Biomedical subjects

R Lalonde

Publications and source records attributed to R Lalonde.

At least 19 recordsLinked to original sources

PubMed2000

Effects of buspirone on brain indoleamines and catecholamines in wild-type mice and Lurcher mutants.

The effects of a chronic serotoninergic stimulation on brain monoamine levels and metabolism were studied in wild-type (+/+) mice and Lurcher (Lc/+) mutants. Endogenous serotonin, dopamine, noradrenaline and some of their major metabolites were measured in the frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord. In +/+ mice, buspirone (1 mg/kg; i.p.) treatment during 40 days increased indoleamines, albeit with moderate changes in the ratios between tissue serotonin metabolites and endogenous serotonin, augmented noradrenaline contents in the spinal cord, and caused elevations of dopamine metabolites in most regions. In Lc/+ mutants, the effects of buspirone were attenuated, but higher L-tryptophan and indoleamine levels, suggest a storage of serotonin in a non-releasable compartment. In the hypoplastic Lc/+ cerebellum, indoleamine content was accrued, but with a decreased [serotonin metabolites]/[serotonin] ratio, indicating that the reorganized nerve terminals in Lc/+ mutants although they can synthesize and accumulate serotonin, may not utilize it efficiently in synaptic transmission.

Animals↗

PubMed2000

Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum.

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with L-tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after L-tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, L-tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Treadmill performance of mice with cerebellar lesions: 2. Lurcher mutant mice.

The sensorimotor skills of a spontaneous mouse mutant with cerebellar cortical atrophy, Lurcher, were examined on either a fast or a slow treadmill inclined at one of three slopes, requiring forward movements in order to avoid footshocks. During the early part of acquisition, Lurcher mutants had lower latencies before falling on either treadmill than normal mice, but not during a retention test. For both Lurcher mutants and controls, the amount of time spent walking as a function of time spent on the belt increased with an increase in belt speed. Lurcher mutants had higher walking time/total time ratios on the slow but not on the fast treadmill. It is concluded that cerebellar cortical degeneration impaired the time course of acquisition but not long-term retention of the treadmill task.

Animals↗

PubMed2000

Regional brain variations of cytochrome oxidase activity and motor co-ordination in staggerer mutant mice.

A mutant mouse with cerebellar cortical atrophy, staggerer, was examined in tests of motor activity and co-ordination as well as in regional brain metabolism as assessed by cytochrome oxidase activity. Compared with non-ataxic controls, staggerer mutants had inferior performances in the open field, the wooden beam, the wooden edge, and the rotorod tests. An increase in cytochrome oxidase activity in the deep cerebellar nuclei and in some cerebellar efferent regions, such as the lateral vestibular nucleus, the parvicellular red nucleus, and the ventral tegmental area, was found in staggerer mutant mice. Abnormally high cytochrome oxidase activity in the interpositus and the dentate nuclei was linearly correlated with poor performance on the wooden beam and on the rotorod. High cytochrome oxidase activity in the lateral vestibular nucleus was also associated with poor performance on the wooden beam. Moreover, high cytochrome oxidase activity in the fastigial nucleus was associated with poor performance on the wooden beam but with high motor activity in the open field. These results indicate that a lack of innervation of Purkinje cells to the deep cerebellar nuclei is in part the cause of motor co-ordination deficits in staggerer mutant mice.

Animals↗

PubMed1999

An unsteady platform test for measuring static equilibrium in mice.

An unsteady platform test is presented in which mice must remain still on a narrow surface in order to prevent a fall. The mouse spontaneous mutation, Lurcher, causing cerebellar cortical degeneration, was evaluated on the unsteady platform, requiring balance in a stable body position (static equilibrium), as opposed to the stationary beam test, in which the animals are free to move on a larger surface (dynamic equilibrium). Lurcher mutants spent less time and had a higher number of slips than controls on the unsteady platform. In contrast, Lurcher mutants did not differ from controls for latencies before falling and distance travelled on the stationary beam. These results are discussed in terms of the possible involvement of two cerebellar circuits in motor control.

Animals↗

PubMed1999

Role of an enriched environment on the restoration of behavioral deficits in Lurcher mutant mice.

