Kannabisaren terapiarako erabilera mugimenduaren asalduretan

Aurkitu ostean egin izan diren ikerkunzek agerian utzi dute endokannabinoideoek funtzio fisiologikoetan duten parte-hartzea. Hain zuzen ere, sistema honen osagaiak (estekatzaile endokannabinoideoak, hartzaileak, biosintesirako eta degradaziorako proteinak) badaude mugimendua kontrolatzen duten garuneko zirkuitu eta nukleoetan (gongoil basaletan) eta ondorioz, parte hartzen dute funtzio motorraren erregulazioan, batez ere dopaminaren maila modulatuz. Bestalde, gongoil basaletan sistema endokannabinoideoan aldaketak deskribatu dira seinale dopaminergikoa gutxitua dagoenean, Parkinsonen gaixotasunean gertatzen den bezala. Horregatik, lanabes berri bezala proposatu da mugimenduaren asaldurak tratatzeko sistema endokannabinoideoaren modulazioa

The Effect of 5-HT1A Receptor Agonists on the Entopeduncular Nucleus is Modified in 6-Hydroxydopamine-Lesioned Rats

Background and Purpose l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT1A receptors. Since the internal segment of the globus pallidus, homologous to the entopeduncular nucleus in rodents, seems to be involved in the etiopathology of l-DOPA-induced dyskinesia, we investigated whether the entopeduncular nucleus is modulated by the 5-HT1A receptor partial and full agonists, buspirone, and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in control and 6-hydroxydopamine (6-OHDA)-lesioned rats with or without long-term l-DOPA treatment. Experimental Approach Extracellular single-unit electrocorticogram and local field potential recordings under anaesthesia, immunostaining assays and optogenetic manipulation coupled to electrophysiological recordings were performed. Key Results Systemic buspirone reduced the entopeduncular nucleus firing rate in the sham animals and burst activity in the 6-OHDA-lesioned rats (with or without l-DOPA treatment), while local administration reduced entopeduncular nucleus activity in all the groups, regardless of DA integrity. Systemic 8-OH-DPAT also induced inhibitory effects only in the sham animals. Effects triggered by buspirone and 8-OH-DPAT were reversed by the 5-HT1A receptor antagonist, WAY-100635. Neither buspirone nor 8-OH-DPAT modified the low-frequency oscillatory activity in the entopeduncular nucleus or its synchronization with the motor cortex. Buspirone did not alter the response induced by subthalamic nucleus opto-stimulation in the entopeduncular nucleus. Conclusion and Implications Systemic 5-HT1A receptor activation elicits different effects on the electrophysiological properties of the entopeduncular nucleus depending on the integrity of the nigrostriatal pathway and it does not alter the relationship between subthalamic nucleus and entopeduncular nucleus neuron activity.Euskal Herriko Unibertsitatea, Grant/Award Number: GIU19/092; Basque Government, Grant/Award Numbers: PIBA 2019-38, T747-13; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: SAF2016-77758-R AEI/FEDER, U

The Role of the Subthalamic Nucleus in L-DOPA Induced Dyskinesia in 6-Hydroxydopamine Lesioned Rats

14 p.L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM) scores and the electrophysiological parameters of STN neurons recorded 24 h or 20–120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR) D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias.This study was supported by grants from the Spanish Ministry of Science SAF 2009-08664 (LU), the department of Industry of the Basque Government S-PE10UN24 (LU and RSP) and Kutxa Obra social (RSP). AA and AS have a fellowship from the University of the Basque Country. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of manuscript

Sistema serotonergikoaren eta gongoil basalen arteko elkarrekintza: inplikazio funtzionala eta terapiaren alderdia Parkinsonen gaixotasunean

Serotonina neurotransmisoreak funtzio ezberdinak betetzen ditu informazio-prozesaketaren modulazioan hainbat familiatako hartzaileen aktibazioaren bidez. Hauen artean, erreten ionikoa den hartza ile bat (5-HT3) eta G proteinei lotutako (5-HT1, 5-HT2 , 5-HT4. 7) hartzaileak daude. Neurona serotonergiko gehienak mesentzefaloan kokatuta daude, rafe nukleoetan bereziki . Gongoil basaletara (GB) iristen diren proiekzioak , batez ere dorsal raphe nucleusetik (DRN) heltzen dira. GBak oso ondo antolatuta dauden nukleo subkot1ikalez eratutako sarea da, GB-etako nukleoak striatuma, subthalamic nucleusa (STN), globus pallidusa (barrukoa, GPi eta kanpokoa, GPe) eta substantia nigra (pars compacta, SNc, eta pars reticulata , SNr) direlarik. GBek kontrol motorrean , emozioan eta funtzio kognitiboan parte hartzen dute, eta oso garrantzitsuak dira Parkinsonen Gaixotasunean (PO). Berrikuspen honek serotoninak GBen modulazioan duen funtzioa laburbiltzen du. Bestalde , elkan·ekintza honek PGaren tratamenduan eta L-DOPArebn tratamendu kronikoak eragindako asaldu ra motorretan duen garrantzia eztabaidatzen da

