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Biomedical subjects

M A Riva

Publications and source records attributed to M A Riva.

At least 19 recordsLinked to original sources
PubMed2006

Chronic cocaine administration modulates the expression of transcription factors involved in midbrain dopaminergic neuron function.

Chronic cocaine use leads to pronounced alterations in neuronal functions in brain circuits associated with reward. In the present study, we examined in the rat midbrain the effects of acute, subchronic (5 days) and chronic cocaine treatments (14 days) on the gene expression of transcription factors involved in the development and maintenance of dopaminergic neurons. We show that chronic, but not acute or subchronic, cocaine administration downregulates Nurr1 and Pitx3 transcripts whereas En1 transcripts are upregulated. Conversely, Lmx1b and En2 transcripts are not affected by the drug treatment, indicating that the modulation of the midbrain transcription factors analyzed is highly selective. Interestingly, modification of the gene expression for these transcription factors persists in midbrain as long as two weeks after the last drug administration, suggesting that it may account for some of the enduring alterations in midbrain dopaminergic circuits associated with chronic cocaine use.

Animals↗
PubMed2005

Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain.

Accumulating evidence indicates that antidepressants alter intracellular signalling mechanisms resulting in long-term synaptic alterations which probably account for the delay in clinical action of these drugs. Therefore, we investigated the effects of chronic fluoxetine administration on extracellular signal-regulated kinase (ERK) 1 and 2, a group of MAPKs that mediate signal transduction from the cell surface downstream to the nucleus. Our data demonstrate that 3-week fluoxetine treatment resulted in long-lasting reduction of phospho-ERK 1 and 2. Such an effect depends on the length of the treatment given that no changes were observed after a single drug injection or after 2 weeks of treatment and it is region specific, being observed in hippocampus and frontal cortex but not in striatum. Finally, phospho-ERK 1 and 2 were differently modulated within nucleus and cytosol in hippocampus but similarly reduced in the same compartments of the frontal cortex, highlighting the specific subcellular compartmentalization of fluoxetine. Conversely, imipramine did not reduce the hippocampal phosphorylation of both ERK subtypes whereas it selectively increased ERK 1 phosphorylation in the cytosolic compartment of frontal cortex suggesting a drug-specific effect on this intracellular target. These results point to modulation of phosphorylation, rather than altered expression, as the main target in the action of fluoxetine on this pathway. The reduction of ERK 1/2 function herein reported may be associated with the therapeutic effects of fluoxetine in the treatment of depression.

Animals↗
PubMed2002

Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus.

It is well accepted that events that interfere with the normal program of neuronal differentiation and brain maturation may be relevant for the etiology of psychiatric disorders, setting the stage for synaptic disorganization that becomes functional later in life. In order to investigate molecular determinants for these events, we examined the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) and the glutamate NMDA receptor following 24 h maternal separation (MD) on postnatal day 9. We found that in adulthood the expression of BDNF as well as of NR-2A and NR-2B, two NMDA receptor forming subunits, were significantly reduced in the hippocampus of MD rats whereas, among other structures, a slight reduction of NR-2A and 2B was detected only in prefrontal cortex. These changes were not observed acutely, nor in pre-weaning animals. Furthermore we found that in MD rats the modulation of hippocampal BDNF in response to an acute stress was altered, indicating a persistent functional impairment in its regulation, which may subserve a specific role for coping with challenging situations. We propose that adverse events taking place during brain maturation can modulate the expression of molecular players of cellular plasticity within selected brain regions, thus contributing to permanent alterations in brain function, which might ultimately lead to an increased vulnerability for psychiatric diseases.

Animals↗
PubMed2001

Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats.

BACKGROUND: A disturbance in glutamate neurotransmission has been hypothesized in schizophrenia. Hence, the beneficial effects of pharmacological treatment may be related to adaptive changes taking place in this neurotransmitter system. METHODS: In this study, we investigated the modulation of ionotropic and metabotropic glutamate receptors in the rat brain following acute or chronic exposure to the novel antipsychotic olanzapine. RESULTS: In accordance with the clear distinction between classical and atypical drugs, olanzapine did not alter glutamate receptor expression in striatum. Chronic, not acute, exposure to olanzapine was capable of up-regulating hippocampal mRNA levels for GluR-B and GluR-C, two alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-forming subunits. This effect could be relevant for the improvement of schizophrenic alterations, which are thought to depend on dysfunction of the glutamatergic transmission within the hippocampal formation. We also found that the expression of group II glutamate metabotropic receptors was up-regulated in the frontal cortex after chronic exposure to clozapine, and to a lesser extent olanzapine, but not with haloperidol. CONCLUSIONS: The adaptive mechanisms taking place in glutamatergic transmission might prove useful in ameliorating some of the dysfunction observed in the brain of schizophrenic patients.

