Publications (10)40.43 Total impact
-
Article: Methylphenidate administration determines enduring changes in neuroglial network in rats.
[show abstract] [hide abstract]
ABSTRACT: Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 05/2011; 22(1):53-63. · 3.68 Impact Factor -
Article: Social withdrawal and gambling-like profile after lentiviral manipulation of DAT expression in the rat accumbens.
[show abstract] [hide abstract]
ABSTRACT: Dysfunction of brain dopamine transporter (DAT) has been associated with sensation seeking and impulse-control disorders. We recently generated a new animal model by stereotaxical inoculation of lentiviral vectors, which allowed localized intra-accumbal delivery of modulators for DAT gene: GFP (green fluorescent protein) control, silencers (Sil), a regulatable enhancer (DAT+), or both (DAT+Sil). Wistar male rats were followed both for socio-emotional profiles and for propensity to seek risky, uncertain rewards. Elevated anxiety and affiliation towards an unfamiliar partner emerged in Sil rats. Interestingly, in DAT+Sil rats (and Sil rats to a lesser extent) levels of playful social interaction were markedly reduced compared to controls. These DAT+Sil rats displayed a marked 'gambling-like' profile (i.e. preference for a large/uncertain over a small/sure reward), which disappeared upon doxycycline-induced switch-off onto DAT enhancer, but consistently reappeared with doxycycline removal. MRI-guided 1H-MRS (at 4.7 T) examinations in vivo (under anaesthesia) revealed changes in the bioenergetic metabolites (phosphocreatine and total creatine) for DAT+Sil rats, indicating a functional up-regulation of dorsal striatum (Str) and conversely a down-regulation of ventral striatum (i.e. nucleus accumbens, NAc). A combined profile of (1) enhanced proneness to gambling and (2) strong social withdrawal is thus associated with altered DAT-induced balance within forebrain dopamine systems. In fact, risk of developing a gambling-prone, social-avoidant psychopathology might be associated with (1) dominant semi-automatic strategies and/or habits, developed within Str circuits, and (2) reduced NAc function, with poorer feedback adjustment on decisions by aversive experiences.The International Journal of Neuropsychopharmacology 11/2010; 13(10):1329-42. · 4.58 Impact Factor -
Article: Methylphenidate to adolescent rats drives enduring changes of accumbal Htr7 expression: implications for impulsive behavior and neuronal morphology.
[show abstract] [hide abstract]
ABSTRACT: Methylphenidate (MPH) administration to adolescent rodents produces persistent region-specific changes in brain reward circuits and alterations of reward-based behavior. We show that these modifications include a marked increment of serotonin (5-hydroxy-tryptamine) receptor type 7 (Htr7) expression and synaptic contacts, mainly in the nucleus accumbens, and a reduction of basal behavioral impulsivity. We show that neural and behavioral consequences are functionally related: administration of a selective Htr7 antagonist fully counteracts the MPH-reduced impulsive behavior and enhances impulsivity when administered alone in naive rats. Agonist-induced activation of endogenous Htr7 significantly increases neurite length in striatal neuron primary cultures, thus suggesting plastic remodeling of neuronal morphology. The mixed Htr (1a/7) agonist, 8-OH-DPAT, reduces impulsive behavior in adolescent rats and in naive adults, whose impulsivity is enhanced by the Htr7 antagonist. In summary, behavioral pharmacology experiments show that Htr7 mediates self-control behavior, and brain primary cultures experiments indicate that this receptor may be involved in the underlying neural plasticity, through changes in neuronal cytoarchitecture.Genes Brain and Behavior 03/2009; 8(3):356-68. · 3.48 Impact Factor -
Article: Comparison of gene expression profile in embryonic mesencephalon and neuronal primary cultures.
[show abstract] [hide abstract]
ABSTRACT: In the mammalian central nervous system (CNS) an important contingent of dopaminergic neurons are localized in the substantia nigra and in the ventral tegmental area of the ventral midbrain. They constitute an anatomically and functionally heterogeneous group of cells involved in a variety of regulatory mechanisms, from locomotion to emotional/motivational behavior. Midbrain dopaminergic neuron (mDA) primary cultures represent a useful tool to study molecular mechanisms involved in their development and maintenance. Considerable information has been gathered on the mDA neurons development and maturation in vivo, as well as on the molecular features of mDA primary cultures. Here we investigated in detail the gene expression differences between the tissue of origin and ventral midbrain primary cultures enriched in mDA neurons, using microarray technique. We integrated the results based on different re-annotations of the microarray probes. By using knowledge-based gene network techniques and promoter sequence analysis, we also uncovered mechanisms that might regulate the expression of CNS genes involved in the definition of the identity of specific cell types in the ventral midbrain. We integrate bioinformatics and functional genomics, together with developmental neurobiology. Moreover, we propose guidelines for the computational analysis of microarray gene expression data. Our findings help to clarify some molecular aspects of the development and differentiation of DA neurons within the midbrain.PLoS ONE 02/2009; 4(3):e4977. · 4.09 Impact Factor -
Article: Pre-filtering improves reliability of Affymetrix GeneChips results when used to analyze gene expression in complex tissues.
