Biomedical subjects

Davide Viggiano

Publications and source records attributed to Davide Viggiano.

10 recordsLinked to original sources

PubMed2005

Trigeminal pain transmission requires reactive oxygen species production.

Three experiments were conducted in order to investigate the possible involvement of the reactive oxygen species in the nociception within the subnucleus caudalis of the spinal trigeminal nucleus (Vc). In the first experiment the extracellular level of hydrogen peroxide was evaluated by microdialysis in the Vc of two groups of six rats before and after a formalin (group 1) or saline solution (group 2) injection into the upper lip. In the second experiment the formalin test was conducted in three groups of 6 rats after a microinjection of 2-methoxyestradiol (2-ME, a superoxide-dismutase inhibitor; group 1) or N-acetylcysteine (NAC, an oxygen intermediate scavenger; group 2) or saline solution (group 3) into the Vc. In the third experiment an histochemical assay for superoxide dismutase activity was performed on two groups of 4 rats each 2 h after a formalin (group 1) or saline solution (group 2) injection into the upper lip. The results showed that (1) the level of hydrogen peroxide increases into the Vc during facial pain (134% of baseline); (2) the inhibition of superoxide dismutase or the removal of oxygen intermediate within the Vc decreases the sensibility to facial pain stimuli; and (3) persistent facial pain stimuli decrease the superoxide activity into the Vc (90% of counter-lateral). These data indicate that reactive oxygen species are produced in the Vc during persistent facial pain and are necessary for the transmission of pain.

2-Methoxyestradiol↗

PubMed2005

The control of responsiveness in ADHD by catecholamines: evidence for dopaminergic, noradrenergic and interactive roles.

We explore the neurobiological bases of attention deficit hyperactivity disorder (ADHD) from the viewpoint of the neurochemistry and psychopharmacology of the catecholamine-based behavioural systems. The contributions of dopamine (DA) and noradrenaline (NA) neurotransmission to the motor and cognitive symptoms of ADHD (e.g. hyperactivity, variable and impulsive responses) are studied in rodent and primate models. These models represent elements of the behavioural units observed in subjects with ADHD clinically, or in laboratory settings (e.g. locomotion, changed sensitivity/responsivity to novelty/reinforcement and measures of executive processing). In particular, the models selected emphasize traits that are strongly influenced by mesocorticolimbic DA in the spontaneously hypertensive (SHR) and the Naples high excitability (NHE) rat lines. In this context, the mode of action of methylphenidate treatment is discussed. We also describe current views on the altered control by mesolimbic catecholamines of appropriate and inappropriate goal-directed behaviour, and the tolerance or intolerance of delayed reinforcement in ADHD children and animal models. Recent insights into the previously underestimated role of the NA system in the control of mesocortical DA function, and the frontal role in processing information are elaborated.

Animals↗

PubMed2004

Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling.

Animal models are useful for characterizing neural substrates of neuropsychiatric disorders. Several models have been proposed for the study of Attention Deficit Hyperactivity Disorder (ADHD). The models can be divided into various groups: (i) genetically derived hyperactivity/ inattention, (ii) animal models showing symptoms after pharmacological intervention, and (iii) those based on spontaneous variations in a random population. Spontaneously hypertensive (SHR) and Naples High Excitability (NHE) rats show behavioral traits featuring the main aspects of ADHD in humans but show different changes in dopamine (DA) systems. In fact, the enzyme tyrosine hydroxylase is hyperexpressed in NHE rats and hypoexpressed in SHR. The DA transporter is hyperexpressed in both lines, although in the SHR, DAT activity is low (reduced DA uptake). The DA levels in the striatum and prefrontal cortex are increased in the juvenile SHR, but are decreased in handled young and non-handled older animals. The mRNA of the D1 DA receptor is upregulated in the prefrontal cortex of SHR and down-regulated in NHE. The D2 DA receptors are likely to be hypofunctioning in SHR, although the experimental evidence is not univocal, whereas their mRNA is hyperexpressed in NHE. Thus, in SHR both the mesocortical and mesolimbic DA pathways appear to be involved, whereas in NHE only the mesocortical system. To understand the effects of methylphenidate, the elective ADHD drug treatment in humans, in a dysfunctioning DA system, we realized a simple mathematical model of DA regulation based on experimental data from electrophysiological, cyclic voltammetry, and microdialysis studies. This model allows the estimation of a higher firing frequency of DA neurons in SHR rats and suggests that methylphenidate increases attentive processes by regulating the firing rate of DA neurons.