Animals↗
PubMed2001

Modulation of fibroblast growth factor-2 by stress and corticosteroids: from developmental events to adult brain plasticity.

Neurotrophic factors are a heterogeneous group of peptides that play important roles on brain function at different development stages. Basic fibroblast growth factor (FGF-2), one of these molecules, is highly expressed in developing and adult brain. Its expression can be regulated under different experimental situations and this may be relevant for cellular vulnerability and brain plasticity. Stress and glucocorticoid hormones produce short- and long-term effects on brain function, which can involve the regulation of specific neurotrophic factors within selected brain structures. Treatments with corticosterone or dexamethasone up-regulate FGF-2 expression in different rat brain regions as well as in cultured astroglial cells. A similar elevation of FGF-2 biosynthesis is also observed in several brain regions following an acute restraint stress. This response is rapid and transient and, as FGF-2 is neuroprotective, may represent a defense mechanism through which the brain may limit the deleterious effect of stress over time. Moreover exposure to corticosterone during late stage of embryonic life (E18-E20) produces a significant reduction of FGF-2 mRNA levels in the adult hippocampus of male rats as well as changes in its acute modulation in response to stress or corticosterone. These data suggest that stress-related events taking place during brain maturation can modulate the expression of FGF-2 within selected brain regions thus contributing to permanent structural and functional alterations leading to an increased vulnerability to challenging life events.

Adrenal Cortex Hormones↗
PubMed2001

Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia.

The neonatal (PND 7) lesion of the ventral hippocampus (VH) with ibotenic acid represents a well-established experimental paradigm that recapitulates many schizophrenia-like phenomena. In order to investigate molecular changes that could contribute to long lasting consequences on brain function, we have investigated the effects of the VH lesion on the expression for the trophic factors FGF-2 and BDNF. We used RNase protection assay to measure their mRNA levels in cortical regions of prepubertal (PND 35) and young adult (PND 56) animals, both under basal condition as well as in response to an acute restraint stress. The expression of BDNF was not altered by the VH lesion in prefrontal (PFC) and frontal cortex (FC) of PND 35 or PND 56 rats. An acute restraint stress at PND 35 produced a significant increase of the neurotrophin expression in PFC of sham as well as lesioned animals. However in young adult animals a significant elevation of BDNF expression was observed only in sham rats. We also found that the VH lesion produced a significant reduction of basal BDNF mRNA levels in the cingulate cortex of young adult, but not prepubertal rats. This effect was not accompanied by changes in the acute modulation of the neurotrophin, which was up-regulated by stress in both experimental groups. Conversely the expression of FGF-2 at PND 35 and PND 56 was not altered by early postnatal VH lesion, and there were no major differences between sham and lesioned animals in response to the acute stress. The changes in trophic factor expression may be relevant for the long-term effects of VH lesion on synaptic plasticity and may determine an increased vulnerability of the brain under challenging situations.

Animals↗
PubMed2000

Calcium-dependent modulation of FGF-2 expression in cultured cerebellar granule neurons.

We investigated the expression for fibroblast growth factor-2 (FGF-2), in cultured rat cerebellar granule cells and its modulation by Ca2+ regulating agents. There were no significant differences in the levels of FGF-2 mRNA in cells cultured in high vs low K+. The expression of the trophic factor is induced by Ca2+ entry through the plasma membrane only in mature neurons but not at an early stage of maturation. Conversely the release of Ca2+ from intracellular stores increased the expression for FGF-2 at 2 or 7 days in culture. suggesting that is not dependent upon cellular maturation. These results suggest that specialized mechanisms can operate to regulate FGF-2 expression and that the integration of electrical and receptor-mediated signals for its modulation within cerebellar granule neurons may depend upon the maturational stage of the cells.

Animals↗
PubMed2000

Corticosteroids regulate the gene expression of FGF-1 and FGF-2 in cultured rat astrocytes.

The present data show that the gene expression of FGF-1 and FGF-2 is regulated by corticosteroids in rat type 1 astrocytes. In particular, the gene expression of FGF-1 is modulated by corticosteroids acting both on type I (minerocorticoid) and type II (glucocorticoid) receptors. In fact, at short times of exposure (2 h) a slight decrease in FGF-1 mRNA levels is induced by deoxycorticosterone, a steroid able to interact with the type I receptors; a similar effect is observed at 6 h following exposure to corticosterone or its 5alpha-reduced metabolite, dihydrocorticosterone. Conversely, at longer times of exposure (24 h) corticosterone is able to strongly increase FGF-1 mRNA levels. Both effects of corticosterone (inhibition and stimulation) were duplicated by dexamethasone, indicating that both effects occur via the type II receptors. Interestingly, the 5alpha-3alpha-reduced metabolite of deoxycorticosterone, tetrahydrodeoxycorticosterone, which does not interact with either corticosteroid receptors, is able to stimulate (at 6 and 24 h of exposure) the gene expression of FGF-1. It is possible that this effect might be induced via the GABA(A) receptor, since muscimol, an agonist of this receptor, exerts a similar effect. The situation is different in the case of FGF-2. The mRNA levels of this growth factor are only stimulated by steroids interacting with type II receptors. Altogether, these observations indicate that corticosteroids modulate the levels of FGF-1 and FGF-2 gene expression in astroglial cells by interaction with classical (type I and II) or nonclassical (GABA(A) receptor) steroid receptors.

Adrenal Cortex Hormones↗
PubMed1999

Selective modulation of fibroblast growth factor-2 expression in the rat brain by the atypical antipsychotic clozapine.

In the present paper we investigated, in the rat brain, the expression of basic fibroblast growth factor (FGF-2) in response to the atypical antipsychotic clozapine. We found that acute or chronic administration of this compound produced a selective increase of FGF-2 mRNA and protein in the striatum. Although acute injection of clozapine did increase FGF-2 expression in parietal cortex and nucleus accumbens we found that, following repeated administration, the induction of the trophic molecule was taking place only at striatal level. The analysis of other antipsychotic drugs did not provide conclusive evidence for the molecular mechanisms involved in clozapine-induced elevation of FGF-2. In fact, chronic administration of classical neuroleptics, haloperidol and chlorpromazine, did not alter the expression of FGF-2. Furthermore the novel drugs quetiapine and olanzapine, despite some similarities in their receptor profiles, were similarly ineffective. Hence these data suggest that, among antipsychotic drugs, the induction of FGF-2 is unique to clozapine. On the basis of the neuroprotective activity of this trophic molecule, our data might be relevant for the potential use of clozapine in tardive dyskinesia and parkinsonism, which develop during long term administration of classical neuroleptic drugs.

Animals↗
PubMed1999

Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic seroquel (quetiapine fumarate).

The interplay between dopamine and glutamate appears to be relevant in the etiopathology of schizophrenia. Although currently used antipsychotics do not interact with glutamatergic receptors, previous results have demonstrated that the expression profile of ionotropic glutamate receptors can be regulated by drugs such as haloperidol or clozapine. In the present investigation, the mRNA levels for NMDA and AMPA receptor subunits were measured after chronic treatment with the novel antipsychotic agent Seroquel (quetiapine fumarate, quetiapine) as compared to haloperidol and clozapine. Similarly to the prototype atypical clozapine, quetiapine reduced the mRNA expression for NR-1 and NR-2C, two NMDA forming subunits, in the nucleus accumbens. Furthermore, quetiapine, but not haloperidol or clozapine, increased the hippocampal expression for the AMPA subunits GluR-B and GluR-C. The differences between classical and atypical antipsychotics, as well as among the novel agents, might be relevant for specific aspects of their therapeutic activity and could provide valuable information for the role of glutamate in specific symptoms of schizophrenia.

Animals↗
PubMed1998

Differential regulation of FGF-2 and FGFR-1 in rat cortical astrocytes by dexamethasone and isoproterenol.

We have used rat cortical astrocytes in culture to investigate the signaling pathways involved in the regulation of fibroblast growth factor-2 (FGF-2) and one of its high affinity receptor FGF receptor-1 (FGFR-1). These cells represent a source of different neurotrophic factors and play important roles in physiological and pathological conditions of the central nervous system. FGF-2 mRNA levels are increased by stimulation of beta-adrenergic receptors or exposure to glucocorticoid hormones and these effects are additive to each other. The regulation of FGFR-1, highly expressed in cultured astroglial cells, appears to be different. Isoproterenol produced an elevation of FGFR-1 mRNA levels, whereas dexamethasone decreased its expression alone or in the presence of isoproterenol, suggesting that the glucocorticoid pathway may predominate over the cAMP-induced up-regulation of the receptor. FGF-2 over-expression may produce different cellular responses depending on the concomitant regulation of its receptor and the cell phenotype where these changes do occur. These mechanisms can contribute to adaptive changes taking place in the CNS in different physiological and pathological situations.

Adrenergic beta-Agonists↗
PubMed1997

Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs.

Based on anatomical and biochemical observations a role of glutamate in schizophrenia has been postulated. In the present work we have investigated the gene expression for two families of NMDA receptor subunits (NR-1 and NR-2) following acute and chronic treatment with typical (haloperidol) and atypical (clozapine) antipsychotic drug (APD) in rats. A single injection of the two drugs elicited a significant increase in the mRNA levels of NR-2B in the nucleus accumbens, whereas only haloperidol was able to elevate NR-2A and NR-2B in the hippocampus. Following a 21 day treatment, significant differences in the regulatory pattern of NMDA-R subunits were observed. Haloperidol increased their mRNA levels in striatum whereas clozapine, consistent with its relatively weaker influence on nigro-striatal dopamine function, did not change the expression of NR subunits in this region. Both APD's were able to decrease the expression of NR-2 subunits in the hypothalamus, but only clozapine was capable of reducing NR-2C in frontal cortex and accumbens. The regulation of NMDA-R subunits in specific brain regions may represent a novel and important mechanism through which APD's exert some of their effects on brain function.

