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1.
Brain Res Mol Brain Res ; 49(1-2): 188-96, 1997 Oct 03.
Article in English | MEDLINE | ID: mdl-9387878

ABSTRACT

Kainate-induced seizure activity causes persistent changes in the hippocampus that include synaptic reorganization and functional changes in the mossy fibers. Using in situ hybridization histochemistry, the expression of PKC alpha, PKC beta, PKC gamma, PKC delta and PKC epsilon mRNAs was investigated in the hippocampus of adult rats following seizures induced by a s.c. injection of kainic acid. In CA1 and CA3, we found a significant decrease in PKC gamma mRNA 1 day after kainic acid which persisted for a 2nd day in CA1. None of the other PKC isoform mRNAs were altered in CA1 or CA3. In granule cells, a significant up-regulation specific to PKC epsilon mRNA was observed. One week after kainic acid administration, a marked increase in PKC epsilon immunoreactivity was found that persisted 2 months after kainic acid administration. PKC epsilon immunoreactivity was found associated with mossy fibers projecting to the hilus of the dentate gyrus and to the stratum lucidum of the CA3 field and presumably with the newly sprouted mossy fibers projecting to the supragranular layer. These data provide the first evidence for a long-lasting increase of the PKC epsilon in the axons of granule cells caused by kainate-induced seizures and suggest that PKC epsilon may be involved in the functional and/or structural modifications of granule cells that occur after limbic seizures.


Subject(s)
Gene Expression Regulation, Enzymologic/physiology , Hippocampus/enzymology , Isoenzymes/biosynthesis , Kainic Acid/pharmacology , Neurons/enzymology , Protein Kinase C/biosynthesis , Seizures/enzymology , Transcription, Genetic/physiology , Amygdala/enzymology , Animals , Axons/enzymology , Caudate Nucleus/enzymology , Dentate Gyrus/enzymology , Gene Expression Regulation, Enzymologic/drug effects , Hippocampus/cytology , Hippocampus/pathology , In Situ Hybridization , Male , Neuroglia/enzymology , Neurons/cytology , Neurons/pathology , Olfactory Bulb/enzymology , Organ Specificity , Protein Kinase C beta , Protein Kinase C-alpha , Protein Kinase C-delta , Protein Kinase C-epsilon , Putamen/enzymology , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/pathology , Time Factors , Transcription, Genetic/drug effects
3.
Eur J Neurosci ; 9(1): 93-101, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9042573

ABSTRACT

Kainic acid-induced seizures, in adult rats produce neurodegeneration in the hippocampus followed by sprouting of the mossy fibres in the inner molecular layer of the dentate gyrus and changes in GAP-43 expression in the granule cells. In the present study we observed that 4 days after kainic acid injection a dense plexus of silver-impregnated degenerating terminals detected by Gallyas's method and a decrease of GAP-43 immunostaining was observed in the inner molecular layer of the dentate gyrus indicating deafferentiation of this region. This was associated with the formation of an intense GAP-43 immunostained band in the supragranular layer. MK-801, a non-competitive inhibitor of the NMDA receptor, which partially inhibited the behavioural seizures induced by KA, also protected from the inner molecular layer deafferentation and markedly reduced the expression of GAP-43 mRNA in the granule cells and the intense GAP-43 immunostained band in the supragranular layer, suggesting a relationship among these events. Two months after kainic acid injection the intense supragranular GAP-43 positive band was no longer evident but the whole inner molecular layer appeared more labelled in association with the formation of the collateral sprouting of the mossy fibres in the inner molecular layer as detected by Timm's staining. These effects were also markedly reduced by the pretreatment with MK-801. Taken together, these experiments indicate for the first time a direct relationship between the increase of GAP-43 immunostaining in the inner molecular layer of the dentate gyrus and the collateral sprouting of mossy fibres in this district in response to kainic acid induced seizures. This further supports the hypothesis that the early induction of GAP-43 in granule cells may be one of the molecular mechanisms required for the synaptic reorganization of the mossy fibres.


Subject(s)
Dentate Gyrus/metabolism , Excitatory Amino Acid Agonists/pharmacology , Hippocampus/physiology , Kainic Acid/pharmacology , Membrane Glycoproteins/biosynthesis , Nerve Fibers/physiology , Nerve Tissue Proteins/biosynthesis , Neurofilament Proteins/biosynthesis , Synapses/physiology , Animals , Dentate Gyrus/drug effects , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , GAP-43 Protein , Hippocampus/cytology , Hippocampus/drug effects , Immunohistochemistry , In Situ Hybridization , Male , Nerve Fibers/drug effects , Pyramidal Cells/physiology , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/pathology , Silver Staining , Synapses/drug effects
4.
J Neurochem ; 67(2): 463-72, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8764569

