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Jeffrey R Bloomquist - One of the best experts on this subject based on the ideXlab platform.

  • neurotoxicity in murine striatal Dopaminergic Pathways following long term application of low doses of permethrin and mptp
    Toxicology Letters, 2007
    Co-Authors: Jinghong Kou, Jeffrey R Bloomquist
    Abstract:

    Abstract The long-term effects of permethrin (PM) and its interaction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal Dopaminergic Pathways were investigated in C57BL/6 mice. In a 3-month exposure, technical PM (1.5 mg/kg) was administered once per week, with MPTP (20 mg/kg) given once on either the 7th week or 11th week. In a 6-month exposure, PM (0.8 mg/kg or 1.5 mg/kg) was administered once per week for 26 weeks, with MPTP (20 mg/kg) given once, on week 24. Alterations in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and α-synuclein proteins were analyzed 1 day after the last PM treatment using western blot assay. PM had no significant effect on striatal Dopaminergic Pathways by itself, whereas MPTP significantly reduced the expression of TH and DAT proteins. In both exposure paradigms, weekly 1.5 mg/kg PM treatments antagonized the toxic effect of MPTP on TH and DAT expression (p

  • striatal Dopaminergic Pathways as a target for the insecticides permethrin and chlorpyrifos
    Neurotoxicology, 2001
    Co-Authors: Daniel J Karen, Paul R Harp, Jeffrey S Gillette, Jeffrey R Bloomquist
    Abstract:

    Because insecticide exposure has been linked to both Parkinsons disease and Gulf War illness, the neurotoxic actions of pyrethroid and organophosphate insecticides on behavior and striatal Dopaminergic Pathways were investigated in C57BL/6 mice treated with permethrin (three i.p. doses at 0.2-200 mg/kg) or chlorpyrifos (three s.c. doses at 25-100 mg/kg) over a 2-week period. Permethrin altered maximal [3H]dopamine uptake in striatal synaptosomes from treated mice, with changes in Vmax displaying a bell-shaped curve. Uptake was increased to 134% of control at a dose of 1.5 mg/kg. At higher doses of PM (25 mg/kg), dopamine uptake declined to a level significantly below that of control (50% of control at 200 mg/kg, P < 0.01). We also observed a small, but statistically significant decrease in [3H]dopamine uptake by chlorpyrifos, when given at a dose of 100 mg/kg. There was no significant effect on the Km for dopamine transport. Evidence of cell stress was observed in measures of mitochondrialfunction, which were reduced in mice given high-end doses of chlorpyrifos and permethrin. Although cytotoxicity was not reflected in decreased levels of striatal dopamine in either 200 mg/kg PM or 100 mg/kg CPF treatment groups, an increase in dopamine turnover at 100 mg/kg CPF was indicated by a significant increase in titers of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid. Both permethrin and chlorpyrifos caused a decrease in open field behavior at the highest doses tested. Although frank Parkinsonism was not observed, these findings confirm that Dopaminergic neurotransmission is affected by exposure to pyrethroid and organophosphorus insecticides, and may contribute to the overall spectrum of neurotoxicity caused by these compounds.

  • neurotoxicity of the organochlorine insecticide heptachlor to murine striatal Dopaminergic Pathways
    Toxicological Sciences, 2001
    Co-Authors: Michael L Kirby, Rebecca L Barlow, Jeffrey R Bloomquist
    Abstract:

    Changes in biochemical status of nerve terminals in the corpus striatum, one of the primary brain regions affected in Parkinson’s disease, were studied in groups of C57BL/6 mice treated by ip injection three times over a 2-week period with 3‐100 mg/kg heptachlor. On average, the maximal rate of striatal dopamine uptake increased > 2-fold in mice treated at doses of 6 mg/kg heptachlor and 1.7-fold at 12 mg/kg heptachlor. Increases in maximal rate of striatal dopamine uptake were attributed to induction of the dopamine transporter (DAT) and a compensatory response to elevated synaptic levels of dopamine. Significant increase in Vmax of striatal DAT was not observed at doses > 12 mg/kg, which suggested that toxic effects of heptachlor epoxide may be responsible for loss of maximal dopamine uptake observed at higher doses of heptachlor. In support of this conclusion, polarigraphic measurements of basal synaptosomal respiration rates from mice treated with doses of heptachlor > 25 mg/kg indicated marked, dose-dependent depression of basal tissue respiration. At doses of 6 and 12 mg/kg heptachlor, which increased expression of striatal DAT, uptake of 5-hydroxytryptamine into cortical synaptosomes was unaffected. Thus, striatal Dopaminergic nerve terminals were found to be differentially sensitive to heptachlor. This reduced sensitivity of serotonergic Pathways was mirrored in the greater potency of heptachlor epoxide to cause release of dopamine from preloaded striatal synaptosomes in vitro compared to release of serotonin from cortical membranes. These results suggest that heptachlor, and perhaps other organochlorine insecticides, exert selective effects on striatal Dopaminergic neurons and may play a role in the etiology of idiopathic Parkinson’s disease.