Animals↗
PubMed1997

L-deprenyl potentiates cAMP-induced elevation of FGF-2 mRNA levels in rat cortical astrocytes.

The expression of fibroblast growth factor-2 (FGF-2, basic FGF) is up-regulated in astroglial cells by different stimuli, including glucocorticoid hormones and agents that cause an increase in cyclic AMP (cAMP) levels. In the present study we showed that L-deprenyl, a drug able to rescue neurons from potentially lethal damage, can potentiate FGF-2 induction by 8Br-cAMP in cultured astrocytes. This effect appears to be independent from its well known inhibitory activity on monoamine oxidase (MAO) type B. As astrocyte activation is an important step in response to neuronal injury, our data suggest that potentiation of neurotrophic factor expression may exert neuroprotection and therefore limit the progression of neuronal damage in several pathological situations.

Animals↗
PubMed1997

Astrocyte-neuron interactions in vitro: role of growth factors and steroids on LHRH dynamics.

The data here reviewed, obtained with in vitro models, indicate that growth factors and steroids play a significant role in astrocyte-neuron interactions. Different designs have been adopted: (1) GT1-1 cells (a cell line derived from a mouse hypothalamic LHRH-producing tumor) were cocultured with type 1 rat astrocytes; and (2) GT1-1 cells were exposed to the conditioned medium (CM) in which type 1 rat astrocytes had been grown for 24 h. LHRH release and mRNA LHRH levels were measured respectively in the medium and in cell homogenates, at different time intervals (LHRH release, by RIA; LHRH mRNA by Northern blot analysis). The data obtained show that type 1 astrocytes secrete in the medium TGFbeta, which is able to modulate the release and the gene expression of LHRH in GT1-1 cells; and that one or more LHRH-degrading enzymes is/are present in the conditioned medium of type 1 astrocytes. A second part of the experiments have indicated that type 1 astrocytes are also able to affect, in different directions, the metabolism of testosterone and progesterone into their 5alpha-reduced metabolites occurring in the GT1-1 cells. In particular, it has been observed that the conversion of testosterone into DHT is decreased by the coculture with type 1 astrocytes, while the conversion of progesterone into DHP is increased by the same coculture conditions. Moreover, type 1 astrocytes are sensitive to steroid hormones, and in particular to the 5alpha-reduced metabolites of progesterone; this has been shown by analyzing the effects exerted by different steroids on the gene expression of the typical astrocyte marker GFAP.

Animals↗
PubMed1997

Corticosteroid effects on gene expression of myelin basic protein in oligodendrocytes and of glial fibrillary acidic protein in type 1 astrocytes.

The paper describes the effects of corticosterone and deoxycorticosterone (DOC), used in their native or in their 5 alpha-reduced molecular forms (dihydrocorticosterone, DHC; dihydrodeoxycorticosterone, DHDOC; and tetrahydrodeoxycorticosterone, THDOC) on the gene expression of the myelin basic protein (MBP) and of the glial fibrillary acidic protein (GFAP) in pure cultures, respectively, of oligodendrocytes and type 1 astrocytes obtained from the neonatal rat brain. Among the different steroids tested (corticosterone, DHC, DOC, DHDOC and THDOC), only DHDOC was effective on the gene expression of MBP in the oligodendrocyte cultures; the mRNA levels of this typical oligodendrocyte marker were decreased following exposure to this steroid for 24 h. In the case of the astrocytic marker GFAP, its gene expression was increased by the exposure to corticosterone for 6 and 24 h, while DHC was ineffective; the mineralocorticoid DOC was also ineffective, while its 5 alpha-reduced derivative, DHDOC, strongly inhibited GFAP gene expression, starting at 6 h after beginning of the treatment. In conclusion, the present data show that: (1) adrenal steroids possessing gluco- and mineralocorticoid activities may influence the gene expression of the astrocytic marker GFAP; (2) the 5 alpha-reduced metabolite of DOC, DHDOC is able to influence the gene expression not only of GFAP but also that of MBP, which are, respectively, typical markers of the astrocytes and the oligodendrocytes; (3) the metabolic conversion of hormonal steroids into their 5 alpha-reduced metabolites, which also occurs in the glia, could be implicated in the biochemical control of oligodendrocyte and astrocyte functions.

Adrenal Cortex Hormones↗