ABSTRACT

After a single intraperitoneal injection of the irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA; 300 mg/kg), there was a rapid down-regulation of serotonin (5-HT) transporter mRNA levels in cell bodies. This change was significant at 1 and 2 days after PCPA administration within the ventromedial but not the dorsomedial portion of the dorsal raphe nucleus. Seven days after PCPA treatment, 5-HT transporter mRNA levels were significantly elevated compared with controls in both regions of the dorsal raphe nucleus. PCPA administration produced no change in the [3H]citalopram binding and synaptosomal [3H]5-HT uptake in terminal regions at 2 and 7 days after treatment but significantly reduced both these parameters by approximately 20% in the hippocampus and in cerebral cortex 14 days after PCPA administration. The striatum showed a lower sensitivity to this effect. No significant changes were observed in the levels of [3H]citalopram binding to 5-HT cell bodies in the dorsal raphe nucleus. In the same animals used for 5-HT transporter mRNA level measurements, levels of tryptophan hydroxylase mRNA in neurons of the ventromedial and dorsomedial portions of the dorsal raphe nucleus were increased 2 days after PCPA administration and fell to control levels 7 days after injection in the ventromedial region but not in the dorsomedial portion of the dorsal raphe nucleus, where they remained significantly higher than controls. Altogether, these results show that changes in 5-HT transporter mRNA are not temporally related to changes in 5-HT transporter protein levels. In addition, our results suggest that the 5-HT transporter and tryptophan hydroxylase genes are regulated by different mechanisms. We also provide further evidence that dorsal raphe 5-HT neurons are differentially regulated by drugs, depending on their location.


Subject(s)
Carrier Proteins/genetics , Enzyme Inhibitors/pharmacology , Fenclonine/pharmacology , Membrane Glycoproteins/genetics , Membrane Transport Proteins , Nerve Tissue Proteins , Tryptophan Hydroxylase/antagonists & inhibitors , Animals , Base Sequence , Citalopram/metabolism , DNA Primers/chemistry , Gene Expression Regulation/drug effects , Molecular Sequence Data , RNA, Messenger/genetics , Raphe Nuclei/drug effects , Raphe Nuclei/metabolism , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins , Synaptosomes/metabolism , Tryptophan Hydroxylase/genetics
5.
Neuroreport ; 5(18): 2645-8, 1994 Dec 20.
Article in English | MEDLINE | ID: mdl-7696623

ABSTRACT

Kainic acid (KA)-induced seizures in adult rats have been reported to cause sprouting of mossy fibres in the inner molecular layer (IML) of the dentate gyrus. In the present study, using electron microscopic immunostaining for GAP-43 we found that 3 months after KA treatment, several GAP-43 positive terminals in the IML showed structural characteristics of mossy fibre boutons. No GAP-43-positive mossy fibre terminals were found in the normal projection areas of granule cells, thus indicating that newly synthesized GAP-43 is transported predominantly in the axonal branches actively undergoing remodelling. These results provide evidence of the involvement of GAP-43 in the structural remodelling of mossy fibres, and suggest a role of this protein in the functional activity of the sprouted mossy fibres as a consequence of KA-induced seizures.


Subject(s)
Hippocampus/metabolism , Hippocampus/ultrastructure , Membrane Glycoproteins/metabolism , Nerve Fibers/metabolism , Nerve Regeneration , Nerve Tissue Proteins/metabolism , Animals , GAP-43 Protein , Hippocampus/drug effects , Immunohistochemistry , Kainic Acid/pharmacology , Male , Microscopy, Electron , Nerve Fibers/ultrastructure , Phosphoproteins/metabolism , Rats , Rats, Sprague-Dawley , Tissue Distribution
6.
Eur J Pharmacol ; 268(3): 439-42, 1994 Aug 16.
Article in English | MEDLINE | ID: mdl-7805769

ABSTRACT

In situ hybridization was used to measure the effects of chronic fenfluramine administration on serotonin transporter messenger RNA expression in cells of the dorsal raphe nucleus complex. Fenfluramine produced a significant, but transient, down-regulation of serotonin transporter mRNA in cells which lie in the ventral portion of the dorsal raphe nucleus, but not in the dorsal part of the dorsal raphe nucleus. Our findings suggest that cells which lie in the ventral part of the dorsal raphe nucleus are more sensitive to the effects of chronic fenfluramine administration, but that fenfluramine does not cause long-term changes in gene expression in serotonin cell bodies.


Subject(s)
Carrier Proteins/biosynthesis , Fenfluramine/pharmacology , Membrane Glycoproteins/biosynthesis , Membrane Transport Proteins , Nerve Tissue Proteins , RNA, Messenger/biosynthesis , Raphe Nuclei/metabolism , Animals , Base Sequence , Depression, Chemical , Down-Regulation/drug effects , Image Processing, Computer-Assisted , In Situ Hybridization , Male , Molecular Sequence Data , Raphe Nuclei/drug effects , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins , Tryptophan Hydroxylase/biosynthesis
7.
Brain Res Bull ; 34(4): 389-94, 1994.
Article in English | MEDLINE | ID: mdl-8082031

