Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat

Barnéoud, Pascal; Parmentier, S; Mazadier, Martine; Miquet, Jean-Marie; Boireau, A.; Dubédat, Pierre; Blanchard, Jean‐Charles

doi:10.1016/0306-4522(95)00112-v

Cited by 79 publications

(38 citation statements)

References 56 publications

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“…Tape removal may be sensitive to mild nigrostriatal dysfunction because it requires coordinated forelimb use. It is known in other rodent PD models that tasks involving forelimb use are especially sensitive in detecting subtle dopaminergic deficits (43)(44)(45)(46). Even though the open field test is known to be sensitive to hypolocomotion often associated with hypodopaminergic function, it is not as sensitive as the tape removal task.…”

Section: Dj-1 Null Mice Did Not Show Loss Of Sn Dopamine Neurons or Omentioning

confidence: 99%

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Chen

Cagniard

Mathews

et al. 2005

Journal of Biological Chemistry

233

171

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Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and taskdependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month-and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.Mutations in DJ-1 were recently identified in an autosomal recessive form of early-onset familial Parkinson disease (PD) 1 (1). The first reported mutation involves one large deletion of the first 5 exons and part of the promoter and another mutation was a missense mutation (L166P) that might cause instability of the DJ-1 protein by preventing it from folding properly and forming homodimers (2-5). Since this first report, a number of other mutations of DJ-1 including deletion mutations, point mutations, and a frameshift mutation have been found to cause PD (6 -10). These studies suggest that the loss of the normal function of DJ-1 leads to PD.However, the nature of the normal function of DJ-1 and the mechanism by which DJ-1 deficiency leads to PD are not well established. Studies prior to the report of its association with PD suggested that DJ-1 might play a role in oncogenesis (11), male fertility (12, 13), control of protein-RNA interaction (14), and in modulating androgen receptor transcription activity (15,16). In addition, the DJ-1 protein was shown to be responsive to oxidation (17, 18), suggesting a potential role in oxidative stress, a process often implicated in PD. Studies on PD-linked DJ-1 mutations indicate that wild-type, but not mutant, DJ-1 protects cells from oxidative stress (19 -21). Canet-Aviles et al. (22) reported that oxidation of the Cys 106 residue in DJ-1 could lead to its relocalization in mitochondria and protect cells from mitochondrial damage. Structurally, DJ-1 closely resembles the members of the ThiJ/PfpI family that have protease and chaperone activities (23-27). Recent biochemical studies suggested that DJ-1 might have protease (5) and redox-dependent chaperone activities (28). Therefore, putative functions of DJ-1 seem to converge on the common pathogenesis of PD implicated in other genetic and sporadic forms of PD.Despite those new insights into the biochemical and cellular functions of DJ-1, th...

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Section: Dj-1 Null Mice Did Not Show Loss Of Sn Dopamine Neurons or Omentioning

confidence: 99%

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Chen

Cagniard

Mathews

et al. 2005

Journal of Biological Chemistry

233

171

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“…As shown in Figure 9B, the reductions in rotational responses were evident even after this extended period of drug withdrawal, clearly indicating an improvement in the underlying pathology rather than simply a symptomatic response to the agonist. Although drug-induced rotation remains the standard measure of functional asymmetry in hemiparkinsonian rats, striatal dopamine depletion has also been shown to impair skilled forelimb use (Montoya et al, 1991;Barnéoud et al, 1995). To assess skilled reaching, we used a "staircase test" (Montoya et al, 1991;Abrous and Dunnett, 1994).…”

Section: Behavioral Recoverymentioning

confidence: 99%

Dopamine D₃Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior

2006

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The presence of endogenous stem cell populations in the adult mammalian CNS suggests an innate potential for regeneration and represents a potential resource for neuroregenerative therapy aimed at the treatment of neurodegenerative disorders, such as Parkinson's disease. However, it is first necessary to examine the microenvironmental signals required to activate these innate reparative mechanisms. The small molecule neurotransmitter dopamine has been shown to regulate cell cycle in developing and adult brain, and the D 3 receptor is known to play an important role in dopaminergic development. Pharmacological activation of the dopamine D 3 receptor has been shown to trigger neurogenesis in the substantia nigra of the adult rat brain. Here, we examined the cell proliferative, neurogenic, and behavioral effects of the dopamine D 3 receptor agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin) in a 6-hydroxydopamine model of Parkinson's disease. Consistent with previous findings, we observed a significant induction of cell proliferation in the substantia nigra pars compacta (SN C ) with a time-dependent adoption of a neuronal dopaminergic phenotype in many of these cells. Indices of nigrostriatal integrity were also affected. Dopaminergic cell counts in the lesioned SN C recovered substantially in a time-dependent manner. Similarly, retrograde tracing revealed a restoration of striatal innervation from these cells, with evidence for projections arising from newly generated cells. Finally, we observed a substantial and persistent recovery of locomotor function in these animals. The results of these studies will further our understanding of the environmental signals regulating neurogenesis in the adult brain and could have significant implications for the design of novel treatment strategies for Parkinson's disease.

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“…For example, administration of the toxin into the Medial Forebrain Bundle, Substantia Nigra Compacta or Caudate Putamen can produce variable results regarding the extent of the lesion and the lesioned pathways (Iwamoto et al, 1976;Amalric et al, 1995;Barneoud et al, 1995;Gerlach and Riederer, 1996). Administration of 6-OHDA into the Medial Forebrain Bundle, the axon bundle that partly projects to the CaudatePutamen (Deumens et al, 2002), promotes almost complete lesions, with very few surviving DA neurons.…”

Section: Nitric Oxide System and Experimental Parkinson'smentioning

confidence: 99%

Role of Nitric Oxide on Motor Behavior

et al. 2005

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The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.

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Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat

Cited by 79 publications

References 56 publications

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Dopamine D₃Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior

Role of Nitric Oxide on Motor Behavior

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Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat

Cited by 79 publications

References 56 publications

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Dopamine D3Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior

Role of Nitric Oxide on Motor Behavior

Contact Info

Product

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About

Dopamine D₃Receptor Agonist Delivery to a Model of Parkinson's Disease Restores the Nigrostriatal Pathway and Improves Locomotor Behavior