The role of the locus coeruleus in the development of Parkinson's disease

Gesi, Marco; Soldani, Paola; Giorgi, Filippo Sean; Santinami, Anna; Bonaccorsi, I; Fornai, Francesco

doi:10.1016/s0149-7634(00)00028-2

Cited by 233 publications

(185 citation statements)

References 109 publications

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“…This may suggest that NE plays a minor role in the physiology of this complex neural circuit; however, empirical evidence indicates a much bigger role for this catecholamine. Experiments have demonstrated that the loss of a trophic influence of neurons form the locus coeruleus might be crucial in Parkinson's disease (Gesi et al, 2000). On the other hand, NE may decrease DA cell excitability through synaptic activation of alpha-1 adrenergic receptors in the VTA (Paladini and Williams, 2004).…”

Section: Discussionmentioning

confidence: 99%

Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area

et al. 2007

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Alterations in the state of excitability of midbrain dopamine (DA) neurons from the ventral tegmental area (VTA) may underlay changes in the synaptic plasticity of the mesocorticolimbic system. Here, we investigated norepinephrine's (NE) regulation of VTA DA cell excitability by modulation of the hyperpolarization-activated cation current, I h in whole cell recordings. Current clamp recordings show that NE (40 µM) hyperpolarizes spontaneously firing VTA DA cells (11.23 ±4 mV; n = 8). In voltage clamp, NE (40 µM) induces an outward current (100 ± 24 pA; n = 8) at − 60 mV that reverses at about the Nernst potential for potassium (−106 mV). In addition, NE (40 µM) increases the membrane cord conductance (179 ± 42%; n = 10) and reduces I h amplitude (68 ± 3% of control at −120 mV; n = 10). The noradrenergic alpha-1 antagonist prazosin (40 µM; n = 5) or the alpha-2 antagonist yohimbine (40 µM; n = 5) did not block NE effects. All NE-evoked events were blocked by the D 2 antagonists sulpiride (1 µM) and eticlopride (100 nM) and no significant reduction of I h took place in the presence of the potassium channel blocker BaCl 2 (300 µM). Therefore, it is concluded that NE inhibition of I h was due to an increase in membrane conductance by a non-specific activation of D 2 receptors that induce an outward potassium current and not a result of a second messenger system acting on h-channels. The results also suggest that I h channels are mainly located at dendrites of VTA DA cells and thus their inhibition may facilitate the transition from single spike firing to burst firing and vice versa.

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Section: Discussionmentioning

confidence: 99%

Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area

et al. 2007

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“…Agingrelated decline in motor function has been associated with noradrenergic (NE) deficits (Chan-Palay and Asan, 1989;Gesi et al, 2000). Furthermore, 18-month-old GDNF ϩ/Ϫ mice have lower NE concentrations and morphological alterations of NE cell bodies in the locus ceruleus, lower NE transporter activity in the cerebellum and brainstem, and fewer TH-positive fibers in the hippocampus, cerebellum, and frontal cortex compared with age-matched WT mice (Zaman et al, 2003).…”

Section: Gdnfmentioning

confidence: 99%

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Boger¹,

Middaugh²,

Patrick³

et al. 2007

J. Neurosci.

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Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function. Two weeks after a methamphetamine binge (4 ϫ 10 mg/kg, i.p., at 2 h intervals), GDNF ϩ/Ϫ mice had a significantly greater reduction of tyrosine hydroxylase immunoreactivity in the medial striatum, a proportionally greater depletion of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum, and a greater increase in activated microglia in the substantia nigra than wild-type mice. At 12 months of age, methamphetamine-treated GDNF ϩ/Ϫ mice exhibited less motor activity and lower levels of tyrosine hydroxylase-immunoreactivity, dopamine, DOPAC, and serotonin than wild-type mice. Greater striatal dopamine transporter activity in GDNF ϩ/Ϫ mice may underlie their differential response to methamphetamine. These data suggest the possibility that methamphetamine use in young adults, when combined with lower levels of GDNF throughout life, may precipitate the appearance of parkinsonian-like behaviors during aging.

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“…Thus, LC-noradrenergic neurotransmitter system consequently plays an important role in a wide variety of brain functions [1] . In Parkinson disease (PD), the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in the midbrain triggers a cascade of functional changes affecting the whole basal ganglia network.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have suggested the involvement of these neurotransmitters in the pathophysiology of PD. Neurochemical studies have found that the levels of noradrenaline (NA) decrease significantly in the striatum, substantia nigra, cerebral cortex, hypothalamus and hippocampus of PD patients [1] . The reduction of NA is attributable to the loss of noradrenergic neurons in the LC.…”

Section: Introductionmentioning

confidence: 99%

Firing activity of locus coeruleus noradrenergic neurons increases in a rodent model of Parkinsonism

et al. 2009

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Objective To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD). Methods 2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording. Results The firing rate of LC noradrenergic neurons increased significantly 2 and 4 weeks after 6-OHDA lesions compared to normal rats, respectively (P < 0.05). The percentage of irregularly firing neurons was obviously higher than that of normal rats during the fourth week after SNc lesion (P < 0.05). Conclusion LC noradrenergic neurons are overactive and more irregular in 6-OHDA-lesioned rats. These changes suggest an implication of the LC in the pathophysiological mechanism of PD.

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The role of the locus coeruleus in the development of Parkinson's disease

Cited by 233 publications

References 109 publications

Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area

Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Firing activity of locus coeruleus noradrenergic neurons increases in a rodent model of Parkinsonism

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