l-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study

Arai, Ryohachi; Karasawa, Nobuyuki; Geffard, M.; Nagatsu, Ikuko

doi:10.1016/0304-3940(95)11817-g

Cited by 162 publications

(83 citation statements)

References 11 publications

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“…Thus, it is unclear whether the integration of these two error terms is representative of typical dopamine release in a non-Parkinsonian brain. For example (and speculatively), exogenously increased levels of dopamine via l-3,4-dihydroxyphenylalanine (L-DOPA) therapy could cause serotonergic terminals to inappropriately load dopamine through cellular reuptake mechanisms or directly convert L-DOPA into dopamine in terminals that normal release serotonin (31,32); thus, signals normally encoded by serotonin release might then be misencoded by dopamine release. Although an integration of these terms is consistent with how a decision-making agent might account for these opponent feedback signals, it is not a priori necessary that dopamine release encodes this specific computation.…”

Section: Discussionmentioning

confidence: 99%

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

Kishida

Sáez

Lohrenz

et al. 2015

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

183

283

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In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.dopamine | reward prediction error | counterfactual prediction error | decision-making | human fast-scan cyclic voltammetry

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Section: Discussionmentioning

confidence: 99%

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

Kishida

Sáez

Lohrenz

et al. 2015

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

183

283

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“…The serotonin neurons are of particular interest in this regard, because they have the capacity to convert L-DOPA to DA, store the newly formed DA in vesicles, and release it in an activitydependent manner (Ng et al, 1970(Ng et al, , 1971Hollister et al, 1979;Arai et al, 1994Arai et al, , 1995Maeda et al, 2005). In dopaminergic terminals DA release is controlled via DA reuptake by the DA transporter (DAT) and D 2 autoreceptor feedback control.…”

Section: Introductionmentioning

confidence: 99%

Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

Carlsson¹,

Carta²,

et al. 2007

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“…Our results indicate that PD patients with advanced disease still have capacity to metabolize levodopa to DA despite probable pronounced nigral degeneration and the question is if other structures/neurons than the dopaminergic neurons are involved in the metabolism of levodopa to DA. Serotonergic neurons are able to convert exogenous levodopa to DA and release it as a "false transmitter" giving symptom relief in PD patients (71)(72)(73)(74)(75) and may therefore play a role in the converting process of exogenous levodopa to DA. One theory is that the autoregulating function of the DA release is lacking in serotonergic neurons resulting in an un-controlled DA release after levodopa administration and thus causing LID (90)(91)(92).…”

Section: Discussionmentioning

confidence: 99%

“…Higher levodopa doses result in higher peaks (C max ) of levodopa concentration and this, together with the dopaminergic degeneration in the brain, is considered to result in motor complications. It is considered that with pronounced degeneration of the dopaminergic neurons it is possible that other structures, such as serotonergic neurons and/or astrocytes, are involved in the metabolism of levodopa to DA (71)(72)(73)(74)(75)(76)(77).…”

Section: Levodopa In the Brainmentioning

confidence: 99%

“…The presynaptic mechanisms are caused by the DA neuron degeneration and there is a 70-80 % depletion of DA when PD patients start to experience PD symptoms. Serotonergic neurons are able to convert exogenous levodopa to DA and release it as a "false transmitter" giving symptom relief in PD patients (71)(72)(73)(74)(75) and even though the serotonin innervation in the striatum also is affected in PD, it is not degenerated to the same extent as for the dopaminergic neurons (89). Serotonergic neurons may therefore play a role in the converting process of exogenous levodopa to DA.…”

Section: Motor Complicationsmentioning

confidence: 99%

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Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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l-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study

Cited by 162 publications

References 11 publications

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

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