Models and biomarkers of motor and neuropsychiatric complications in Parkinson’s disease

Research output: ThesisDoctoral Thesis (compilation)

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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 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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Cenci Nilsson, Angela, Supervisor
  • Petersson, Per, Assistant supervisor
  • Halje, Pär, Assistant supervisor
  • Olsson, Roger, Assistant supervisor
Award date2023 Jan 19
Place of PublicationLund
Publisher
ISBN (Print)978-91-8021-342-4
Publication statusPublished - 2023

Bibliographical note

Defence details
Date: 2023-01-19
Time: 13:00
Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/66723183004
External reviewer(s)
Name: Cruz Rodríguez-Oroz, Maria
Title: Dr.
Affiliation: University of Navarre, Pamplona, Spain

Subject classification (UKÄ)

  • Neurosciences
  • Physiology
  • Pharmacology and Toxicology

Free keywords

  • Parkinson's disease/Parkinsonism
  • Dyskinesia, Drug-Induced
  • Oscillations
  • Local field potentials
  • Impulsive-compulsive behaviours
  • Dopamine agonists
  • Animal Models
  • Pharmacology

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