ABSTRACT

Intracerebroventricularly (ICV) injected 5,7-dihydroxytryptamine (5,7-DHT), which reduced by 70-90% forebrain serotonin levels, significantly raised glial fibrillary acidic protein (GFAP) mRNA levels in the hippocampus and nucleus raphe dorsalis 5 days but not 15 days after the lesion. A significant increase of mitochondrial benzodiazepine receptors (MBR), measured by binding autoradiography of 3H-PK 11195, was found in the nucleus raphe dorsalis 5 and 15 days after the ICV 5,7-DHT and also in the hippocampus, ventral tegmental area, and substantia nigra at 15 days. No significant effect was observed in the striatum and cortex for either GFAP mRNA or MBR binding. Unlike the ICV route, bilateral injection of 5,7-DHT into the medial forebrain bundle, which caused a 65-90% reduction of serotonin levels in different forebrain regions, significantly raised GFAP mRNA and MBR binding only at the site of injection with no effect in hippocampus, striatum, and cortex. MBR binding slightly increased in the nucleus raphe dorsalis 15 days after the lesion. High doses of d-fenfluramine (10 mg/kg intraperitoneally twice daily for 4 days) caused 80-90% reduction of serotonin levels 5 days after the last injection but did not change the GFAP mRNA or the MBR binding in any of the brain regions considered. These findings suggest that the effect of 5,7-DHT on microglial and glial markers is probably related to a nonspecific interaction with other neuronal systems besides the serotonin or to direct interaction with glial cells; the use of these parameters for detecting selective degeneration of serotonin axons presents some obvious limitations.


Subject(s)
Glial Fibrillary Acidic Protein/biosynthesis , Mitochondria/metabolism , Nerve Degeneration/physiology , Neurons/metabolism , Neurons/physiology , RNA, Messenger/biosynthesis , Receptors, GABA-A/metabolism , Serotonin/physiology , 5,7-Dihydroxytryptamine/administration & dosage , 5,7-Dihydroxytryptamine/pharmacology , Animals , Autoradiography , Blotting, Northern , Brain/anatomy & histology , Brain Chemistry/drug effects , In Situ Hybridization , Injections , Injections, Intraventricular , Isoquinolines , Male , Medial Forebrain Bundle , Mitochondria/drug effects , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Serotonin/metabolism
8.
Neurosci Lett ; 160(2): 197-200, 1993 Oct 01.
Article in English | MEDLINE | ID: mdl-7902549

ABSTRACT

The levels of neuropeptide Y and somatostatin may change when serotoninergic neurotransmission is altered in different brain regions. To assess whether serotonin regulates the synthesis of these peptides, we measured the levels of preproneuropeptide Y (ppNPY) and preprosomatostatin (ppSOM) mRNA in different brain regions after intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), a selective serotonin neurotoxin. The mRNA of these peptides significantly increased in the striatum but not in hippocampus and frontal cortex. It thus appears that serotonin has an inhibitory effect on the biosynthesis of neuropeptide Y and somatostatin in striatum whereas it probably acts by stimulating the release of these peptides in hippocampus and frontal cortex.


Subject(s)
Cerebral Ventricles/physiology , Corpus Striatum/metabolism , Gene Expression/physiology , Hippocampus/metabolism , Neuropeptide Y/biosynthesis , Protein Precursors/biosynthesis , RNA, Messenger/biosynthesis , Somatostatin/biosynthesis , 5,7-Dihydroxytryptamine/toxicity , Animals , Cerebral Ventricles/drug effects , Frontal Lobe/metabolism , Gene Expression/drug effects , Male , Organ Specificity , Rats , Rats, Sprague-Dawley
9.
Brain Res Mol Brain Res ; 19(3): 257-61, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8412572

ABSTRACT

Repeated high doses of d-fenfluramine (dF; 10 mg/kg, i.p. twice daily for 4 days) markedly reduced serotonin (5-HT) concentrations in the hippocampus and striatum of rat brain up to 1 month after treatment, while tryptophan hydroxylase (TPH) levels were reduced only in the hippocampus 5 days after injection. Unlike dF, an intracerebroventricular (i.c.v.) injection of 5,7-dihydroxytryptamine (5,7-DHT 150 micrograms/20 microliters) induced a marked and long-lasting reduction of 5-HT and TPH in both brain regions. Thirty days after injection, 5,7-DHT, but not dF, markedly reduced the number of labelled neurons in the dorsal and ventral regions of the nucleus raphe dorsalis (NRD) and raised the levels of TPH mRNA in the spared neurons at all times examined. TPH mRNA levels were raised 5 and 15 days after dF treatment in the NDR suggesting that changes in the TPH gene expression or transcript stability result following 5-HT depletion. These data are in agreement with the suggestion that 5,7-DHT damages 5-HT nerve terminals and perikarya, but leave unanswered the question of the mechanism of the long-lasting reduction of 5-HT levels caused by high, repeated doses of dF.


Subject(s)
5,7-Dihydroxytryptamine/pharmacology , Brain/drug effects , Fenfluramine/pharmacology , RNA, Messenger/drug effects , Serotonin/metabolism , Tryptophan Hydroxylase/drug effects , Animals , Brain/enzymology , Brain/metabolism , Corpus Striatum/drug effects , Hippocampus/drug effects , In Situ Hybridization , Injections, Intraventricular , Male , RNA, Messenger/metabolism , Raphe Nuclei/drug effects , Rats , Rats, Sprague-Dawley , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolism
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