Lurcher mutant mice, characterized by massive degeneration of the cerebellar cortex, and normal littermate controls were reared from birth either in standard conditions or in an enriched environment. The effects of this manipulation on motor functions, landmark water maze learning, exploration, and anxiety were evaluated at 3 months of age. Under standard conditions, Lurcher mutants were impaired in comparison to controls on tests of sensorimotor function and had altered exploratory tendencies. The enriched housing improved the motor coordination of Lurcher mutants and decreased the number of trials before reaching criterion in the landmark water maze. In addition to its effects in Lurcher mutants, enriched rearing also increased some behavioral abilities in normal mice. It is hypothesized that enriched housing altered brain morphology or neurochemistry in both normal and cerebellar-damaged animals.

Animals↗

PubMed1999

Motor coordination and spatial orientation are affected by neurofilament maldistribution: correlations with regional brain activity of cytochrome oxidase.

NFH-LacZ transgenic mice are characterized by an early accumulation of the neurofilament cytoskeleton in the cell bodies of neurons with age-associated abnormalities of motor neurons and cerebellar Purkinje cells. In comparison to normal littermate controls, irrespective of age (3 and 12-20 months), NFH-LacZ transgenic mice had a lower number of rears in an open field, deficiencies in some motor-coordination tests, and a higher number of quadrant entries and escape latencies while swimming toward a visible platform. Decreased cytochrome oxidase activity in the lateral reticular nucleus of NFH-LacZ mice was associated with poor performance in two motor coordination tests. Lower metabolic activity in the lateral reticular nucleus may be secondary to previously described cerebellar abnormalities, leading to deficient motor control. The dramatic cytoskeletal perturbation characterizing NFH-LacZ mice affects only selective neuronal populations and results in selective behavioral deficits, which can be correlated with regional brain metabolic activity.

Aging↗

PubMed1999

Effects of dopaminergic agents and of an NMDA receptor antagonist on motor coordination in Lurcher mutant mice.

Lurcher mutant mice, characterized by an ataxic gait and olivocerebellar degeneration, were evaluated for motor coordination in the coat-hanger test after peripheral injections of two doses of dextromethorphan, a noncompetitive N-methyl-D-aspartate receptor antagonist, L-dopa/carbidopa, and SKF 77434, a dopamine D1 receptor agonist. There was an improvement in the distance traveled on the suspended horizontal string after 25 and 50 mg/kg of dextromethorphan and 37.5 mg/kg of L-dopa/carbidopa, but not after SKF 77434. None of the drugs reduced movement times or increased latencies before falling. These results indicate that NMDA receptor antagonism or stimulation of some dopaminergic mechanisms partially improve genetically determined cerebellar ataxia in mice.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1999

Effects of electrolytic lesions of the lateral pallidum on motor coordination, spatial learning, and regional brain variations of cytochrome oxidase activity in rats.

In view of recent theories suggesting a role for basal ganglia circuits in motor control and cognition, rats with bilateral electrolytic lesions of the lateral part of the globus pallidus were compared with control rats on motor coordination tasks and spatial learning in the Morris water maze. By comparison with sham-operated controls, rats with lesions of the lateral pallidum were impaired during acquisition of the rotorod task. Deficits were observed in a wooden beam task, but not in hole-board and suspended string tests. In addition, lesioned rats were impaired during acquisition of place learning but not of visuomotor guidance in the Morris water maze. Alterations of brain metabolism, as assessed by cytochrome oxidase activity, were found in three regions of lesioned rats, the subthalamic nucleus, the superior colliculus, and the centromedial thalamus of lesioned rats, probably as a result of interrupted neocortico-basal ganglia circuitry as a secondary consequence of the primary lesion.

Animals↗

PubMed1999

Regional brain distribution of noradrenaline uptake sites, and of alpha1-alpha2- and beta-adrenergic receptors in PCD mutant mice: a quantitative autoradiographic study.

