Biomedical subjects

A G Sadile

Publications and source records attributed to A G Sadile.

At least 19 recordsLinked to original sources

PubMed2004

Involvement of norepinephrine in the control of activity and attentive processes in animal models of attention deficit hyperactivity disorder.

Functional and morphological studies in children affected by Attention Deficit Hyperactivity Disorder (ADHD) suggest a prefrontal cortex (PFc) dysfunction. This cortical region is regulated by subcortical systems including noradrenergic (NEergic), dopaminergic (DAergic), cholinergic, serotonergic, and histaminergic pathways. A wealth of data in humans and in animal models demonstrates altered dopamine (DA) regulation. Drugs that modulate norepinephrine (NE) transmission are also effective in ADHD patients, thus leading to the hypothesis of a NEergic disorder. This review covers the regulation of PFc functions by NE and the interaction between the NE and DA systems, as suggested by pharmacological, electrophysiological, morphological, and gene knock out (KO) studies. A negative feedback between NE and DA neurons emerges from KO studies because KO mice showing increased (NE transporter (NET) KO) or decreased (DBH and VMAT2 KO) NE levels are respectively associated with lower and higher DA levels. Locomotor activity can be generally predicted by the DA level, whereas sensitivity to amphetamines is by NE/DA balance. Some animal models of ADHD, such as spontaneously hypertensive rats (SHR), show alterations in the PFc and in the DA system. Evidence about a correlation between the NE system and hyper-locomotion activity in such animals has not yet been clarified. Therefore, this review also includes recent evidence on the behavioral effects of two NET blockers, reboxetine and atomoxetine, in two animal models of ADHD: SHR and Naples High Excitability rats. As these drugs modulate the DA level in the PFc, certain effects are likely to be due to a rebalanced DA system. We discuss the significance of the results for theories of ADHD and make suggestions for future experimentation.

Adrenergic Uptake Inhibitors↗

PubMed2002

A rostro-caudal dissociation in the dorsal and ventral striatum of the juvenile SHR suggests an anterior hypo- and a posterior hyperfunctioning mesocorticolimbic system.

Functional molecular neuroimaging techniques have been applied to the study of the neural substrates of Attention-Deficit Hyperactivity Disorder (ADHD) in an animal model, the juvenile SHR rat. They include quantitative receptor autoradiography and immunocytochemistry for neuronal markers such as Ca2+/Calmodulin Dependent Kinase II (CaMKII) and transcription factors. Multiple evidence emerges for a rostro caudal dissociation within the dorsal (DS) and ventral striatum (VS) (n. accumbens) and olfactory tubercle (OT). It consists in (i) a higher density of dopamine (DA) D-1/D-5 receptor binding sites in a discrete segment of the anterior forebrain that comprises the DS, VS and OT, (ii) a lower density of DA D-2/D-3 autoreceptors in the caudal portion of the n. accumbens shell subterritory, (iii) a reduced number of CaMKII and c-FOS positive elements only in the anterior portion of DS and VS (iv) reversal by repeated injections of methylphenidate (MP) (3 mg/kg, 14 days) with 'downregulation' in SHR and 'up-regulation' in the WKY control rats of DS and VS of DA D-1/D-5 receptors. Thus, under basal conditions the mesocorticolimbic (MCL) DA system appears to be hyperfunctioning rather than hypofunctioning, as demonstrated (i) by subsensitivity of presynaptic D-3 autoreceptors and (ii) by phasic inhibition of MCL activity induced by acute blockade of endocannabinoid reuptake using AM404. Following MP treatment, the hyperfunctioning MCL DA system turns into a hypofunctioning one, as earlier suggested by Solanto. Since the target neurons of MCL fibers seem to be uncoupled to D-1 receptors, the medium spiny GABA neurons projecting to the ventral pallidum and ventral tegmental area (VTA) exert a weak feedback inhibition on the neurons of origin of MCL system. Therefore, MCL neurons maintain a high basal activity with consequences on the cortico-striato-pallido-thalamo-cortical system and amygdala complex through the 'extended amygdala system'. While the former explains the attention, motivation and activity alterations of this rat model of ADHD, the latter explains the emotional symptoms of the syndrome. It remains to be ascertained the starting point in the network leading eventually to the segmental defect as well as its significance in humans.

Animals↗

PubMed2002

Selective inhibition of neuronal nitric oxide synthesis reduces hyperactivity and increases non-selective attention in the Naples High-Excitability rat.

The involvement of neuron-derived NO in the process of orienting and scanning times (non-selective attention: NSA) towards environmental stimuli has been investigated in the Naples High-Excitability rat (NHE), a putative animal model of Hyperactivity and Attention Deficit (ADHD). To this aim, orienting and scanning times have been monitored by the frequency and duration of rearing episodes, respectively. Adult male NHE rats were tested in a novelty situation (Làt-maze) for 30 min following single or repeated injections of the non competitive inhibitor 7-Nitroindazole (7-NINA) of the neuronal isoform of the enzyme nitric oxide synthase (n-NOS). In the acute experiments, rats received a single injection of 7-NINA (1 mg/kg) intraperitonealy in a saline vehicle (exp. 1, fast release) or subcutaneously in a lipid carrier, dimethyl sulfoxide (DMSO; exp. 2, slow release) or the vehicles alone as controls 30 min before testing. In the repeated injection experiments, rats received a subcutaneus injection of 1 mg/kg in DMSO or DMSO alone daily for 14 days, and tested 24 h after the last injection (exp. 3, slow release). The results showed a significant differential effect of the drug that was dependent on the release rate, i.p. saline-diluted 7-NINA increased the duration of individual rearing episodes whereas, both single and repeated subcutaneous DMSO-carried 7-NINA exerted an opposite effect. Thus, selective inhibition of n-NOS by an allosteric inhibitor that increases arginine availability without displacing the inhibitor from n-NOS, strengthens the hypothesized role of NO in NSA. These findings may shed light on the mechanism of action of drug treatment of and be useful in the treatment of ADHD in children.

Animals↗

PubMed2002

Environmental factors during postnatal period modify activity and non-selective attention in the Naples High-Excitability rat.

The involvement of epigenetic factors in the phenotypic expression of the neural systems underlying activity and attentive processes has been investigated in an animal model of hyperactivity and attention-deficit, the Naples High-Excitability rat (NHE). To this aim, male NHE pups have been reared in small (four) or normal litter size (nine) during the first 4 weeks of postnatal life. Both groups underwent a differential handling procedure occurring once, twice or four times a week. After weaning (28 days), rats were housed in groups of two and tested as young adults for activity and non-selective attention in a spatial novelty situation for three consecutive tests at 24-h intervals. The behaviour was videotaped and analysed off line for the frequency of corner crossings and rearings and duration of rearings. The results indicate that the increased maternal care and high fat diet induced by the small litter size produced long lasting effects on activity and duration of rearing episodes that indexes non-selective attention. These effects were complex as differential handling was beneficial only at low stimulation level. Thus, these findings suggest that epigenetic factors acting during critical periods of post-natal development may interact with genetic determinants that in turn influence the maturation of the neural systems controlling activity, orienting and scanning time.

Animals↗

PubMed2002

Impaired metabolic capacity in the perirhinal and posterior parietal cortex lead to dissociation between attentional, motivational and spatial components of exploration in the Naples High-Excitability rat.

