Reuptake of l-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters

Kannari, Kazuya; Shen, Hongyan; Arai, Akira; Tomiyama, Masahiko; Baba, Masayuki

doi:10.1016/j.neulet.2006.03.059

Cited by 58 publications

(40 citation statements)

References 13 publications

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“…We found no effect of buspirone pretreatment on UPDRS-III scores compared with levodopa alone in either the PD MM LIDs group (F (1,11) = 0.62; P > 0.1; Figure 4F) or the PD MS LIDs group (F (1,11) = 0.17; P > 0.1; Figure 4G). …”

Section: Figurementioning

confidence: 82%

“…Preclinical studies have shown that serotonergic terminals are able to convert exogenous levodopa to dopamine, store and release this into the extracellular space (3)(4)(5)10). Serotonergic terminals can also take up dopamine from the extracellular space via SERT (8,9,11). Such a mechanism becomes relevant to PD when striatal serotonergic terminals are still relatively preserved or less damaged than degenerating dopaminergic terminals and can therefore influence synaptic dopamine levels.…”

Section: Discussionmentioning

confidence: 99%

“…Serotonergic terminals may therefore contribute to the aberrant regulation of motor behavior through mishandling of exogenous levodopa (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Politis¹,

Wu²,

Loane³

et al. 2014

J. Clin. Invest.

212

183

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Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11 C-DASB PET to evaluate serotonin terminal function and 11 C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopaevoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

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Section: Figurementioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Politis¹,

Wu²,

Loane³

et al. 2014

J. Clin. Invest.

212

183

View full text Add to dashboard Cite

show abstract

“…5 Serotonergic terminals have been found capable of converting exogenous levodopa into dopamine, store it in synaptic vesicles, and release it in an activity-dependent manner. [6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model [10][11][12] and PD. 13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over dopaminergic terminals' activity.…”

mentioning

confidence: 99%

Serotonin-to-dopamine transporter ratios in Parkinson disease

et al. 2016

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Objective: To investigate whether a serotonin-to-dopamine terminal ratio is related to the appearance of dyskinesias in patients with Parkinson disease (PD).Methods: Twenty-eight patients with idiopathic PD (17 with levodopa-induced dyskinesias [LIDs], 11 without dyskinesias) and 12 age-matched healthy controls were studied with PET and 5[11 C]-3-amino-4-(2-dimethylaminomethylphenyl-sulfanyl)-benzonitrile ( 11 C-DASB) and with SPECT and [ 123 I]N-w-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)nortropane ( 123 I-ioflupane), which are in vivo specific markers of the serotonin and dopamine transporters' availability, respectively. We have employed a simplified reference tissue model for the quantification of 11 C-DASB, whereas a semiquantification approach was used for 123 I-ioflupane data. We calculated 11 C-DASB binding to 123 I-ioflupane uptake ratios for the caudate and the putamen.Results: Patients with PD showed striatal decreases in 11 C-DASB binding potential (p , 0.01) and in 123 I-ioflupane mean uptake (p , 0.001) compared to controls. The mean 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen was 0.779 (increased by 75.8% of the controls' mean) for the nondyskinetic group and 0.901 (increased by 103.4% of the controls' mean) for the patients with dyskinesias. There was a statistically significant difference (p , 0.001) in 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen between the group of patients with and without dyskinesias. Higher 11 C-DASB to 123 I-ioflupane binding ratios correlated with longer disease duration for the 28 patients with PD (r 5 0.52; p , 0.01).Conclusions: Serotonin-to-dopamine transporter binding ratio increases as PD progresses and patients experience LIDs. Our findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs. Studies in the animal model of Parkinson disease (PD)1 as well as in humans 2-4 have indicated that degeneration of dopaminergic presynaptic terminals in the striatum is critical in the development of L-dopa-induced dyskinesias (LIDs). Due to the progressive degeneration, striatal dopaminergic terminals lose their dopamine storage capacity and the ability to maintain a stable dopamine release rate in the synapse. 5 Serotonergic terminals have been found capable of converting exogenous levodopa into dopamine, store it in synaptic vesicles, and release it in an activity-dependent manner. [6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model 10-12 and PD.13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over

