Clinical treatments with typical antipsychotic drugs (APDs) are accompanied by extrapyramidal motor side-effects (EPS) such as hypokinesia and catalepsy. As little is known about electrophysiological substrates of such motor disturbances, we investigated the effects of a typical APD, alpha-flupentixol, on the motor behavior and the neuronal activity of the whole basal ganglia nuclei in the rat.The motor behavior was examined by the open field actimeter and the neuronal activity of basal ganglia nuclei was investigated using extracellular single unit recordings on urethane anesthetized rats. We show that alpha-flupentixol induced EPS paralleled by a decrease in the firing rate and a disorganization of the firing pattern in both substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN). Furthermore, alpha-flupentixol induced an increase in the firing rate of globus pallidus (GP) neurons. In the striatum, we recorded two populations of medium spiny neurons (MSNs) after their antidromic identification. At basal level, both striato-pallidal and striato-nigral MSNs were found to be unaffected by alpha-flupentixol. However, during electrical cortico-striatal activation only striato-pallidal, but not striato-nigral, MSNs were found to be inhibited by alpha-flupentixol. Together, our results suggest that the changes in STN and SNr neuronal activity are a consequence of increased neuronal activity of globus pallidus (GP). Indeed, after selective GP lesion, alpha-flupentixol failed to induce EPS and to alter STN neuronal activity.Our study reports strong evidence to show that hypokinesia and catalepsy induced by alpha-flupentixol are triggered by dramatic changes occurring in basal ganglia network. We provide new insight into the key role of GP in the pathophysiology of APD-induced EPS suggesting that the GP can be considered as a potential target for the treatment of EPS.
Parkinson's disease is a neurological disorder characterized by the manifestation of motor symptoms, such as akinesia, muscle rigidity and tremor at rest. These symptoms are classically attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra (SNc), which results in a marked dopamine depletion in the striatum. It is well established that dopamine neurons in the SNc innervate not only the striatum, which is the main target, but also other basal ganglia nuclei including the two segments of globus pallidus and the subthalamic nucleus. The role of dopamine and its depletion in the striatum is well known, however, the role of dopamine depletion in the pallidal complex and the subthalamic nucleus in the genesis of their abnormal neuronal activity and in parkinsonian motor deficits is still not clearly determined. Based on recent experimental data from animal models of Parkinson's disease in rodents and non-human primates and also from parkinsonian patients, this review summarizes current knowledge on the role of dopamine in the modulation of basal ganglia neuronal activity and also the role of dopamine depletion in these nuclei in the pathophysiology of Parkinson's disease.
Event Abstract Back to Event Subthalamic nucleus D5 receptors: role in the pathophysiology and therapy of Parkinson's disease Jonathan Chetrit1* 1 Université de Bordeaux 2, Laboratoire MAC, France Burst firing in basal ganglia is a hallmark of Parkinson’s disease (PD). Activation of dopamine D5 receptors (DRD5), which are characterized by a high constitutive activity, has been shown to potentiate burst firing of subthalamic nucleus (STN) neurons in vitro. The aim of the present study was to investigate whether inhibiting the constitutive activity of DRD5 results in depressed burst firing of STN neurons and consequently improves motor disturbances in a rat model of PD. First, we confirmed that DRD5 exhibits a high constitutive activity in vivo, leading to GTP γS experiments on brain slices containing STN. Using α-flupentixol as a DRD5 invert-agonist we have studied the effect of constitutive activity blockade on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in an experimental modele of PD: 6-hydroxydopamine (6-OHDA)-lesioned rats. Local injection of α-flupentixol directly into the STN improved locomotor activity of 6-OHDA-lesioned rats and diminished bursty neurons proportion. Taking together, our results demonstrate that DRD5 located in the STN are involved in the pathophysiology of PD and that local administration of invert-agonist of these receptors could be beneficial in the treatment of PD. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 26 - Exploring new therapies for Parkinson's disease" Citation: Chetrit J (2009). Subthalamic nucleus D5 receptors: role in the pathophysiology and therapy of Parkinson's disease. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.139 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Nov 2009; Published Online: 24 Nov 2009. * Correspondence: Jonathan Chetrit, Université de Bordeaux 2, Laboratoire MAC, Bordeaux, France, jonathanchetrit@yahoo.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jonathan Chetrit Google Jonathan Chetrit Google Scholar Jonathan Chetrit PubMed Jonathan Chetrit Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.