Animals↗

PubMed2003

Dopamine phenotype and behaviour in animal models: in relation to attention deficit hyperactivity disorder.

The phenotypic expression of behaviour is the outcome of interacting neuronal networks and is modulated by different subcortical systems. In the present paper the role of a major subcortical neurochemical system, dopamine (DA), is reviewed. In particular, knockout (KO) technology has given an overwhelming insight into the effects of specific component of the dopaminergic system. Therefore, the behavioural profile of dopamine transporter (DAT), tyrosine hydroxylase (TH), DA and cAMP-regulated phosphoprotein (DARPP 32), and D1, D2, D3, D4 and D5 dopamine receptors knockouts (and their combination) is reviewed.TH, D1, D2, D4 KO mice exhibit decreased locomotor activity, perhaps due to decreased motivational level. D3 KO and DAT KO mice show an increase in basal and novelty-induced activity respectively. It is possible that the increased dopamine levels in DAT KO mice enhance motivation. These observations support the hyperDA hypothesis in hyperactive phenotypes. Moreover, they suggest that the inhibitory effect of psychostimulant drugs, such as methylphenidate and amphetamines, in Attention Deficit Hyperactivity Disorder may be the outcome of an altered balance between auto- and hetero-receptors. However, since KO technology is hampered by blockade of the target at early stages of development, some alternatives have been proposed, such as inducible mutagenesis and inhibitory small RNAs conveyed to target by viral vectors in adulthood.

Animals↗

PubMed2003

Altered midbrain dopaminergic neurotransmission during development in an animal model of ADHD.

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.

Animals↗

PubMed2003

Behavioural, pharmacological, morpho-functional molecular studies reveal a hyperfunctioning mesocortical dopamine system in an animal model of attention deficit and hyperactivity disorder.

Clinical and experimental evidence suggest an involvement of dopamine systems, mainly the mesocorticolimbic one (MCL), in Attention-Deficit Hyperactivity Disorder (ADHD). However, it remains to be ascertained whether the systems are hyper- or hypo-functioning, for the implications of the functional state. Indeed, differential functional states of the MCL branches are suggested to be the neural substrate of different ADHD variants. This review covers published and unpublished data from the Naples-High Excitability (NHE) rat, an animal model of ADHD, featuring its main aspects, with no hypertension. Therefore, a multiple approach based on morphological studies of dopamine, norepinephrine, glutamate, acetylcholine and GABA systems, synaptic (Calcium/Calmodulin kinase II) and extrasynaptic (chondroitin sulphates) environments, and molecular biology and pharmacological studies on the dopamine system has been carried out. Morphological findings suggest dopamine neurons in the Ventral Tegmental Area (VTA) to be hypertrophic in NHE rats. The mesostriatal and mesolimbic dopamine branches appear to be normal in basal conditions. However, the striatal interface is probably defective following activation. Conversely, the prefrontal cortex, which represents the second main target of VTA dopamine neurons, has many alterations at the basal level. Therefore, the emerging picture is the association of a hyperinnervating and hyperfunctioning mesocortical branch of the dopamine system. Thus, the evidence gathered so far might improve our understanding of the neural substrates of neuropsychiatric disorders such as ADHD, schizophrenia and drug addiction.

Animals↗

PubMed2003

Quantitative histochemical assay for superoxide dismutase in rat brain.

Superoxide anions are highly reactive radicals overproduced in many pathological situations such as inflammation and ischemia. One of the major factors in the protection from superoxide anions is the enzyme superoxide dismutase (SOD), which catalyzes the dismutation of superoxide to hydrogen peroxide. This study presents a quantitative histochemical method to estimate SOD activity in rat brain tissue sections. This method is based on the cerium capture method and 3,3'-diaminobenzidine amplification of transition cerium compounds. Substrate for SOD was provided by reduction of oxygen during the autoxidation of riboflavin in the presence of UV light. This histochemical method reveals the overall activity of the three different forms of SOD described in mammalian tissues: cytosolic copper-zinc SOD, mitochondrial manganese SOD, and the high molecular weight extracellular SOD. Eventually, this method can be used to quantify SOD activity in tissue sections by image analysis.