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“…It has been proposed that SERT may contribute to the clearance of striatal DA release enhanced by L-DOPA. 73 However, the fact that citalopram, a blocker of SERT, suppresses L-DOPA-induced DA release 16 supports a role for SERT in the release (see section II.A.3) rather than the clearance of extracellular DA. In contrast, NET may Figure 4.…”

Section: 21mentioning

confidence: 99%

Multisite Intracerebral Microdialysis to Study the Mechanism of L-DOPA Induced Dopamine and Serotonin Release in the Parkinsonian Brain

Navailles

Lagière

Contini

et al. 2013

ACS Chem. Neurosci.

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L-DOPA is currently one of the best medications for Parkinson's disease. It was assumed for several years that its benefits and side effects were related to the enhancement of dopamine release in the dopamine-depleted striatum. The use of intracerebral microdialysis combined with a pharmacological approach has led to the discovery that serotonergic neurons are responsible for dopamine release induced by L-DOPA. The subsequent use of multisite microdialysis has further revealed that L-DOPA-stimulated dopamine release is widespread and related to the serotonergic innervation. The present Review emphasizes the functional impact of extrastriatal release of dopamine induced by L-DOPA in both the therapeutic and side effects of L-DOPA. KEYWORDS: multisite intracerebral microdialysis, L-DOPA, DA and 5-HT release, 5-HT neurons, region-dependent effects, clearance mechanisms L-DOPA is the best medication for Parkinson's disease. The use of L-DOPA as a treatment for Parkinson's disease began soon after the discovery that the striatal tissue concentration of dopamine (DA) was lower in Parkinsonian patients compared to age-matched individuals.1 The efficacy of L-DOPA was improved by combination with a peripheral inhibitor of Laromatic amino acid decarboxylase (AADC) to prevent the conversion of L-DOPA into DA in the bloodstream, thus enhancing the brain penetration of L-DOPA. Although L-DOPA is highly effective in relieving motor symptoms, numerous motor and nonmotor side-effects including L-DOPA-induced dyskinesias and psychosis can gradually emerge over time.2 The functional impact of L-DOPA in the Parkinsonian brain may not be solely restricted to its ability to restore "physiological levels" of DA in the striatum. Further investigations of its mechanism of action are thoroughly needed in order to address the motor and nonmotor side-effects of L-DOPA.Intracerebral microdialysis is a powerful sampling technique used to monitor steady-state extracellular levels of neurotransmitters in vivo. This technique has helped to decipher the mechanism of action of numerous drugs and medications with respect to their action toward neurotransmitter systems. Furthermore, the development of simultaneous implantation of multiple microdialysis probes in distinct brain regions (referred to here as multisite microdialysis) has proven its strength in revealing region-dependent dynamics of neurotransmitter release in response to pharmacological challenges and the neurochemical interactions between brain regions.Here, we summarize data showing the numerous advantages of intracerebral microdialysis to decipher the diverse features of the mechanism of action of L-DOPA in the Parkinsonian brain by using both a classical neuropharmacological approach and a multisite microdialysis approach. The present Review emphasizes the effect of L-DOPA in extrastriatal brain regions and how the region-dependent pattern of DA release induced by L-DOPA through serotonergic (5-HT) neurons may be relevant to its therapeutic and/or side-effects. I. THE US...

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Reuptake of l-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters

Cited by 58 publications

References 13 publications

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Serotonin-to-dopamine transporter ratios in Parkinson disease

Multisite Intracerebral Microdialysis to Study the Mechanism of L-DOPA Induced Dopamine and Serotonin Release in the Parkinsonian Brain

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