The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles

Breese, George R.; Knapp, Darin J.; Criswell, Hugh E.; Moy, Sheryl S.; Papadeas, Sophia T.; Blake, Bonita L.

doi:10.1016/j.brainresrev.2004.08.004

Cited by 92 publications

(70 citation statements)

References 141 publications

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“…Clinical and experimental data suggest that neonatal loss of central dopaminergic transmission, increased serotonergic activity and deficient neurotrophic factors play important roles. [21][22][23] Consistent with this knowledge, post-mortem analysis of MRL-lpr brains revealed accumulation of dopamine in paraventricular nucleus and median eminence, as well as increased levels of serotonin in the hippocampus. 18 Functional damage of the nigrostriatal pathway was inferred from excessive rotational behavior after a single injection of a D1/D2-receptor agonist apomorphine.…”

Section: Introductionsupporting

confidence: 67%

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

et al. 2007

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Systemic lupus erythematosus is frequently accompanied by psychiatric manifestations of unknown origin. Although damage of central neurons had been documented, little is known about neurotransmitter systems affected by the autoimmune/inflammatory process. Recent studies on lupus-prone MRL-lpr mice point to imbalanced dopamine function and neurodegeneration in dopamine-rich brain regions. We follow up on anecdotal observations of singly housed mice developing chest wounds. Compulsive grooming and/or skin biting accounted for open lesions, lending itself to the operational term 'self-injurious behavior' (SIB). Low incidence of spontaneous SIB increased significantly after repeated injections of dopamine-2/ 3 receptor (D2/D3R) agonist quinpirole (QNP). To further probe the dopaminergic circuitry and examine whether SIB is associated with development of lupus-like disease, we compared behavioral responses among cohorts that differed in the immune status. Two-week treatment with QNP (intraperitoneal, 0.5 mg kg À1 body weight per day) induced SIB in 60% of diseased MRL-lpr mice, and exacerbated their splenomegaly. Although increased grooming and stereotypy were observed in less symptomatic MRL þ / þ controls, only one mouse (10%) developed SIB. Similarly, SIB was not seen in young, asymptomatic groups despite dissimilar ambulatory responses to QNP. In situ hybridization revealed treatment-independent upregulation of D2R mRNA in substantia nigra of diseased MRL-lpr mice. The above results suggest that development of systemic autoimmunity alters sensitivity of the dopaminergic system and renders MRL-lpr mice prone to SIB. Although pathogenic factors were not examined, we hypothesize that immune and endocrine mechanisms jointly contribute to early neuronal damage, which underlies behavioral deficiency in the adulthood.

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Section: Introductionsupporting

confidence: 67%

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

et al. 2007

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“…Animal PD model is obtained through injection of neurotoxins: the most used toxin is 6-hydroxydopamine (6-OHDA stereotaxical injected), 16 but also 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP i.p. injected) is used 18 : both agents destroy neurons by generating active oxygen species such as superoxide radicals.…”

Section: Parkinson Diseasementioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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“…It is also true for rodents, since dopamine depletion by 6-hydroxydopamine (6-OHDA) in adult rats causes akinesia (37)(38)(39). However, neonatal 6-OHDA treatment in rats causes hyperactivity (40)(41)(42).…”

Section: Figurementioning

confidence: 99%

Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia

Lee¹,

Nakayama²,

Xu³

et al. 2012

J. Clin. Invest.

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Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder.Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neurotransmitter release in response to stress and other precipitating factors. IntroductionThe paroxysmal dyskinesias consist of clinically and genetically distinct phenotypes, including paroxysmal kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and paroxysmal nonkinesigenic dyskinesia (PNKD) (1, 2). PNKD is a highly penetrant autosomal dominant disorder in which individuals have 1- to 4-hour attacks consisting of dystonia and choreoathetosis (3). These attacks can be induced reliably by administration of caffeine or alcohol and frequently when patients are stressed. The causative gene was mapped to chromosome 2q33-q35 (4, 5), and mutations in the PNKD gene (formerly called MR-1) were subsequently identified in PNKD families (6)(7)(8)(9)(10).The PNKD gene has at least 3 alternate splice forms, which encode proteins of 385, 361, and 142 amino acids. The long isoform of PNKD (PNKD-L) is specifically expressed in CNS, while the medium isoform (PNKD-M) and short isoform (PNKD-S) are ubiquitously expressed (7). Two missense mutations (Ala to Val) located at amino acids 7 or 9 of PNKD-L and PNKD-S were found in most patients, and a third mutation (Ala to Pro) at position 33 was reported in 1 family (11). Both PNKD-L and PNKD-M have a putative catalytic domain that is homologous to hydroxyacylglutathione hydrolase (HAGH), a member of the zinc metallo-hydrolase enzyme family, which contains β-lactamase domains. HAGH functions in a pathway to detoxify methylglyoxal, a by-product of oxidative stress (12). The normal role of PNKD in cells and the contribution of mutations to pathophysiology of PNKD are not known.Dyskinesia is seen with many genetic and acquired disorders of the brain. Theoretically, such hyperkinetic movements could have their genesis in the basal ganglia, the cerebellum, or even in the cortex. Having cloned the gene and shown by in situ hybridization that it is...

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The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles

Cited by 92 publications

References 141 publications

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Nanoparticle transport across the blood brain barrier

Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia

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