Dopaminergic metabolism in various rat brain areas after L-dopa loading

Gemayel, Gladys; Trouvin, J H; Prioux-Guyonneau, M; Jacquot, C.; Cohen, Yves

doi:10.1111/j.2042-7158.1986.tb03112.x

Cited by 8 publications

(2 citation statements)

References 1 publication

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“…The increased dopamine metabolites in the cerebellum suggest diffusions from dopamine terminals. This is consistent with the observed increases of HVA and DOPAC in the cerebellum of L-DOPA-treated animals (el Gemayel et al, 1986).…”

Section: Ectopic Dat Overexpression In the Forebrain Significantly Alsupporting

confidence: 80%

Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

Chen¹,

Ding²,

Cagniard³

et al. 2008

J. Neurosci.

219

159

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The role of dopamine as a vulnerability factor and a toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed dopamine toxicity is partly responsible for the "DOPA-sparing" clinical practice that avoids using L-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, in early PD. There is a lack of studies on animal models that directly isolate dopamine as one determining factor in causing neurodegeneration. To address this, we have generated a novel transgenic mouse model in which striatal neurons are engineered to take up extracellular dopamine without acquiring regulatory mechanisms found in dopamine neurons. These mice developed motor dysfunctions and progressive neurodegeneration in the striatum within weeks. The neurodegeneration was accompanied by oxidative stress, evidenced by substantial oxidative protein modifications and decrease in glutathione. Ultrastructural morphologies of degenerative cells suggest necrotic neurodegeneration. Moreover, L-DOPA accelerated neurodegeneration and worsened motor dysfunction. In contrast, reducing dopamine input to striatum by lesioning the medial forebrain bundle attenuated motor dysfunction. These data suggest that pathology in genetically modified striatal neurons depends on their dopamine supply. These neurons were also supersensitive to neurotoxin. A very low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5 mg/kg) caused profound neurodegeneration of striatal neurons, but not midbrain dopamine neurons. Our results provide the first in vivo evidence that chronic exposure to unregulated cytosolic dopamine alone is sufficient to cause neurodegeneration. The present study has significant clinical implications, because dopamine replacement therapy is the mainstay of PD treatment. In addition, our model provides an efficient in vivo approach to test therapeutic agents for PD.

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Section: Ectopic Dat Overexpression In the Forebrain Significantly Alsupporting

confidence: 80%

Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

Chen¹,

Ding²,

Cagniard³

et al. 2008

J. Neurosci.

219

159

View full text Add to dashboard Cite

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“…In addition, Navailles and colleagues (2010a, 2011) recently observed reduced 5-HT and increased DA efflux in response to both acute and chronic L-DOPA treatment in the hippocampus and prefrontal cortex. Since such extrastriatal areas may lack sufficient DA regulatory systems (el Gemeyel et al, 1986) but do express DA receptors (Missale et al, 1998), supraphysiological swings in DA content also may induce functional alterations in neuronal activity. For example, L-DOPA treatment has been associated with detrimental effects on cognition (Gotham et al, 1988), impulsivity (Cools et al, 2003), and fluctuations in mood including depression and anxiety (Black et al, 2005; Richard et al, 2005; Kulisevsky et al, 2007).…”

mentioning

confidence: 99%

L-DOPA-induced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson’s disease

2012

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Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine(L-DOPA) as a treatment for Parkinson’s disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague-Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-OHDA infusions and treated for at least 28 days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA’s effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24 hours after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD.

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l-DOPA exacerbates amphetamine-induced dopamine depletion

Myers

Witten

et al. 1998

Molecular and Chemical Neuropathology

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Administration of L-DOPA to Parkinson patients has been suggested to exacerbate "functional denervation" of the nigrostriatal system. Therefore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride) would potentiate amphetamine-induced neurotoxicity. Mice received two injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) interspersed with four injections of amphetamine (15.0 mg/kg) at 2-h intervals. Significant depletion of striatal dopamine, DOPAC, and HVA was evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to increased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal systems of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ benserazide depleted 5-HT to 82% of control values. No changes were evident in the frontal cortex following amphetamine with or without concurrent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.

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Dopaminergic metabolism in various rat brain areas after L-dopa loading

Cited by 8 publications

References 1 publication

Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice

L-DOPA-induced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson’s disease

l-DOPA exacerbates amphetamine-induced dopamine depletion

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