Abnormal involuntary movements (AIMs) following pulsatile dopaminergic stimulation: Severe deterioration and morphological correlates following the loss of locus coeruleus neurons

Fulceri, Federica; Biagioni, Francesca; Ferrucci, Michela; Lazzeri, Gloria; Bartalucci, Alessia; Galli, Valentina; Ruggieri, Stefano; Paparelli, Antonio; Fornai, Francesco

doi:10.1016/j.brainres.2006.12.030

Cited by 50 publications

(42 citation statements)

References 46 publications

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“…In the present study we used the DBH-Saporin immunotoxin to obtain a near complete destruction of the NA neurons, resulting in a ≥90% reduction of NA in both cortex and striatum. The worsening of L-DOPA-induced dyskinesia induced by severe damage to the NA projections from the LC neurons, as seen here, is consistent with the observations of Fulceri et al (2007) in MFB-6-OHDA lesioned rats. In their study a loss of around 80% of striatal NA (as seen in the rats that did not receive the protective desipramine treatment) was associated with an increased level of dyskinesia.…”

Section: Discussionsupporting

confidence: 92%

“…Both Fulceri et al (2007) and Barnum et al (2012) have used 6-OHDA injected into the MFB, with or without systemic injection of the uptake blocker desipramine (to protect NA terminals) in order to achieve DA depletion with or without loss of forebrain NA. The former study reported more severe dyskinesia in double lesioned group while the latter study saw the opposite result: decreased dyskinesia in double lesioned group.…”

Section: Discussionmentioning

confidence: 99%

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Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Shin

Rogers

Devoto

et al. 2014

Experimental Neurology

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Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the brain.Animals with combined DA and NA lesions were more prone to develop L-DOPAinduced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to the NA neurons in the central nervous system contributes to the development of motor impairments and the appearance of L-DOPAinduced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.3

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Shin

Rogers

Devoto

et al. 2014

Experimental Neurology

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“…Therefore, the only way to create a pure DA lesion would be to pretreat animals with a selective NE transporter inhibitor before toxin administration. A recent study in rats has shown that unilateral infusion of 6-OHDA into the medial forebrain bundle (NE and DA loss) produced dyskinesias of earlier onset and greater severity than in rats given a NE transporter inhibitor ϩ 6-OHDA (DA loss alone) (43). It is not our opinion that a noradrenergic loss rather than a DA loss is solely responsible for the behavioral manifestations of PD.…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

175

116

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Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

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“…LID severity could also be diminished by other interactions with noradrenergic inputs to the basal ganglia (Gomez-Mancilla and Bedard, 1993;Lundblad et al, 2002;Dekundy et al, 2007). Furthermore, rats with combined noradrenergic and dopaminergic lesions have greater LID severity, compared with dopaminergic lesions alone (Fulceri et al, 2007;Shin et al, 2014). Indeed, noradrenergic lesions can produce dyskinesias through DA-mediated locomotor impairment (Donaldson et al, 1976;Rommelfanger et al, 2007).…”

Section: Norepinephrine Transporter and L-dopa Dyskinesiamentioning

confidence: 99%

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

2014

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Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI 1 L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI 1 L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI 1 L-DOPA group compared with the L-DOPA-and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.

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Abnormal involuntary movements (AIMs) following pulsatile dopaminergic stimulation: Severe deterioration and morphological correlates following the loss of locus coeruleus neurons

Cited by 50 publications

References 46 publications

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

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