Animals↗

PubMed2002

Testing the model of optic chiasm formation in human beings.

Recent data from animal studies allow us to understand how the optic commissure formed. However, their validity in humans has not yet been demonstrated. Clues from human teratological cases provide useful information to test the validity of animal models and suggest other morphogenetic mechanisms. Janiceps are non-viable, rare cases of co-joined embryos fused along the frontal plane, with two composite faces, half formed by each of the embryos. Their development after fusion is of interest to study the optic chiasm. The analysis of the optic nerves and of the skull by magnetic resonance imaging or direct inspection of three different cases of Janiceps showed a shared hypophyseal fossa that laterally could contain a compound optic commissure between the eyes of the same composite face (heterologues), but not between the eyes from the same individual (homologue). The current model of the optic commissure formation correctly predicts these findings in humans because the optic commissure are driven toward the midline by local factors and not by target regions. However, our data suggest that the overall geometry of the region is important for a successful decussation of the axons, and additional mechanisms are involved in midline differentiation.

Female↗

PubMed2002

A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD.

The hyperfunctioning dopamine hypothesis in the mesocorticolimbic (MCL) system has been addressed by a neurogenetic approach in model systems. Thus, a morphometric analysis was carried out on neurons of origin of Substantia Nigra (SN) and Ventral Tegmental Area (VTA) dopamine systems of the Naples High-Excitability (NHE), Low-Excitability (NLE) and control lines. Male adult rats were tested in a spatial novelty for indices of activity and non-selective attention. Mesencephalic coronal sections were processed for tyrosine hydroxylase (TH) immunohistochemistry and cytochromoxidase (C.O.) histochemistry. Image analysis in the rostro-caudal plane showed (i) a higher neuron size of TH+ elements in the VTA of NHE and NLE, across the entire structure in the NHE, and only in the middle portion in the NLE; (ii) a higher expression of TH in the neuropil of the VTA in NHE; (iii) a lower C.O. activity in both NLE and NHE; (iv) no differences in the SN. The larger neuron size in both NHE and NLE rats as compared with control rats, along with higher TH expression mainly in the NHE, in absence of any relevant alteration in the SN, reveals an unbalance between the two dopamine systems and a subsequent alteration in limbic (reward, motivation, sustained attention) functions. The decreased C.O. activity might be due to reduced feedback inhibition by striatal GABA neurons and interneurons leading to increased DA neuron firing. In conclusion, the increased behavioral activity and impaired attention observed in the NHE rats are associated to hyperfunctioning MCL system in this genetic model of Attention-Deficit Hyperactivity Disorder (ADHD).

Animals↗

PubMed2002

The Naples High- and Low-Excitability rats: selective breeding, behavioral profile, morphometry, and molecular biology of the mesocortical dopamine system.

The Naples High- (NHE) and Low-Excitability (NLE) rat lines have been selected since 1976 on the basis of behavioral arousal to novelty (Làt-maze). Selective breeding has been conducted under continuous genetic pressure, with no brother-sister mating. The behavioral analyses presented here deal with (1) activity in environments of different complexity, i.e., holeboard and Làt maze; (2) maze learning in hexagonal tunnel, Olton, and Morris water mazes and; (3) two-way active avoidance and conditioned taste aversion tests. Morphometric analyses deal with central dopaminergic systems at their origin and target sites, as well as the density of dopamine transporter immunoreactivity. Molecular biology analyses are also presented, dealing with recent experiments on the prefrontal cortex (PFc), cloning and identifying differentially expressed genes using subtractive libraries and RNAase protection. The divergence between NLE and NHE rats varies as a function of the complexity level of the environment, with an impaired working and reference memory in both lines compared to random bred (NRB) controls. Moreover, data from the PFc of NHE rats show a hyperdopaminergic innervation, with overexpression of mRNA species involved in basal metabolism, and down-regulation of dopamine D1 receptors. Altogether, the evidence gathered so far supports a hyperfunctioning mesocorticolimbic system that makes NHE rats a useful tool for the study of hyperactivity and attention deficit, learning and memory disabilities, and drug abuse.

Analysis of Variance↗