Models and biomarkers of motor and neuropsychiatric complications in Parkinson’s disease
(2023) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Parkinson's disease (PD) is a neurodegenerative disorder characterised by typical
motor symptoms that are caused by severe dopamine depletion in the cortico-basal
ganglia network. Parkinsonian motor symptoms are improved by dopaminergic
medications, the most effective being the dopamine precursor L-DOPA. This
compound exerts its motor effects by stimulating dopamine D1 and D2 receptors,
whose expression are segregated between the movement-promoting and movement-suppressing pathways of the basal ganglia circuitry. As the disease progresses,
treatment with L-DOPA give rise to involuntary movements (dyskinesia), which
limits its utility. Drugs that directly stimulate dopamine receptors, referred to as
dopamine... (More) - Parkinson's disease (PD) is a neurodegenerative disorder characterised by typical
motor symptoms that are caused by severe dopamine depletion in the cortico-basal
ganglia network. Parkinsonian motor symptoms are improved by dopaminergic
medications, the most effective being the dopamine precursor L-DOPA. This
compound exerts its motor effects by stimulating dopamine D1 and D2 receptors,
whose expression are segregated between the movement-promoting and movement-suppressing pathways of the basal ganglia circuitry. As the disease progresses,
treatment with L-DOPA give rise to involuntary movements (dyskinesia), which
limits its utility. Drugs that directly stimulate dopamine receptors, referred to as
dopamine agonists, are commonly used to delay the use of L-DOPA or reduce its
dosage. Although less prone to induce dyskinesia, dopamine agonists have a high
liability to induce neuropsychiatric side effects, in particular, impulsive-compulsive
behaviours. However, it remains to be established whether pharmacotherapies
combining L-DOPA and dopamine agonists give rise to specific profiles of motor
and non-motor complications.
The overarching aim of this thesis is to develop improved experimental models
to advance translational research on the motor and neuropsychiatric complications
of PD therapy. Both well-established and new experimental models are used to
define correlations and causal links between regimens of dopaminergic treatment,
behavioural changes, and biomarkers of network and cellular dysfunction in the
cortico-basal ganglia system.
Using in vivo local field potential recordings to study biomarkers of network
dysfunctions, we show that changes in broad-band oscillatory activities of cortico-striatal circuits are correlated to ongoing motions and do not reflect parkinsonian-specific states. Moreover, we demonstrate that dyskinesias induced by D1 receptor
stimulation are associated with prominent narrowband cortico-striatal oscillations
in the high gamma range (70-110 Hz). Following treatment with a D2 agonist, these
narrowband gamma oscillations are less pronounced, whereas this treatment induces
prominent theta oscillations (5-10 Hz) in the deep basal ganglia nuclei. Thus, the
composition of the dopaminergic therapies might affect these neurophysiological
biomarkers and should be considered in future investigations.
Next, using a set of pharmacological tools and markers of cellular dysfunctions,
we show that adjuvant treatment with D2/3 agonists alters the pattern of dopamine-related neuroplasticity in the basal ganglia compared to L-DOPA monotherapy,
despite similar dyskinetic behaviours. The antidyskinetic effects of compounds modulating D1 receptor signalling were stronger in L-DOPA-treated animals, while
NMDA receptor antagonists produced markedly larger effects in the combined
treatment group. Thus, adjuvant dopamine agonist treatment has a significant
impact on the neuroplasticity and pharmacological response profiles of L-DOPA-induced dyskinesia. In a last study, we show that treatment with a D2/3 agonist
induces compulsive behaviours and impulsive decision-making in both intact and
partially dopamine-depleted rats regardless of L-DOPA coadministration.
Taken together, the findings of this thesis shed new light on the maladaptive
cellular changes and network dynamics through which dopaminergic pharmacotherapies for PD affects motor behaviours. Moreover, this thesis work reveals the importance of including realistic models of combined therapies in future translational research on L-DOPA-induced dyskinesia. (Less) - Abstract (Swedish)
- Parkinsons sjukdom är en kronisk neurodegenerativ sjukdom karaktäriserad av
typiska motoriska symtom i form av långsamma rörelser, muskelstelhet och
vilotremor. Dessa symtom orsakas av en brist på signalsubstansen dopamin i de
områden av hjärnan som kontrollerar rörelser (hjärnbarken, basala ganglierna och
thalamus). Parkinsonmedicin, varav det mest effektiva är levodopa, mildrar
symtomen genom att öka mängden dopamin i hjärncellerna. Levodopa stimulerar
dopaminreceptorer i hjärnan, mer specifikt D1- och D2-receptorer, som uttrycks i
rörelsefrämjande respektive rörelsehämmande signalvägar i basala ganglierna. Med
tiden kan behandling med levodopa ge upphov till ofrivilliga rörelser (dyskinesier),
vilket... (More) - Parkinsons sjukdom är en kronisk neurodegenerativ sjukdom karaktäriserad av
typiska motoriska symtom i form av långsamma rörelser, muskelstelhet och
vilotremor. Dessa symtom orsakas av en brist på signalsubstansen dopamin i de
områden av hjärnan som kontrollerar rörelser (hjärnbarken, basala ganglierna och
thalamus). Parkinsonmedicin, varav det mest effektiva är levodopa, mildrar
symtomen genom att öka mängden dopamin i hjärncellerna. Levodopa stimulerar
dopaminreceptorer i hjärnan, mer specifikt D1- och D2-receptorer, som uttrycks i
rörelsefrämjande respektive rörelsehämmande signalvägar i basala ganglierna. Med
tiden kan behandling med levodopa ge upphov till ofrivilliga rörelser (dyskinesier),
vilket begränsar nyttan av behandlingen. Dopaminagonister, som verkar direkt på
nervcellernas dopaminreceptorer, används ofta för att försena eller minska bruket
av levodopa. Risken att utveckla dyskinesier är lägre med dopaminagonister, men å
andra sidan för de med sig en större risk att utveckla neuropsykiatriska biverkningar,
i synnerhet impulskontrollsstörningar. Det är fortfarande oklart om
läkemedelsbehandlingar som kombinerar levodopa och dopaminagonister ger
upphov till specifika profiler av motoriska och neuropsykiatriska symtom.
Det överordnade syftet med denna avhandling är att utveckla förbättrade
experimentella modeller för att främja translationell forskning om de motoriska och
neuropsykiatriska komplikationer som uppstår som en följd av behandling av
Parkinsons sjukdom. Både väletablerade och nya experimentella modeller användes
till att definiera korrelationer och orsakssamband mellan olika typer av dopaminerga
behandlingar, beteendeförändringar och biomarkörer för dysfunktion på
nätverksnivå och cellulär nivå i hjärnkretsar involverade i Parkinsons sjukdom.
Genom att mäta rytmiska mönster i hjärnaktiviteten (neuronala oscillationer) i
basala ganglie-kretsar i en djurmodell av Parkinsons sjukdom, visar vi att ändringar
i hjärnaktiviteten i breda frekvensband korrelerar med pågående rörelser och inte
specifikt med det parkinsonistiska tillståndet. Dessutom visar vi att dyskinesier
inducerade av behandling med en D1-receptoragonist är förbundna med
framträdande gammaoscillationer i ett smalt frekvensband (70-110 Hz) i
motorkortex och striatum. Efter behandling med en D2-receptoragonist är dessa
gammaoscillationer inte lika framträdande. Istället induceras framträdande
thetaoscillationer (5-10 Hz) i de djupa kärnorna av basala ganglierna (globus
pallidus och substantia nigra). Olika kombinationer av dopaminerga läkemedel kan
således ha olika påverkan på dessa neurofysiologiska biomarkörer, vilket bör
beaktas i framtida vetenskapliga undersökningar.
Vidare visar vi med hjälp av farmakologiska verktyg och markörer för cellulära
dysfunktioner att tilläggsbehandling med D2/3-receptoragonister ändrar den
dopaminrelaterade neuroplasticiteten i basala ganglierna jämfört med
monobehandling med levodopa, trots att båda behandlingarna inducerar liknande
dyskinesier. De antidyskinetiska effekterna av substanser som påverkar D1-
receptorsignalering har dessutom störst effekt i djur behandlade med levodopa,
medan glutamatreceptor-antagonister (NMDA-antagonister) har en markant större
effekt i djur behandlade med en kombination av levodopa och en D2/3-
receptoragonist. Tilläggsbehandling med dopaminagonister har således en
signifikant påverkan på levodopa-inducerad neuroplasticitet och på effekten av
farmakologiska behandlingar mot dyskinesi. I en sista undersökning visar vi att
behandling med D2/3-receptoragonister inducerar tvångsmässiga beteenden och
impulsivitet under normala och sänkta dopaminnivåer i striatum, oavsett om
behandlingen ges ensamt eller tillsammans med levodopa.
Sammantaget kastar resultaten i denna avhandling nytt ljus över de
dysfunktionella förändringar på cellulär- och nätverksnivå genom vilka olika typer
av dopaminerg behandling påverkar motoriska beteenden i Parkinsons sjukdom.
Dessutom visar resultaten på vikten av att inkludera realistiska modeller av
kombinationsterapier i framtida translationell forskning på levodopa-inducerade
dyskinesier. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/b212a59f-5280-43e1-9c33-f7d5bcb23472
- author
- Skovgård, Katrine LU
- supervisor
-
- Angela Cenci Nilsson LU
- Per Petersson LU
- Pär Halje LU
- Roger Olsson LU
- opponent
-
- Dr. Cruz Rodríguez-Oroz, Maria, University of Navarre, Pamplona, Spain
- organization
- publishing date
- 2023
- type
- Thesis
- publication status
- published
- subject
- keywords
- Parkinson's disease/Parkinsonism, Dyskinesia, Drug-Induced, Oscillations, Local field potentials, Impulsive-compulsive behaviours, Dopamine agonists, Animal Models, Pharmacology
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2023:3
- pages
- 118 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/66723183004
- defense date
- 2023-01-19 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-342-4
- language
- English
- LU publication?