This study aimed at investigating the neural substrates of spatial and non-spatial Behavioural components of exploration to novelty by a neurogenetic approach. Thus, functional imaging and Behavioural analysis were carried out in the Naples High-Excitability (NHE) rats, a model of hyperactivity and attention-deficit. Quantitative cytochrome oxidase (C.O.) histochemistry was used to measure the basal metabolic capacity of different forebrain structures. In parallel experiments, exploration in an 8-arm radial maze (Olton-maze) with extra-maze cues was used to measure attentional, motivational and spatial components of Behaviour after feeding rats' ad-libitum or at a reduced diet. Functional imaging analysis: brains from naive rats were stained for quantitative C.O. histochemistry along with standards. NHE rats showed lower C.O. activity in perirhinal and posterior-parietal cortex (all layers) and cortical amygdala, and greater activity in entorhinal cortex (superficial layers). The outer granular cell layer of the dentate gyrus had greater activity in NHE. Behavioural analysis: at low and high motivational level, maze exploration was reinforced during shaping throughout and then only a single arm. The Behaviour was monitored by a CCD camera and videotaped. (i) There was no line difference in working memory during non reinforced maze exploration, independent of the motivational level; (ii) during shaping with all baited arms, there was no line difference in working memory, but NHE rats showed a very low or lower food consumption at low and high motivational level, respectively; (iii) rats showed a higher working memory in finding the single baited arm at high motivational level; (iv) NHE rats paid little attention towards reinforcement upon visiting the baited arm only at low motivational level. Thus, Behavioural and functional neuroimaging analysis suggests the neural substrates of spatial and non-spatial components of exploration to be underlined by different network operations in the neocortical and limbic cortices in the NHE rat lines. Therefore, they appear as an useful tool to the understanding of Attention-Deficit Hyperactivity Disorder (ADHD) in children.

Animals↗

PubMed2002

Activity, non-selective attention and emotionality in dopamine D2/D3 receptor knock-out mice.

In order to assess the role of dopamine (DA) D2 and D3 receptors in the modulation of behaviour, we analysed exploration in a spatial novelty in mouse model systems. Genetically engineered mice mutants have been used that carry normal, partial or no expression of D2R, D3R, or both D2R/D3R (double mutants) DA receptor subtypes. Adult male mice were exposed for 30 min to a Làte-maze. The behaviour was analysed for indices of activity, orienting (rearing frequency), scanning times (rearing duration) and defecation score (emotionality). D2R - / - and + / - as well as the D2R/D3R double homozygous mutants were less active than wild-type (WT) controls in travelled distance. In contrast D3R + / - were more active than WT mice in the first part of the test. As to orienting frequency, the D2R - / - were less active than WT during the entire test-period, whereas the D2 + / - mutants were less active than WT only in the second part of the test. Moreover, the D3R - / - and + / - mutants showed less and more rearing frequency than WT, respectively, during the entire test. Finally, the D2/D3R - / - double mutants were also less active than WT during the entire test period. As to scanning times, D2R + / - and - / - mutants were higher than WT during the entire test or only in the second part, respectively. The D3R + / - and - / - were not different from WT, whereas the D2/D3R - / - double mutants showed shorter scanning times only in the first part of the test. As to emotionality index, the defecation score, was lower only in D3R + / - mutants. Thus, the dopamine D2 and D3 receptor subtypes appear to be differentially involved in the modulation of activity, orienting and scanning phases of attention. Lastly double mutation experiments reveal an interaction between D2R and D3R with the former prevailing on the latter.

Animals↗

PubMed2002

Aged endothelial nitric oxide synthase knockout mice exhibit higher mortality concomitant with impaired open-field habituation and alterations in forebrain neurotransmitter levels.

Endothelial nitric oxide synthase (eNOS) has been implicated in various brain and peripheral pathologies such as renal failure, heart failure or stroke. Consequently, the mortality rate of aged eNOS knockout mice (eNOS-/-) was higher than that of age-matched (18-22 months old) controls. Only seven of the original 14 eNOS-/- animals that participated in the study reached the age of 18 months or older, whereas no control mice died during this life span. In order to assess the behavioral and neurochemical consequences of chronic eNOS deficiency we examined whether the surviving aged eNOS-/- mice showed changes in terms of motor, emotional, exploratory and neurochemical parameters. Aged eNOS-/- mice showed reduced exploratory activity in the open-field with no habituation observable neither within sessions nor after repeated exposures. Pole test performance of eNOS-/- mice was comparable to controls. In the elevated plus-maze eNOS-/- mice did not differ from controls in terms of time spent in and entries into arms, but showed less locomotion on the open arms. The most prominent neurochemical alterations in the forebrains of aged eNOS-/- mice were: (a) increased acetylcholine levels in the neostriatum; (b) decreased noradrenaline concentrations in the ventral striatum; and (c) lower serotonin levels in the frontal cortex and ventral striatum. The present findings suggest that mice which survived chronic eNOS-deficiency into old age, show some behavioral and neurochemical phenotypes distinct from adult eNOS-/- mice.