Burst firing has been reported as a pathological activity of subthalamic nucleus (STN) neurons in Parkinson's disease. However, the origin of bursts and their causal link with motor deficits remain unknown. Here we tested the hypothesis that dopamine D 5 receptors (D 5 Rs), characterized by a high constitutive activity, may contribute to the emergence of burst firing in STN. We tested whether inhibiting D 5 R constitutive activity depresses burst firing and alleviates motor impairments in the 6-OHDA rat model of Parkinson's disease. Intrasubthalamic microinjections of either an inverse agonist of D 5 Rs, flupenthixol, or a D 2 R antagonist, raclopride, were applied. Behavioral experiments, in vivo and in vitro electrophysiological recordings, and ex vivo functional neuroanatomy studies were performed. Using [ 5 S]GTPγ binding autoradiography, we show that application of flupenthixol inhibits D 5 R constitutive activity within the STN. Furthermore, flupenthixol reduced evoked burst in brain slices and converted pathological burst firing into physiological tonic, single-spike firing in 6-OHDA rats in vivo . This later action was mimicked by calciseptine, a Cav1 channel blocker. Moreover, the same treatment dramatically attenuated motor impairment in this model and normalized metabolic hyperactivity in both STN and substantia nigra pars reticulata, the main output structure of basal ganglia in rats. In contrast, raclopride as well as saline did not reverse burst firing and motor deficits, confirming the selective action of flupenthixol on D 5 Rs. These results are the first to demonstrate that subthalamic D 5 Rs are involved in the pathophysiology of Parkinson's disease and that administering an inverse agonist of these receptors may lessen motor symptoms.
Event Abstract Back to Event Serotonin and norepinephrine depletions can promote anxiety and depression in a rat model of Parkinson's disease: an electrophysiological and behavioural study. Claire Delaville1*, Jonathan Chetrit2, Sylvia Navailles2, Philippe De Deurwaerdère2 and Abdelhamid Benazzouz2 1 National Institutes of Health, NINDS, United States 2 CNRS, Neurodegenerative Diseases Institute UMR 5293, France The loss of dopamine (DA) neurons has been the pathophysiological focus of the devastating motor conditions of Parkinson's disease (PD). Beyond DA, PD is a multi-system disorder characterized also by the loss of serotonin (5-HT) neurons from the dorsal raphe nucleus and norepinephrine (NE) neurons from the locus coeruleus. 5-HT and NE are widely recognized in the development of depression and anxiety and both symptoms are reported with a high prevalence in PD patients. However, a specific role for each neurotransmitter in the pathophysiology of PD is not clearly determined. Here, we investigated, in rats, the respective influence of DA, 5-HT and NE depletions on motor and non-motor behaviors as well as on the neuronal activity measured in vivo by single cell extracellular recordings in subthalamic (STN), globus pallidus (GP) and substantia nigra pars reticulata (SNr). DA, 5-HT and NE depletions were achieved by using classic protocols with 6-hydroxydopamine/desipramine, parachlorophenylalanine and DSP-4, respectively. We showed that NE or DA, but not 5-HT depletion significantly decreased locomotor activity and enhanced the proportion of bursty and irregular STN neurons. Anxiety-like states required DA depletion plus the depletion of 5-HT or NE. Anhedonia and "depressive-like" behavior emerged only from the combined depletion of all three monoamines, an effect paralleled by an increase in the firing rate and the proportion of bursty and irregular STN neurons. As for the STN, DA depletion increased the proportion of bursty neurons in GP and SNr. 5-HT, but not NE depletion modified GP and SNr neuronal activity. Thus, our data show that 5-HT and NE modulate specifically the basal ganglia activity and provides evidence for the exacerbation of behavioral deficits when 5-HT and/or NE depletions are combined with DA depletion. These data bring up new insight into the influence of 5-HT system in non-motor symptoms of PD. Keywords: Parkinson Disease, Norepinephrine, Serotonin, non-motor symptoms, Motor Activity Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Symposium Topic: Abstracts Citation: Delaville C, Chetrit J, Navailles S, De Deurwaerdère P and Benazzouz A (2013). Serotonin and norepinephrine depletions can promote anxiety and depression in a rat model of Parkinson's disease: an electrophysiological and behavioural study.. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00022 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers' terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Jan 2013; Published Online: 11 Apr 2013. * Correspondence: Dr. Claire Delaville, National Institutes of Health, NINDS, Bethesda, Maryland, MD 20892-3702, United States, cdelaville@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz Google Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz Google Scholar Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz PubMed Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.
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