Kannabisaren terapiarako erabilera mugimenduaren asalduretan

Aurkitu ostean egin izan diren ikerkunzek agerian utzi dute endokannabinoideoek funtzio fisiologikoetan duten parte-hartzea. Hain zuzen ere, sistema honen osagaiak (estekatzaile endokannabinoideoak, hartzaileak, biosintesirako eta degradaziorako proteinak) badaude mugimendua kontrolatzen duten garuneko zirkuitu eta nukleoetan (gongoil basaletan) eta ondorioz, parte hartzen dute funtzio motorraren erregulazioan, batez ere dopaminaren maila modulatuz. Bestalde, gongoil basaletan sistema endokannabinoideoan aldaketak deskribatu dira seinale dopaminergikoa gutxitua dagoenean, Parkinsonen gaixotasunean gertatzen den bezala. Horregatik, lanabes berri bezala proposatu da mugimenduaren asaldurak tratatzeko sistema endokannabinoideoaren modulazioa

Zergatik egiten digu alkoholak kalte?

Alcohol consumption has widespread use and acceptance in today’s society.Besides the euphoric effect, alcohol can also produce unpleasant psychological and physical side effects. The acute effects of alcohol depend on its kinetics which varies among the individuals. On the other hand, prolonged use can also produce severe unwanted effects, such as dependence. As a consequence, the person will have an urgent need to drink alcohol. At the same time, the alcoholic will develop tolerance and therefore higher amounts of alcohol will be required for obtaining the same effects. In this article, we will review the kinetic processes that have a higher impact in alcohol plasmatic concentrations. We will also analyze the acute and chronic effects induced by alcoholic beverages.; Gaur egun, alkohol-kontsumoa oso hedatua dago gure gizartean. Nahiz eta gizartearen aldetik oso onartua egon, iradoki izan da batetik efektu euforikoak eragiten dituela, eta bestetik asaldura fisiko zein psikiko kaltegarriak eragin diezazkiokeela organismoari. Alkoholaren zinetika nahiko aldakorra izan daiteke eta horrek nabarmen baldintzatzen ditu organismoan sortzen diren eragin akutuak. Bestalde, alkoholaren luzaroko kontsumoak ere efektu kaltegarriak ditu, esate baterako, menpekotasuna. Ondorioz, gizakiak alkoholdun edariak hartzeko behar handia sumatzen du.Horrekin lotuta, alkoholikoak tolerantzia garatuko du, eta gero eta alkohol kantitate handiagoak beharko ditu. Artikulu honetan, berrikusi egingo dira gorputzeko alkohol kontzentrazio handiagoak baldintzatzen dituzten prozesu zinetiko garrantzitsuenak, baita alkoholak eragindako efektu akutuak zein kronikoak ere

Acute L-DOPA administration reverses changes in firing pattern and low frequency oscillatory activity in the entopeduncular nucleus from long term L-DOPA treated 6-OHDA-lesioned rats

The pathophysiology of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) is associated with aberrant neuronal activity and abnormal high levels of oscillatory activity and synchronization in several basal ganglia nuclei and the cortex. Previously, we have shown that the firing activity of neurons in the substantia nigra pars reticulata (SNr) is relevant in dyskinesia and may be driven by subthalamic nucleus (STN) hyperactivity. Conversely, low frequency oscillatory activity and synchronization in these structures seem to be more important in PD because they are not influenced by prolonged L-DOPA administration. The aim of the present study was to assess (through single-unit extracellular recording techniques under urethane anaesthesia) the neuronal activity of the entopeduncular nucleus (EPN) and its relationship with LID and STN hyperactivity, together with the oscillatory activity and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned rats that received long term L-DOPA treatment (or not). Twenty-four hours after the last L-DOPA injection the firing activity of EPN neurons in long term L-DOPA treated 6-OHDA-lesioned rats was more irregular and bursting compared to sham rats, being those alterations partially reversed by the acute challenge of L-DOPA. No correlation between EPN neurons firing activity and abnormal involuntary movements score was found. However, there was a significant correlation between the firing activity parameters of EPN and STN neurons recorded from long term L-DOPA treated 6-OHDA-lesioned rats. Low frequency oscillatory activity and synchronization both within the EPN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals. These changes were reversed by the acute L-DOPA challenge only in long term L-DOPA treated 6-OHDA-lesioned rats. Altogether, these results obtained from long term L-DOPA treated 6-OHDA-lesioned rats suggest (1) a likely relationship between STN and EPN firing patterns and spiking phases induced by changes after prolonged L-DOPA administration and (2) that the effect of L-DOPA on the firing pattern, low frequency oscillatory activity and synchronization in the EPN may have a relevant role in LID

Deep brain stimulation-guided optogenetic rescue of parkinsonian symptoms

International audienceDeep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson's disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation