Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats

Tanaka, Hiroyasu; Kannari, Kazuya; Maeda, Tetsuya; Tomiyama, Masahiko; Suda, Toshio; Matsunaga, M

doi:10.1097/00001756-199902250-00034

Cited by 286 publications

(217 citation statements)

References 8 publications

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“…L-dopa, however, is thought to cause global increases in tonic dopamine levels in target areas, such as the neostriatum, consistent with recent pharmacological studies in rodents suggesting that L-dopa acts via non-dopaminergic neurons (Miller & Abercrombie, 1999;Tanaka et al, 1999;Yamato, Kannari, Shen, Suda, & Matsunaga, 2001). If midbrain dopamine signals are indeed critical for providing stimulus-specific, feedback-based information, enhanced levels of dopamine in the striatum coming from the 'wrong' neurons at the 'wrong' time may disrupt or mask critical stimulus-specific and temporally specific signals essential for feedback-based error-correction learning.…”

Section: Introductionsupporting

confidence: 73%

l-dopa impairs learning, but spares generalization, in Parkinson's disease

et al. 2006

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In this study we examined the effect of dopaminergic modulation on learning and memory.Parkinson's patients were tested 'on' versus 'off' dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested 'on' medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson's disease.

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Section: Introductionsupporting

confidence: 73%

l-dopa impairs learning, but spares generalization, in Parkinson's disease

et al. 2006

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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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“…Striatal serotonergic neurons are able to take up, convert exogenous levodopa into dopamine, and subsequently release it from the serotonergic terminals (Maeda, Nagata, Yoshida, & Kannari, 2005;Ng, Chase, & Kopin, 1970;Tanaka et al, 1999). This feature is of great interest in advanced stages of PD when the majority of the striatal dopaminergic terminals degenerated, and serotonin terminals might play a role in handling striatal synaptic dopamine concentrations following levodopa treatment.…”

Section: Serotonergic Systemmentioning

confidence: 99%