Teiji Sawa - One of the best experts on this subject based on the ideXlab platform.

Renping Zhou - One of the best experts on this subject based on the ideXlab platform.

  • Ephrin-A5 regulates the formation of the ascending midbrain Dopaminergic Pathways
    Developmental neurobiology, 2009
    Co-Authors: Margaret A. Cooper, Kazuto Kobayashi, Renping Zhou
    Abstract:

    Dopaminergic neurons from the substantia nigra and the ventral tegmental area of the midbrain project to the caudate/putamen and nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic Pathways. However, the mechanisms underlying the development of these Pathways are not well understood. In the current study, the EphA5 receptor and its corresponding ligand, ephrin-A5, were shown to regulate Dopaminergic axon outgrowth and influence the formation of the midbrain Dopaminergic Pathways. Using a strain of mutant mice in which the EphA5 cytoplasmic domain was replaced with β-galactosidase, EphA5 protein expression was detected in both the ventral tegmental area and the substantia nigra of the midbrain. Ephrin-A5 was found in both the dorsolateral and the ventromedial regions of the striatum, suggesting a role in mediating Dopaminergic axon-target interactions. In the presence of ephrin-A5, Dopaminergic neurons extended longer neurites in in vitro coculture assays. Furthermore, in mice lacking ephrin-A5, retrograde tracing studies revealed that fewer neurons sent axons to the striatum. These observations indicate that the interactions between ephrin-A ligands and EphA receptors promote growth and targeting of the midbrain Dopaminergic axons to the striatum. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009

  • Differentiation of the midbrain Dopaminergic Pathways during mouse development.
    The Journal of comparative neurology, 2004
    Co-Authors: Margaret A. Cooper, David P. Crockett, Renping Zhou
    Abstract:

    Dopaminergic (DA) neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic Pathways. Disruptions in this system have been implicated in Parkinson's disease, drug addiction, schizophrenia, and attention deficit hyperactivity disorder. However, progress in our understanding has been hindered by a lack of knowledge of how these Pathways develop. In this study, different retrograde tracers, placed into the dorsolateral caudate/putamen and the nucleus accumbens, were used to analyze the development of the Dopaminergic Pathways. In embryonic day 15 mouse embryos, both SN and VTA neurons, as well as their fibers, were doubly labeled by striatal injections into the dorsolateral and ventromedial striatum. However, by birth, the SN DA neurons were labeled exclusively by DiA placed in the dorsolateral striatum, and the VTA DA neurons were labeled only by DiI injected into the ventromedial striatum. These data suggest that initial projections from midbrain DA neurons target nonspecifically to both the dorsolateral striatum and the nucleus accumbens. Later during development, the separate mesostriatal and mesolimbic Pathways differentiate through the selective elimination of mistargeted collaterals.

Liisa Ahtee - One of the best experts on this subject based on the ideXlab platform.

  • Differential nicotinic regulation of the nigrostriatal and mesolimbic Dopaminergic Pathways: implications for drug development.
    Neuroscience and biobehavioral reviews, 2006
    Co-Authors: Sanna Janhunen, Liisa Ahtee
    Abstract:

    Neuronal nicotinic acetylcholine receptors (nAChRs) modulate Dopaminergic function. Discovery of their multiplicity has lead to the search for subtype-selective nAChR agonists that might be therapeutically beneficial in diseases linked to brain Dopaminergic Pathways. The regulation and responses of the nigrostriatal and mesolimbic Dopaminergic Pathways are often similar, but some differences do exist. The cerebral distribution and characteristics of various nAChR subtypes differ between nigrostriatal and mesolimbic Dopaminergic Pathways. Comparison of nicotine and epibatidine, two nAChR agonists whose relative affinities for various nAChR subtypes differ, revealed differences in the nAChR-mediated regulation of Dopaminergic activation between these dopamine systems. Nicotine preferentially stimulates the mesolimbic pathway, whereas epibatidine's stimulatory effect falls on the nigrostriatal pathway. Thus, it may be possible to stimulate the nigrostriatal pathway with selective nAChR agonists that do not significantly affect the mesolimbic pathway, and thus lack addictive properties. Furthermore, dopamine uptake inhibition revealed a novel inhibitory effect of epibatidine on accumbal dopamine release, which could form a basis for novel antipsychotics that could alleviate the elevated accumbal Dopaminergic tone found in schizophrenia during the active psychotic state. Different regulation of nigrostriatal and mesolimbic Dopaminergic Pathways by nAChRs could be an important basis for developing novel drugs for treatment of Parkinson's disease and schizophrenia.

