly codistribute. Coexistence of SP and GRP-BN-like immunoreactivities was demonstrated in trigeminal and spinal ganglion nerve cells. Thus, GRP-BN-like immunoreactivity may coexist with SP in certain SP-immunoreactive nerve terminal systems.

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Evidence for interactions between [3H]glutamate and [3H]kainic acid binding sites in rat striatal membranes. Possible relevance for kainic acid neurotoxicity.

In vitro studies have shown that kainic acid (10(-6) M) but not N-methyl-D-aspartate (NMDA) in the same concentration reduces the number of striatal [3H]glutamate binding sites and increases their affinity in striatal membranes. In vitro studies also show that L-glutamate (10(-8) M) but not NMDA (10(-6) M) increases the number of [3H]kainic acid binding sites and reduces their affinity in striatal membranes. Ibotenic acid (10(-6) M) can also reduce the affinity of [3H]kainic acid binding sites in striatal membranes. These results give indications for the existence of bidirectional receptor-receptor interactions between two receptors for excitatory amino acids in local striatal circuits. These interactions could partly explain the involvement of glutamate in kainate neurotoxicity.

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