The ‘magic’ of -dopa: why is it the gold standard Parkinson's disease therapy?

Mercuri, Nicola Biagio; Bernardi, Giorgio

doi:10.1016/j.tips.2005.05.002

Cited by 214 publications

(150 citation statements)

References 39 publications

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“…Such interaction potentially may explain the enhanced outflow of DA after amphetamine in TAAR1-KO mice (Wolinsky et al, 2006). A second possibility suggests that TAAR1 localized at cell bodies of monoaminergic neurons may directly modulate activity of these neurons in response to various compounds active at TAAR1 (Mercuri and Bernardi, 2005;Lindemann et al, 2008). Finally, it is possible that TAAR1 directly interacts with dopamine receptors as a heterodimer or at the level of signaling intermediates, thereby providing important modulatory influence over dopaminergic neurotransmission.…”

Section: Biochemistry and Pharmacology Of Taar1mentioning

confidence: 99%

Trace Amine-Associated Receptors as Emerging Therapeutic Targets

Sotnikova

Caron

Gainetdinov

2009

Molecular Pharmacology

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Endogenous trace amines (TAs) of unknown biological function are structurally related to classic monoaminergic neurotransmitters and found at low concentrations in the mammalian brain. Their recently discovered group of G protein-coupled receptors, trace amine-associated receptors (TAARs), may represent putative targets not only for trace and other amines but also for a variety of monoaminergic compounds, including amphetamines and monoamine metabolites. The trace amineassociated receptor 1 (TAAR1), which is in part associated with the monoaminergic neuronal circuitry controlling various functions, including movement, is the best characterized of the class, although little is known about its regulation and function.Here we review the pharmacology and biochemical properties of the TAAR1 and its physiological functions as revealed in studies involving knockout mice lacking this receptor. Potential therapeutic applications of future selective TAAR1 agonists and antagonists are also discussed. Although understanding of biology and functions mediated by other TAARs is still in its infancy, it is expected that further characterization of the functional roles and biochemical properties of TAARs and identification of endogenous and exogenous ligands will eventually promote these receptors as an attractive class of targets to correct monoaminergic processes that could be dysfunctional in a host of disorders of brain and periphery.

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Section: Biochemistry and Pharmacology Of Taar1mentioning

confidence: 99%

Trace Amine-Associated Receptors as Emerging Therapeutic Targets

Sotnikova

Caron

Gainetdinov

2009

Molecular Pharmacology

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“…L-DOPA and direct DA agonists are the most common medications for PD. Compared with direct DA agonists, however, the DA precursor L-DOPA is more effective in relieving the motor symptoms of PD, although its long-term use is associated with an increased incidence of motor complications (see reviews by Mercuri and Bernardi, 2005;Cenci and Odin, 2009). The reason for the superior therapeutic efficacy of L-DOPA is still unclear (Mercuri and Bernardi, 2005;Cenci and Odin, 2009).…”

Section: Introductionmentioning

confidence: 99%

Effects of l-DOPA on Nigral Dopamine Neurons and Local Field Potential: Comparison with Apomorphine and Muscimol

Xu¹,

Karain²,

Brantley³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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L-DOPA is more effective than direct dopamine (DA) agonists in relieving the motor deficits in Parkinson's disease. Using in vivo recording, we compared the effect of L-DOPA and the direct DA agonist apomorphine on DA neurons in rat substantia nigra (SN). L-DOPA (50 -100 mg/kg i.v.) decreased the firing rate as well as the variability and slow oscillation (SO) of firing. All effects were blocked by raclopride and mimicked by quinpirole, suggesting that they are mediated through D2-like receptors. Autoreceptor-selective doses of apomorphine (5-20 g/kg i.v.) also inhibited all three parameters. The magnitude of the inhibition, however, was significantly greater than that induced by L-DOPA. Neither L-DOPA nor apomorphine had a consistent effect on SN local field potentials (LFPs). The GABA agonist muscimol, known to preferentially inhibit SN non-DA neurons, consistently inhibited the SO in both DA cell firing and LFPs. These results suggest that SN LFPs mainly reflect the synaptic potentials in non-DA neurons, and L-DOPA and apomorphine, unlike muscimol, affect DA neurons primarily through DA autoreceptors. DA autoreceptor activation is known to hyperpolarize DA cells by increasing the membrane conductance to K ϩ . This increase in membrane conductance would shunt synaptic input to DA neurons, thereby decreasing the variability and SO in DA cell firing. The low potency of L-DOPA to inhibit DA cell firing and reduce their responses to synaptic input may partially account for its superior therapeutic efficacy in Parkinson's disease compared with apomorphine and other direct DA agonists.

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“…At present, there is no cure for Parkinson's disease although L-dopa alleviates Parkinsonian symptoms [1]. As the disease progresses, the efficacy of L-dopa decreases and the incidence and severity of the side effects increase [2].…”

Section: Introductionmentioning

confidence: 99%

Effects of STN DBS on Rigidity in Parkinson's Disease

Shapiro

Vaillancourt

Sturman

et al. 2007

IEEE Trans. Neural Syst. Rehabil. Eng.

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We quantified the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and medication on Parkinsonian rigidity using an objective measure of work about the elbow joint during a complete cycle of imposed 1-Hz sinusoidal oscillations. Resting and activated rigidity were analyzed in four experimental conditions: 1) off treatment; 2) on DBS; 3) on medication; and 4) on DBS plus medication. Rigidity at the elbow joint was also assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). We tested ten patients who received STN DBS and ten age-matched neurologically healthy control subjects. The activated rigidity condition increased work in both Parkinson's disease (PD) patients and control subjects. In PD patients, STN DBS reduced both resting and activated rigidity as indicated by work and the UPDRS rigidity score. This is the first demonstration that STN stimulation reduces rigidity using an objective measure such as work. In contrast, the presurgery dose of antiparkinsonian medication did not significantly improve the UPDRS rigidity score and reduced work only in the activated rigidity condition. Our results suggest that STN DBS may be more effective in alleviating rigidity in the upper limb of PD patients than medications administered at presurgery dosage level.

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The ‘magic’ of -dopa: why is it the gold standard Parkinson's disease therapy?

Cited by 214 publications

References 39 publications

Trace Amine-Associated Receptors as Emerging Therapeutic Targets

Trace Amine-Associated Receptors as Emerging Therapeutic Targets

Effects of l-DOPA on Nigral Dopamine Neurons and Local Field Potential: Comparison with Apomorphine and Muscimol

Effects of STN DBS on Rigidity in Parkinson's Disease

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