Dopamine Systems in Parkinson's Disease and L-DOPA-induced Dyskinesia What Goes Wrong? (original) (raw)
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D1 and D2 dopamine receptor regulation of striatonigral and striatopallidal neurons
Seminars in Neuroscience, 1992
Dopamine modulates the response of striatal projection neurons to excitatory cortical and thalamic input. The two major dopamine-receptor subtypes, the D, and D2 receptors, are selectively localized on striatonigral and striatopallidal output neurons, respectively. Activation of these receptors has opposite effects on these striatal neurons and consequently dopamine functions to modulate the relative activity of the striatonigral and striatopallidal pathways. Thus, striatal circuitry converts excitatory cortical and thalamic inputs into antagonistic inputs to the output neurons of the basal ganglia, which are the GABA neurons of the entopeduncular and substantia nigra nuclei. The behavioural relevance of these antagonistic mechanisms is evident in Parkinson's disease, in which the degeneration of dopamine input to the striatum results in an imbalance in the striatal output pathways, which has been directly related to the clinical akinesia of this disease .
2004
Recent in vivo electrophysiological studies suggest that chronic dopamine depletion alters profoundly the firing pattern of basal ganglia neurons. These changes may disrupt the processing of cortical information flow from the striatum to the output nuclei, and presumably underlie the clinical manifestations of Parkinson's disease. We have recently reported that chronic nigrostriatal lesions induce changes in the functional state of striatal medium-spiny neurons (MSNs) that could facilitate spreading of cortical synchronous activity (approximately 1 Hz) to striatal target nuclei. Here we show that systemic administration of D1 dopamine agonists was sufficient to restore the changes induced by chronic nigrostriatal lesions on striatal neuronal activity into the normal state. Following systemic administration of SKF38393 or SKF81279 the membrane potential of striatal MSNs was upheld into a more hyperpolarized value and action potential firing probability decreased. D1 agonists also increased the latency to the cortically driven plateau depolarization and reduced the peak potential of the short latency depolarizing postsynaptic response to a more hyperpolarized value. The present study provides in vivo evidence indicating that pharmacological stimulation of D1-class dopamine receptors can modulate the flow of cortical information through the striatum in the parkinsonian state.
L-dopa-induced dyskinesia: Beyond an excessive dopamine tone in the striatum
2014
L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, treatment is complicated by L-dopa-induced dyskinesias (LID). Current evidence links LID to excessive striatal L-dopa-derived dopamine (DA) release, while the possibility of a direct involvement of L-dopa itself in LID has been largely ignored. Here we show that L-dopa can alter basal ganglia activity and produce LID without enhancing striatal DA release in parkinsonian non-human primates. These data may have therapeutic implications for the management of advanced PD since they suggest that LID could result from diverse mechanisms of action of L-dopa.
Proceedings of the National Academy of Sciences, 2011
Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID. aphakia mouse | choline acetyltransferase | SL-327 | dicyclomine | A2A antagonist D opaminergic drugs are effective treatments for the motor symptoms of Parkinson disease (PD), but long-term therapy is limited by disabling abnormal involuntary movements, referred to as L-DOPA-induced dyskinesias (LID) (1). Thus, understanding the molecular and cellular mechanisms underlying LID will help identify more effective treatments for PD, and may also help elucidate the role of dopamine (DA) signaling in motor control.
How does Parkinson's disease begin? The role of compensatory mechanisms. Autor's reply
Trends in Neurosciences, 2004
Bezard and colleagues have to be congratulated on their studies and discussions of the mechanisms involved in compensation of striatal dopamine loss in Parkinson's disease (PD). To understand how PD begins and progresses is a major requirement in developing more definitive therapies for PD (A.E. Lang and J.A. Obeso, unpublished). Bezard et al. have conclusively shown that classically accepted dopamine-mediated mechanisms are not primarily involved in the initial compensation of striatal dopamine depletion in PD [1]. They proposed a series of functional compensatory changes within and outside the basal ganglia. We would like to discuss an alternative hypothesis for the onset of PD and the role of compensatory changes. Before that, some methodological comments are also pertinent. The Bordeaux group has established an N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model that provokes a full parkinsonian syndrome within three weeks, unlike PD, which develops over several years. Importantly, PD has a unilateral or asymmetrical onset whereas MPTP-intoxicated monkeys exhibited bilateral symptoms from the beginning. Both differential features of the model are relevant when analysing the onset of PD and initial compensatory mechanisms.
Molecular effects of dopamine on striatal-projection pathways
Trends in Neurosciences, 2000
Gene regulation studies demonstrate that dopamine differentially regulates the direct and indirect projection neurons of the striatum through their respective expression of the D I and D2 dopamine receptors. Induction of immediate-early genes (lEGs) in striatal neurons is used to study dopaminereceptor-mediated neuronal plasticity. In the dopamine-depleted striatum there is a switch in receptor-mediated signal transduction mechanisms to produce a supersensitive form of D I-mediated neuronal plasticity. This switch is suggested to underlie dopamine-agonist-induced dyskinetic movements that develop during the treatment of Parkinson's disease.
Movement Disorders, 2019
Direct and indirect pathway spiny projection neurons in the striatum bidirectionally modulate the output nuclei of the basal ganglia [1]. An imbalance of these two pathways is a key contributor to the motor symptoms of Parkinson's disease (PD) [2]. In the classical model of striatal function, dopamine promotes movement by activating stimulatory D1 dopamine receptors on "direct" striatonigral spiny projection neurons (dSPNs) and inhibitory D2 receptors on "indirect" striatopallidal SPNs (iSPNs). In this model, dopamine loss tips the scales toward the movementsuppressing indirect pathway, resulting in hypokinetic PD symptoms.
The vast majority of striatal neurons are GABAergic medium-sized spiny neurons. These cells receive glutamatergic input from the cortex, thalamus and limbic areas and dopaminergic input from the mesencephalon. Most relevant evidence indicates that dopamine D 1 receptors are located on striatonigral projection neurons, 5,7 and that adenosine A 2A receptors 4,12,14 and most dopamine D 2 receptors 5,7,14 are located on striatopallidal projection neurons (see, however, Refs 1 and 13). Here we have utilized regulation of the phosphorylation of dopamine-and cyclic AMPregulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible interactions among nigrostriatal dopaminergic neurons and the two classes of dopaminoceptive target neurons. We show that, in striatal slices, the D 2 receptor agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by either the D 1 receptor agonist, SKF 81297, or the A 2A receptor agonist, CGS 21680. Tetrodotoxin abolished the effect of quinpirole on the D 1 agonistinduced but not the A 2A agonist-induced phosphorylation of DARPP-32. These data indicate that: (i) adenosine A 2A and dopamine D 2 receptors interact within the same striatopallidal neurons, and (ii) D 2 receptors present on the striatopallidal neurons modulate the effects of D 1 receptors on the striatonigral neurons. Thus, a single neurotransmitter is capable of activating distinct classes of receptors on distinct populations of target neurons, which, in turn, interact with each other through intercellular communication. 1998 IBRO. Published by Elsevier Science Ltd.