[show abstract] [hide abstract]
ABSTRACT: Affymetrix GeneChip represents a very reliable and standardized technology for genome-wide gene expression screening. However, in experiments carried out on complex biological samples (e.g. brain tissues composed of several diverse cell types), significant noise can arise due to important transcripts being expressed in a relatively small number of cells. This noise results in many observations coming from unreliable hybridization reactions. Here we propose a method for pre-filtering Affymetrix data according to measures of hybridization reliability. We used our pre-filtering method on a microarray dataset obtained from the brains of rats chronically treated with a psychostimulant drug. Our pre-filter protocol facilitates selection of biologically relevant candidate genes, which could be validated by real-time PCR with a rate of 98%.Molecular and Cellular Probes 05/2008; 22(2):115-21. · 2.08 Impact Factor -
Article: FLUOXETINE modifies the expression of serotonergic markers in a differentiation-dependent fashion in the mesencephalic neural cell line A1 mes c-myc.
[show abstract] [hide abstract]
ABSTRACT: Serotonin (5-HT) is a neurotransmitter involved in a variety of CNS functions during development and in adulthood. 5-HT neurons are also involved in the pathogenesis of a number of psychiatric disorders. FLUOXETINE (FLX), a prototypic antidepressant, is a selective 5-HT uptake inhibitor (SSRI) with a demonstrated clinical efficacy in these disorders. SSRI, in a short-term period, binds 5-HT transporter (SERT) raising 5-HT levels at the synapse. Nevertheless, clinical improvement is observed only after 3-4 weeks of treatment. Recently, it has been shown that antidepressants, besides interfering with neurotransmission, can also display an effect on neural cells' proliferation and differentiation. Therefore it has been proposed that antidepressant may exert their clinical effects also acting on cellular functions other then neurotransmission. Here we show that a mesencephalic neural cell line, mes-c-myc A1 (A1) produces 5-HT and expresses SERT and both peripheral (TPH1) and CNS-specific (TPH2) form of tryptophan hydroxylase, the limiting enzyme in 5-HT biosynthesis. Cyclic AMP-dependent neuronal differentiation of A1 cells modulates the expression of TPHs. FLX, as well as citalopram (CIT), another SSRI inhibitor, modulates expression of serotonergic markers depending on the differentiation status of the cells. Interestingly, long-term but not short-term FLX treatment selectively modulates mRNA levels of TPH2, only in differentiated A1 cells. Finally, FLX and citalopram selectively decrease the proliferation rate of undifferentiated A1 cells, whereas have no effects on NIH-3T3 fibroblasts proliferation. In conclusion, neuronal differentiation of A1 cells not only modulates the expression of serotonergic markers, but appears to affect the response to FLX.Brain Research 05/2007; 1143:1-10. · 2.73 Impact Factor -
Article: Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression.
[show abstract] [hide abstract]
ABSTRACT: Administration of methylphenidate (MPH, Ritalin) to children with attention deficit hyperactivity disorder (ADHD) is an elective therapy, but raises concerns for public health, due to possible persistent neurobehavioral alterations. Wistar adolescent rats (30 to 46 day old) were administered MPH or saline (SAL) for 16 days, and tested for reward-related and motivational-choice behaviors. When tested in adulthood in a drug-free state, MPH-pretreated animals showed increased choice flexibility and economical efficiency, as well as a dissociation between dampened place conditioning and more marked locomotor sensitization induced by cocaine, compared to SAL-pretreated controls. The striatal complex, a core component of the natural reward system, was collected both at the end of the MPH treatment and in adulthood. Genome-wide expression profiling, followed by RT-PCR validation on independent samples, showed that three members of the postsynaptic-density family and five neurotransmitter receptors were upregulated in the adolescent striatum after subchronic MPH administration. Interestingly, only genes for the kainate 2 subunit of ionotropic glutamate receptor (Grik2, also known as KA2) and the 5-hydroxytryptamine (serotonin) receptor 7 (Htr7) (but not GABA(A) subunits and adrenergic receptor alpha1b) were still upregulated in adulthood. cAMP responsive element-binding protein and Homer 1a transcripts were modulated only as a long-term effect. In summary, our data indicate short-term changes in neural plasticity, suggested by modulation of expression of key genes, and functional changes in striatal circuits. These modifications might in turn trigger enduring changes responsible for the adult neurobehavioral profile, that is, altered processing of incentive values and a modified flexibility/habit balance.Neuropsychopharmacology 10/2006; 31(9):1946-56. · 7.99 Impact Factor -
Article: Short-term effects of adolescent methylphenidate exposure on brain striatal gene expression and sexual/endocrine parameters in male rats.