Acetylcholine↗

PubMed2000

Hypertrophic A10 dopamine neurones in a rat model of attention-deficit hyperactivity disorder (ADHD).

To clarify whether a hypo or hyperfunctioning mesocorticolimbic system is the neural substrate of Attention-Deficit Hyperactivity Disorder (ADHD), we carried out a morphometric analysis on an animal model, the Naples high excitability rat (NHE). Male adult NHE and control rats were used for tyrosine hydroxylase (TH) immunocytochemistry in the ventral tegmental area and substantia nigra in coronal cryostat sections. PC-assisted image analysis showed larger DA neurones in the ventral tegmental area but not in the substantia nigra of NHE rats than in controls, associated with a higher expression of TH in the neuropil. Thus, the increased activity and impaired attention of NHE rats are associated with a hyperfunctioning mesocorticolimbic system in this ADHD model.

Animals↗

PubMed2000

Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor.

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D(2) family receptors. Rat brain slices accumulated [(3)H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D(2) family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines.

Animals↗

PubMed2000

Non-selective attention in a rat model of hyperactivity and attention deficit: subchronic methylphenydate and nitric oxide synthesis inhibitor treatment.

The involvement of dopamine (DA) and nitric oxide (NO) in the process of non-selective attention (NSA) to environmental stimuli has been investigated in the juvenile Spontaneously Hypertensive rat (SHR). To this aim the frequency and duration of rearing episodes in a novelty situation, which is thought to monitor NSA, have been measured in male SHR and Wistar-Kyoto (WKY) control rats following subchronic treatment with methylphenidate (MP; 3 mg/kg) or the nitric oxide synthase (NOS) inhibitor L-Nitro-arginine-methylester (L-NAME; 1 mg/kg) or vehicle daily for two weeks. Different groups were tested at 0.5 h or 24 h after the last injection in a Làt-maze. Tests were repeated twice at a 24 h interval and lasted 10 min each. Upon first exposure, there was a differential drug effect only in the SHR. In fact, MP and L-NAME yielded a shift to the left and to the right, i.e. towards episodes of lower or higher duration, respectively. This shift was more pronounced in the group tested 0.5 h after the last injection. In contrast, both drugs produced a significant lengthening of the rearing episodes in the SHR only in comparison with the vehicle-treated rats over days of testing. Therefore both MP and L-NAME appear to shear a similar effect on non-selective attention, although the effect of L-NAME is somewhat paradoxical. The latter is likely to be due to increased arginine selective uptake due to negative feedback with the NO production. The consequent increased arginine availability displaces the NOS inhibitor, thus leading to increased NO production. In conclusion, dopamine and nitric oxide play a role in non-selective attention by synaptic and extrasynaptic mechanisms, respectively, in a rat model of hyperactivity and attention-deficits.

Animals↗

PubMed2000

Network operations revealed by brain metabolic mapping in a genetic model of hyperactivity and attention deficit: the naples high- and low-excitability rats.

Genetic rat models are important for research on the neural networks of attention and emotionality. Naples-High Excitability (NHE) rats and Naples Low-Excitability (NLE) rats were investigated with random-bred (NRB) rats as controls. These rat lines were named for their respective behavior on spatial novelty tasks. Quantitative cytochrome oxidase (CO) histochemistry has been demonstrated to reflect long-lasting changes in tissue metabolic capacity. CO metabolic differences between the NLE and NHE were found in the granular cell layer of the outer blade of the dentate gyrus. In addition, NLE showed greater CO activity than NRB in medial frontal cortex, and lower activity in perirhinal cortex (dorsal region). NHE showed greater CO activity than NRB in entorhinal cortex (superficial layers) and lower activities in perirhinal cortex and cortical amygdala. These data support the hypothesis that NLE/NHE rats may be an appropriate model for studying genetically altered limbic regions related to impaired emotional processing. The results support the involvement of limbic circuits in attentive processes and impulsiveness, and support the use of the NLE and NHE strains as animal models of Attention Deficit Hyperactivity Disorder (ADHD) in children.

Animals↗

PubMed2000

Remodeling of neural networks in the anterior forebrain of an animal model of hyperactivity and attention deficits as monitored by molecular imaging probes.

Remodeling of neural networks in the anterior forebrain of an animal model of hyperactivity and attention deficits as monitored by molecular imaging probes. These studies report on the remodeling of neural networks which are likely to be the consequences of the segmental defect in the anterior forebrain of an animal model of hyperactivity and attention-deficit, the juvenile prehypertensive male spontaneously hypertensive rat (SHR). Molecular biology and microscope imaging techniques were used such as: (i) dopamine (DA) D-1 and D-2 receptors by radioligand binding studies; (ii) the Ca2+/Calmodulin-dependent protein kinase II (CaMKII); (iii) transcription factors (TF) such as c-FOS by Immunocytochemistry; and (iv) the respiratory chain enzyme cytochrome-oxidase (C.O.), as markers of neuronal activity in the anterior forebrain of SHR and Wistar Kyoto normotensive (WKY) controls rats. Microcomputer-assisted high-resolution image analysis using DA receptor binding and C.O., as probes revealed by cross-correlations among different regions within brain an altered cross-talk in the anterior forebrain of the SHR as compared to the controls. In particular, an altered cross-talk was also observed within the amygdala complex in the SHR by CaMKII and c-FOS expression. Therefore, the hypothesized segmental defect in the anterior forebrain of the SHR produces network consequences leading to behavioral alteration in the attentional activity and emotional domains. Subchronic treatment with metilphenidate (MP) that is known to block the reuptake of biogenic amines (mainly DA) produced network remodeling which are known to be paralleled by behavioral modifications in the attentive activity and emotional domains. Imperspective, the results from this model system that features the main aspects of attention-deficit hyperactivity disorder (ADHD), can be useful for the understanding of the neural substrates of hyperactivity and attention deficits and possibly for an early diagnosis and appropriate treatment of ADHD children.

Animals↗

PubMed2000

Multiple evidence of a segmental defect in the anterior forebrain of an animal model of hyperactivity and attention deficit.

Molecular biology and microscope imaging techniques were used to map putative neural substrates of hyperactivity and attention deficit in an animal model, the juvenile prehypertensive male spontaneously hypertensive rat (SHR). We have studied in anterior forebrain sections of SHR and Wistar-Kyoto Normotensive (WKY) controls the spatial distribution of neural markers such as: (i) dopamine (DA) D-1 and D-2 receptor families by radioligand binding studies; (ii) the Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (iii) the transcription regulators of gene expression (TFs) c-FOS and JUN-B by Immunocytochemistry (ICC). Microcomputer-assisted high-resolution image analysis showed in the SHR a higher density of DA D-1 receptors and a lower density of D-3 autoreceptors paralleled by a reduced number of elements positive for CaMKII and TFs in a restricted segment of the anterior forebrain that included the most rostral portions of the caudate-putamen, pole and shell of the nucleus accumbens and olfactory tubercle. The differential rostro-caudal distribution of D-1 receptors and D-3 autoreceptors is discussed in the light of current hypotheses of DA mesocorticolimbic system functioning. In addition, the segmental defect was partially reversed by subchronic treatment with a DA re-uptake blocker, Methylphenidate (MPH; 3 mg/kg) and by environmental stimulation during the fifth and sixth postnatal week. The findings are consistent with the role of genetic determinants and environmental factors in the phenotypic expression of hyperactivity and attention deficit.

Animals↗

PubMed1998

Differential distribution, affinity and plasticity of dopamine D-1 and D-2 receptors in the target sites of the mesolimbic system in an animal model of ADHD.

The distribution of dopamine (DA) D-1 and D-2 receptors has been studied by autoradiography in the anterior forebrain of the pre-hypertensive spontaneously hypertensive rat (SHR) as an animal model of attention-deficit hyperactivity disorder (ADHD) in children. Juvenile male SHR and Wistar Kyoto (WKY) controls were given either vehicle or the DA re-uptake blocker methylphenidate (MP; 3 mg/kg, i.p.), daily during a 2-week period. A saturation analysis for the D-1 receptor subfamily was carried out with 0.1-5.0 nM of [3H]SCH23390 and two competition studies for the D-2 receptor subfamily with 4 nM of [3H]raclopride or 5 nM of [3H]quinpirole were carried out with unlabelled spiperone and 7-OH-DPAT as unlabelled displacers on cryostat coronal sections of the anterior forebrain. Quantitative receptor autoradiography and computer-assisted image analysis with reference to co-exposed 3H-microscale standards showed in vehicle-treated SHR higher density of DA D-1/D-5 receptor subtypes in the caudate-putamen (CPU), the nucleus accumbens (ACB) core and shell and the olfactory tubercle (OT), which was associated to a lower affinity. MP treatment normalised the DA D-1/D-5 receptors by decreasing the number of binding sites and increasing the affinity to control level. In addition, MP treatment 'down-regulated' DA D-2/D-4 subtypes in the CPU, ACB and OT, and 'up-regulated' mostly D-3 subtype in CPU, ACB, OT in both rat lines and in the globus pallidus, ventral pallidum and lateral septum in WKY rats only. In contrast, D-3 receptors were 'down-regulated' in the islands of Calleja in both rat lines. Moreover, regional cross-correlative analyses revealed a modulatory influence of DA receptors in the cross-talk within the anterior forebrain, which was altered in the SHR. Thus, the differential distribution and regulation of DA receptor subtypes following DA re-uptake blocker as well as the different regional cross-talk in the target sites of nigrostriatal and mesolimbic DA systems lend support to the DA hypothesis of ADHD in children.

Animals↗

PubMed1998

Reduced transduction mechanisms in the anterior accumbal interface of an animal model of Attention-Deficit Hyperactivity Disorder.

The aim of this study was to map the neural substrates of attention-deficit hyperactivity disorder (ADHD) in the spontaneously hypertensive rat (SHR), which is thought to be a model for ADHD. To this aim, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and transcription factors (TF) were used as markers. The focus of interest was the nucleus accumbens complex (ACB) which is thought to be an interface between limbic and motor systems. Juvenile, male rats of the SHR line and Wistar-Kyoto (WKY) controls were perfused and the brains processed for immunocytochemistry for CaMKII and the TF peptides of the FOS, JUN-B and ZIF-268 families. The results revealed that: (i) in both groups there were more CaMKII-positive neurones in the shell than in the core of the ACB; (ii) SHR had a reduced number of CaMKII-positive elements in anterior portions of the shell; and (iii) SHR had a lower expression of peptide products of the FOS family (c-FOS, in particular) and ZIF-268. In addition, there was a lower expression of c-FOS and zif-268 in the core of the ACB in the SHR. In contrast, there was an increased basal level of JUN-B in the core of the ACB of SHR. The reduced number of CaMKII and TF-positive elements in the most rostral portions of the accumbal complex of SHR, associated to the higher number of binding sites for the DA D-1/D-5 subtype, appears as a discrete alteration in the prosomeric development of the anterior basal forebrain and could be the key to the understanding of ADHD.

Animals↗

PubMed1998

A quantitative cytochrome oxidase mapping study, cross-regional and neurobehavioural correlations in the anterior forebrain of an animal model of Attention Deficit Hyperactivity Disorder.