  • nicotine and epibatidine alter differently nomifensine elevated dopamine output in the rat dorsal and ventral striatum
    European Journal of Pharmacology, 2005
    Co-Authors: Sanna Janhunen, Raimo K Tuominen, Petteri T Piepponen, Liisa Ahtee
    Abstract:

    We studied the effects of nicotine and epibatidine given in combination with dopamine uptake inhibitor, nomifensine, on striatal extracellular dopamine and its metabolites by using brain microdialysis in freely moving rats. Nomifensine (3 mg/kg) elevated extracellular dopamine in the caudate-putamen, and clearly more in the nucleus accumbens. In the caudate-putamen, nicotine (0.5 mg/kg) and epibatidine (0.6 μg/kg but not 3.0 μg/kg) enhanced nomifensine's effect on dopamine. The effect of nomifensine on accumbal dopamine was enhanced by nicotine, but inhibited by epibatidine at 0.6 μg/kg. The larger dose of epibatidine had no effect. Thus, the effects of the smaller epibatidine dose (0.6 μg/kg) on the dopamine output in the caudate-putamen but not in the accumbens resemble those of nicotine 0.5 mg/kg. Discrepancies in the effects of epibatidine and nicotine are most probably due to differences in their affinities to nicotinic receptor subtypes regulating dopamine release. Further, different responses to low concentrations of epibatidine between the brain areas suggest that there are differences in the nicotinic regulation of nigrostriatal and mesolimbic Dopaminergic Pathways.

Benoit Labonte - One of the best experts on this subject based on the ideXlab platform.

  • stress induced alterations of mesocortical and mesolimbic Dopaminergic Pathways
    Scientific Reports, 2021
    Co-Authors: Francis Quessy, Thibault P Bittar, Leajeanne Blanchette, Martin Levesque, Benoit Labonte
    Abstract:

    Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidence suggests that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical Dopaminergic Pathways. Yet, the molecular interactions underlying these changes are still poorly understood, and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and mesocortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of activity-dependent markers pERK and c-fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Our results show that social stress decreases the density of TH+ Dopaminergic axonal projections in the deep layers of the mPFC in susceptible but not resilient male and female mice. Consistently, our analyses suggest that pERK expression is decreased in the mPFC but increased in the NAc following CSDS in males and females, with no change in c-fos expression in both sexes. Overall, our findings indicate that social defeat stress impacts the mesolimbic and mesocortical Pathways by altering the molecular interactions regulating somatic and axonal plasticity in males and females.

  • stress induced alterations of mesocortical and mesolimbic Dopaminergic Pathways
    bioRxiv, 2021
    Co-Authors: Francis Quessy, Thibault P Bittar, Leajeanne Blanchette, Martin Levesque, Benoit Labonte
    Abstract:

    Our ability to develop the cognitive strategies required to deal with daily-life stress is regulated by region-specific neuronal networks. Experimental evidences suggest that prolonged stress in mice induces depressive-like behaviors via morphological, functional and molecular changes affecting the mesolimbic and mesocortical Dopaminergic Pathways. Yet, the molecular interactions underlying these changes are still poorly understood and whether they affect males and females similarly is unknown. Here, we used chronic social defeat stress (CSDS) to induce depressive-like behaviors in male and female mice. Density of the mesolimbic and cortical projections was assessed via immuno-histochemistry combined with Sholl analysis along with the staining of the activity-dependent markers pERK and c-Fos in the ventral tegmental area (VTA), nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We showed that social stress decreases the density of Dopaminergic axonal projections to the mPFC but not to the NAc in susceptible and resilient mice. This was accompanied by sex-specific alterations of pERK and c-Fos expression in the VTA of susceptible but not resilient mice. Our results indicate that social defeat stress impacts the mesolimbic and mesocortical Pathways by altering the molecular interactions regulating somatic and axonal plasticity differently in males and females.