The mouse "Purkinje cell degeneration" (pcd) is characterized by a primary loss of Purkinje cells, as well as by retrograde and secondary partial degeneration of cerebellar granule cells and inferior olivary neurons; this neurological mutant can be considered as an animal model of human degenerative ataxia. To determine the consequences of this cerebellar pathology on the noradrenergic system, noradrenaline transporters as well as alpha1-, alpha2- and beta-adrenergic receptors were evaluated by quantitative ligand binding autoradiography in adult control and pcd mice using, respectively, [3H]nisoxetine, [3H]prazosin, [3H]idazoxan and [3H]CGP12177. In cerebellar cortex and deep nuclei of pcd mutants, [3H]nisoxetine labelling of noradrenaline transporters was higher than in control mice. However, when binding densities were corrected by surface area, they remained unchanged in the cerebellar cortex but associated with 25% and 40% lower levels of labelling of alpha1 and beta receptors, as well as a very important increase (275%) of alpha2 receptors. In deep cerebellar nuclei, surface corrections did not reveal any changes either in transporter or in receptor densities. Higher densities of [3H]nisoxetine labelling were found in several regions related with the cerebellum, namely inferior olive, inferior colliculus, vestibular, reticular, pontine, raphe and red nuclei, as well as in primary motor and sensory cerebral cortex; they may reflect an increased noradrenergic innervation related to motor adjustments for the cerebellar dysfunction. Increased [3H]nisoxetine labelling was also measured in vegetative brainstem regions and in dorsal hypothalamus, implying altered autonomic functions and possible compensation in pcd mutants. Other changes found in extracerebellar regions affected by the mutation, such as thalamus and the olfactory system implicated both noradrenaline transporters and adrenergic receptors. In contrast to the important alterations of the noradrenergic system in cerebellar cortex, the lack of receptor changes in deep cerebellar nuclei suggests that local adaptations may be sufficient to minimize the consequence of the cerebellar atrophy on motor control. An intense labelling by [3H]idazoxan of the inner third of the molecular layer was a novel, albeit unexplained finding, and could represent a postsynaptic subset of alpha2-adrenergic receptors.

Adrenergic alpha-Antagonists↗

PubMed1999

Effects of L-tryptophan on indoleamines and catecholamines in discrete brain regions of wild type and Lurcher mutant mice.

The biochemical parameters of the serotoninergic system were examined in wild type mice and Lurcher mutants after chronic treatment (40 days) with the serotonin (5-HT) precursor L-tryptophan (50 mg/kg; i.p.). Tissue contents in 5-HT, dopamine and noradrenaline, as well as some of their metabolites, were measured in frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord by high-performance liquid chromatography. The tissue levels were used as a biochemical index of the function of the monoamine innervations in this animal model of cerebellar ataxia. The results show that Lurcher mutants retain higher concentrations of L-tryptophan and total indoleamines, but that 5-HT is probably stored in a non-releasable compartment. In the particular case of the hypoplastic cerebellum, the reorganization of 5-HT nerve terminals leads to an accrued indoleamine synthesis, indicating that the Lurcher mutants can accumulate 5-HT, but do not utilize it efficiently in synaptic transmission.

Animals↗

PubMed1999

Expression of the late cytomegalovirus (CMV) pp150 transcript in leukocytes of AIDS patients is associated with a high viral DNA load in leukocytes and presence of CMV DNA in plasma.

The expression of a late cytomegalovirus (CMV) transcript (pp150) was sought in peripheral blood leukocytes (PBL) of subjects with AIDS and correlated with the amounts of CMV DNA in PBL and plasma, by means of quantitative polymerase chain reaction (PCR). The detection of the late CMV transcript was associated with a high number of CMV DNA copies in PBL (P=.0015) and with a positive CMV PCR assay in plasma (P<.001). Expression of CMV pp150 mRNA was best predicted by viral DNA thresholds corresponding to 7058 and 30 copies in PBL and plasma, respectively. The detection of CMV pp150 mRNA was associated with the presence of CMV disease in a univariate analysis but not in a multivariate analysis after controlling for the viral DNA load in PBL. Thus, active viral replication as determined by a high CMV DNA load in PBL is reflected by expression of the late CMV transcript in the same cells and by the presence of CMV DNA in plasma.

AIDS-Related Opportunistic Infections↗

PubMed1999

Human herpesvirus 8 DNA load in leukocytes of human immunodeficiency virus-infected subjects: correlation with the presence of Kaposi's sarcoma and response to anticytomegalovirus therapy.

Specific human herpesvirus 8 (HHV-8) DNA sequences were found in leukocytes of 12 of 29 (41.4%) AIDS subjects with Kaposi's sarcoma (KS), whereas they were found in 4 of 43 (9.3%) AIDS subjects without KS (P = 0.003), although the peak HHV-8 DNA load in PCR-positive subjects with KS (mean, 425 copies per 0.2 microgram of DNA) did not significantly differ from the one found in PCR-positive patients without KS (mean, 218 copies). The use of intravenous ganciclovir or foscarnet therapy to treat cytomegalovirus disease did not affect the HHV-8 DNA load in seven patients for whom serial samples were analyzed.

AIDS-Related Opportunistic Infections↗

PubMed1999

Amantadine hydrochloride treatment in olivopontocerebellar atrophy: a long-term follow-up study.