The aim of this study was to trace by molecular imaging techniques the neural substrates of attention deficit hyperactivity disorder (ADHD) using the spontaneously hypertensive rat (SHR) as animal model. Adult SHR and Wistar-Kyoto (WKY) controls were used throughout this study. In experiment 1, naive male SHR and WKY were used, whereas in experiment 2 SHR and WKY rats of both genders were trained on a multiple fixed interval (FI (120 s for water, 5-min extinction)) paradigm and sacrificed 6 months later. In both experiments coronal sections of the anterior forebrain were processed for quantitative cytochrome oxidase (COase) histochemistry by the method of Gonzalez-Lima. Optical density values were transformed into actual enzyme activity units by using tissue-calibrated standards. In experiment 1, non-trained male rats of the SHR line showed lower COase activity in the medial and lateral prefrontal cortices, compared with WKY controls. In experiment 2, there was a line x treatment interaction effect in the pole of the nucleus accumbens (ACB). Regional correlative analyses revealed that: (i) under basal conditions, SHR are more synchronized than WKY rats in the COase level of different brain regions; and (ii) the training desynchronizes COase activity in the WKY, further synchronizes it and increases the cross-talk between hemispheres in male SHR only. Neurobehavioral covariations between behavioural scores and metabolic capacity in the medial and lateral prefrontal/frontal cortices, the caudate-putamen complex (CPU), the pole, core, and shell of the accumbal complex (ACB), and the ventral pallidum (VP), indicated that, in the WKY rats, the frequency of lever pressing covaried positively with the COase activity in the CPU, whereas in the SHR covaried with both medial and lateral prefrontal/frontal cortices. The bursts of activity during the 1-1.33-s segment was positively correlated, in the WKY rats only, with the core and shell of the ACB, and with the VP. Finally, the correlative profiles showed significant gender differences with effects in male SHR only. Thus, the results lend support to the involvement of the cortico-striato-pallidal system in ADHD.

Animals↗

PubMed1998

Non-selective attention and nitric oxide in putative animal models of Attention-Deficit Hyperactivity Disorder.

Non-selective attention (NSA) to environmental stimuli has been measured in putative animal models of Attention-Deficit Hyperactivity Disorder (ADHD), such as the Spontaneously Hypertensive (SHR) and the Naples High-Excitability (NHE) rat lines. A series of experiments has been carried out on male juvenile SHR and Wistar-Kyoto (WKY) controls (experiment 1) and on the NHE and two controls, i.e. the Naples Low-Excitability (NLE) and a random-bred (NRB) line (experiment 2). It was done under basal conditions or following a single injection of the nitric oxide synthase (NOS) inhibitor L-nitro-arginine-methylester (L-NAME: 0.1-10 mg/kg, i.p.), or vehicle, 30 min before testing on day 1 and vehicle alone before testing on days 2 and 3 in SHR/WKY (experiment 3) and the Naples lines (experiment 4). The behavior in a Lát maze during three consecutive 10-min exposures at 24-h intervals was monitored by a CCD video camera and analyzed off-line for frequency and duration of rearings on hindlimbs per 1-min blocks. The results demonstrated that both SHR and NHE rats showed a higher frequency of rearings of shorter duration than controls. With time of testing, the duration of rearings tended to increase in the WKY but not the SHR. In the Naples lines the duration tended to increase in all but mostly in the NHE rats. The acute inhibition of NOS by L-NAME significantly increased the duration of rearing episodes both in SHR and NHE rats only at 10 mg/kg in the second part of the testing period. Therefore, NSA, as indexed by the duration of rearings, is defective in both hyperactivity models against different genetic backgrounds. In addition, this impairment is dependent upon nitric oxide (NO), which appears to play a significant role in these processes.

Animals↗

PubMed1997

Differential expression of transcription factors in the accumbens of an animal model of ADHD.

Transcription factors have been used as neuronal markers in the nucleus accumbens (ACB) of male juvenile spontaneously hypertensive rats (SHR), an animal model of attention-deficit hyperactivity disorder (ADHD), to trace putative neural substrates. In SHR, immunocytochemistry and PC-assisted image analysis showed lower expression of pan-fos, c-fos, zif/268 in the shell, and the c-fos and zif/268 in the core, with an increased level of Jun-B in the core. The differential lower basal expression of transcription factors in the ACB of an animal model of ADHD implies a reduced number of modules and might represent a neural substrate of the attention deficits seen in SHR and children with ADHD at low motivational levels.

Animals↗