- yes
- id
- b212a59f-5280-43e1-9c33-f7d5bcb23472
- date added to LUP
- 2022-12-19 21:20:47
- date last changed
- 2023-01-03 12:08:17
@phdthesis{b212a59f-5280-43e1-9c33-f7d5bcb23472,
abstract = {{Parkinson's disease (PD) is a neurodegenerative disorder characterised by typical<br/>motor symptoms that are caused by severe dopamine depletion in the cortico-basal<br/>ganglia network. Parkinsonian motor symptoms are improved by dopaminergic<br/>medications, the most effective being the dopamine precursor L-DOPA. This<br/>compound exerts its motor effects by stimulating dopamine D1 and D2 receptors,<br/>whose expression are segregated between the movement-promoting and movement-suppressing pathways of the basal ganglia circuitry. As the disease progresses,<br/>treatment with L-DOPA give rise to involuntary movements (dyskinesia), which<br/>limits its utility. Drugs that directly stimulate dopamine receptors, referred to as<br/>dopamine agonists, are commonly used to delay the use of L-DOPA or reduce its<br/>dosage. Although less prone to induce dyskinesia, dopamine agonists have a high<br/>liability to induce neuropsychiatric side effects, in particular, impulsive-compulsive<br/>behaviours. However, it remains to be established whether pharmacotherapies<br/>combining L-DOPA and dopamine agonists give rise to specific profiles of motor<br/>and non-motor complications.<br/>The overarching aim of this thesis is to develop improved experimental models<br/>to advance translational research on the motor and neuropsychiatric complications<br/>of PD therapy. Both well-established and new experimental models are used to<br/>define correlations and causal links between regimens of dopaminergic treatment,<br/>behavioural changes, and biomarkers of network and cellular dysfunction in the<br/>cortico-basal ganglia system.<br/>Using in vivo local field potential recordings to study biomarkers of network<br/>dysfunctions, we show that changes in broad-band oscillatory activities of cortico-striatal circuits are correlated to ongoing motions and do not reflect parkinsonian-specific states. Moreover, we demonstrate that dyskinesias induced by D1 receptor<br/>stimulation are associated with prominent narrowband cortico-striatal oscillations<br/>in the high gamma range (70-110 Hz). Following treatment with a D2 agonist, these<br/>narrowband gamma oscillations are less pronounced, whereas this treatment induces<br/>prominent theta oscillations (5-10 Hz) in the deep basal ganglia nuclei. Thus, the<br/>composition of the dopaminergic therapies might affect these neurophysiological<br/>biomarkers and should be considered in future investigations.<br/>Next, using a set of pharmacological tools and markers of cellular dysfunctions,<br/>we show that adjuvant treatment with D2/3 agonists alters the pattern of dopamine-related neuroplasticity in the basal ganglia compared to L-DOPA monotherapy,<br/>despite similar dyskinetic behaviours. The antidyskinetic effects of compounds modulating D1 receptor signalling were stronger in L-DOPA-treated animals, while<br/>NMDA receptor antagonists produced markedly larger effects in the combined<br/>treatment group. Thus, adjuvant dopamine agonist treatment has a significant<br/>impact on the neuroplasticity and pharmacological response profiles of L-DOPA-induced dyskinesia. In a last study, we show that treatment with a D2/3 agonist<br/>induces compulsive behaviours and impulsive decision-making in both intact and<br/>partially dopamine-depleted rats regardless of L-DOPA coadministration.<br/>Taken together, the findings of this thesis shed new light on the maladaptive<br/>cellular changes and network dynamics through which dopaminergic pharmacotherapies for PD affects motor behaviours. Moreover, this thesis work reveals the importance of including realistic models of combined therapies in future translational research on L-DOPA-induced dyskinesia.}},
author = {{Skovgård, Katrine}},
isbn = {{978-91-8021-342-4}},
issn = {{1652-8220}},
keywords = {{Parkinson's disease/Parkinsonism; Dyskinesia, Drug-Induced; Oscillations; Local field potentials; Impulsive-compulsive behaviours; Dopamine agonists; Animal Models; Pharmacology}},
language = {{eng}},
number = {{2023:3}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Models and biomarkers of motor and neuropsychiatric complications in Parkinson’s disease}},
url = {{https://lup.lub.lu.se/search/files/131878636/Thesis_Katrine_Skovga_rd_WEB_copy.pdf}},
year = {{2023}},
}