[show abstract] [hide abstract]
ABSTRACT: Exposure to methylphenidate (MPH) during adolescence is the elective therapy for attention deficit/hyperactivity disorder (ADHD) children, but raises major concerns for public health, due to possibly persistent neurobehavioral changes. Rats (30- to 44-days old) were administered MPH (2 mg/kg, i.p once daily) or saline (SAL). At the end of the treatment we collected plasma, testicular, liver, and brain (striatum) samples. The testes and liver were used to evaluate conventional reproductive and metabolic endpoints. Testes of MPH-exposed rats weighed more and contained an increased quantity of sperm, whereas testicular levels of testosterone (TST) were markedly decreased. The MPH treatment exerted an inductive effect on enzymatic activity of TST hydroxylases, resulting in increased hepatic TST catabolism. These findings suggest that subchronic MPH exposure in adolescent rats could have a trophic action on testis growth and a negative impact on TST metabolism. We have analyzed striatal gene expression profiles as a consequence of MPH exposure during adolescence, using microarray technology. More than 700 genes were upregulated in the striatum of MPH-treated rats (foldchange >1.5). A first group of genes were apparently involved in migration of immature neural/glial cells and/or growth of novel axons. These genes include matrix proteases (ADAM-1, MMP14), their inhibitors (TIMP-2, TIMP-3), the hyaluronan-mediated motility receptor (RHAMM), and growth factors (transforming growth factor-beta3 [TGF-beta3] and fibroblast growth factor 14 [FGF14]). A second group of genes were suggestive of active axonal myelination. These genes mediate survival of immature cells after contact with newly produced axonal matrix (laminin B1, collagens, integrin alpha 6) and stabilization of myelinating glia-axon contacts (RAB13, contactins 3 and 4). A third group indicated the appearance and/or upregulation of mature processes. The latter included genes for: K+ channels (TASK-1, TASK-5), intercellular junctions (connexin30), neurotransmitter receptors (adrenergic alpha 1B, kainate 2, serotonin 7, GABA-A), as well as major proteins responsible for their transport and/or anchoring (Homer 1, MAGUK MPP3, Shank2). All these genes were possibly involved in synaptic plasticity, namely the formation, maturation, and stabilization of new neural connections within the striatum. MPH treatment seems to potentiate synaptic plasticity, which is an age-dependent developmental phenomenon that adolescent rats are very likely to show, compared to adults. Our observations suggest that adolescent MPH exposure causes only transient changes in reproductive and hormonal parameters, and a more enduring enhancement of neurobehavioral plasticity.Annals of the New York Academy of Sciences 08/2006; 1074:52-73. · 3.15 Impact Factor -
Article: Altered midbrain dopaminergic neurotransmission during development in an animal model of ADHD.
[show abstract] [hide abstract]
ABSTRACT: To understand the onset and the molecular mechanisms triggering dopaminergic (DA) dysregulation in Attention-Deficit Hyperactivity Disorder (ADHD), we have used the Spontaneously Hypertensive Rats (SHR), the most widely studied animal model for this disease. We have studied the pattern of expression of specific genes involved in DA neuron differentiation, survival and function during postnatal (P) development of the ventral midbrain in SHR males. Our results show that tyrosine hydroxylase and DA transporter gene expression are significantly and transiently reduced in the SHR midbrain during the first month of postnatal development, although with a different kinetic. The other genes analyzed do not show significant variation between SHR and control rats. In addition, high-affinity DA uptake activity is significantly reduced in synaptosomes obtained from the striatum of 1-month-old SHR, when compared to controls. Our data suggest that down-regulation of DA neurotransmission occurs in the midbrain of SHR in a developmentally regulated temporal window during postnatal development, thus strengthening the hypodopaminergic hypothesis in the pathogenesis of ADHD.Neuroscience & Biobehavioral Reviews 12/2003; 27(7):661-9. · 8.65 Impact Factor -
Article: Correction: Comparison of Gene Expression Profile in Embryonic Mesencephalon and Neuronal Primary Cultures
Top co-authors
Top Journals
Institutions
-
2003–2009
-
National Research Council
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso" IGB
Roma, Latium, Italy
-
-
2006
-
IGB - Institute of Genetics and Biophysics - CNR
Napoli, Campania, Italy
-