The efficacy of amantadine, a dopamine-releasing agent and antagonist of the N-methyl-D-aspartate glutamate receptor, was evaluated in patients with olivopontocerebellar atrophy. By contrast to an untreated control group whose terminal performance deteriorated on 8 of 8 measurements of reaction time and movement time, patients treated with amantadine for a mean duration of over 40 months had improved performances in 1 of 4 reaction time measurements and in 3 of 4 movement time measurements and remained stable on the others. These results demonstrate long-term benefits of amantadine in olivopontocerebellar atrophy-induced deficits of movement initiation and movement completion.

Adult↗

PubMed1999

The neurobiological basis of time estimation and temporal order.

Time estimation may be evaluated with the use of four major paradigms: temporal discrimination, verbal estimation, temporal production, and temporal reproduction. On the basis of testing of normal subjects and patients with brain lesions, it has been shown that the cerebellum, the basal ganglia, and the prefrontal cortex are involved in time estimation. In particular, studies in humans and animals have indicated that facilitation of dopamine transmission speeds up the internal clock, while inhibition of dopamine transmission slows it down. It has been hypothesized that the central timer is located in the cerebellum, while the planning abilities subserving the estimation of longer intervals are mediated by the prefrontal cortex. It remains to be determined whether time estimation is related to memory of temporal order or context and whether time-related tasks are correlated with working memory.

Animals↗

PubMed1999

Relationship between choice reaction time and the Tower of Hanoi test.

The aim of this study was to examine a possible relation between the speed of information processing, as measured by simple and choice visual RT, and problem-solving, as measured by the Tower of Hanoi test. For 20 normal teenagers, performing all tests, significant correlations were found between choice RT and both measures of performance on the Tower of Hanoi, number of disk moves, and time taken to complete the task. Simple RT was correlated with Completion time but not with the number of moves, while the reverse pattern was discerned for decision time. Choice movement time was also associated with both measures, but simple movement time was not. These results are consistent with the hypothesis of a common neurobiological basis to information-processing speed and executive functions.

Adolescent↗

PubMed1999

Human cytomegalovirus glycoprotein B genotypes in blood of AIDS patients: lack of association with either the viral DNA load in leukocytes or presence of retinitis.

It has been suggested that human cytomegalovirus (HCMV) glycoprotein B (gB) genotypes could be used as a marker for viral virulence in patients with AIDS. The present study was designed to evaluate a possible association between specific gB genotypes, the presence of HCMV retinitis, and the HCMV viral load. Fifty-four blood samples were obtained from 54 HIV- and HCMV-infected patients. Twenty-seven of these patients were asymptomatic for HCMV, whereas the other 27 patients had been diagnosed recently with HCMV retinitis. HCMV gB genotyping was carried out by using restriction enzyme analysis of PCR-amplified PMNL extracts. Determination of the HCMV viral load in the same specimens was carried out using a quantitative-PCR. HCMV gB genotype 2 was found more frequently than other genotypes in PCR-amplified polymorphonuclear leukocytes (PMNL) of patients with AIDS (P < 0.05) but not more frequently in samples from patients with HCMV retinitis. No significant association was found between any HCMV gB genotypes and the viral load in blood. In conclusion, the actual HCMV gB genotyping system using PMNL provides no additional benefit over the viral load in blood for identification of HIV-infected subjects at risk of HCMV disease.

AIDS-Related Opportunistic Infections↗

PubMed1998

Brain dopamine and amino acid concentrations in Lurcher mutant mice.

Lurcher mutant mice are characterized by massive degeneration of the cerebellum, including Purkinje cells and granule cells, as well as for the loss of neurons from the inferior olive. Concentrations of dopamine and two of its metabolites and of several amino acid neurotransmitters were determined in the cerebellum and in other brain regions of these mutants. By comparison to wild-type mice of the same background strain, glutamate and taurine concentrations were reduced in the Lurcher cerebellum. No decrease was found for aspartate, gamma-aminobutyric acid (GABA), glycine, as well as dopamine and its metabolites. Moreover, no neurochemical alterations occurred in the brain stem, thalamus, or neostriatum of Lurcher mutants. A selective reduction of glutamate concentration was found in the hippocampus, while all amino acids measured were decreased in the entorhinal-piriform areas. These results indicate region-selective reductions of neurotransmitter concentrations in a mouse mutant with a defined cerebellar cortical pathology.

Amino Acids↗