Relationship between parkinson¿s disease and depressionan electrophysiological and behavioural study

Supervised by:
  1. Luisa Ugedo Urruela Director

Defence university: Universidad del País Vasco - Euskal Herriko Unibertsitatea

Fecha de defensa: 24 November 2008

  1. Juan Antonio Micó Segura Chair
  2. José Ángel Ruiz Ortega Secretary
  3. Anne Taupignon Committee member
  4. Riccardo Brambilla Committee member
  5. Concepció Marin Agustin Committee member
  1. Farmacología

Type: Thesis

Teseo: 186242 DIALNET


This work focuses on the implications of locus coeruleus (LC) and dorsal raphe nucleus (DRN) in Parkinson's disease (PD) and also in levodopa-induced dyskinesia. In this project several techniques have been used, among others, electrophysiological recordings in anaesthetized rats and in brain slices, behavioural tests (cylinder test, drug-induced rotations, dyskinesia, locomotor activity and levodopa-induced dyskinesia), histological stainings (neutral red and thionine staining) and immunostainings (tyrosine-hydroxylase, dopamine-ß-hydroxylase and FosB/¿FosB). In the first study, the effect of the selective serotonin reuptake inhibitor fluoxetine, on LC noradrenergic neurons has been characterized demonstrating that fluoxetine inhibits the firing of LC neurons by an indirect mechanism that involves the alfa2-adrenoceptors. In the second part of the project it has been observed that LC and DRN neurons are altered after the dopaminergic lesion and that the response to antidepressants varies in parkinsonian rats compared with control animals. In the third part, it has been demonstrated that an interaction between antidepressants and levodopa exits. When levodopa is co-administered with the noradrenaline reuptake inhibitor reboxetine, potentiates the effect of the antidepressant. However levodopa administered together with fluoxetine blocks the effect of the antidepressant. This interaction is observed in LC neuron activity and also in the behavioural test modified forced swimming test. In the last part of the project, the changes in the LC and DRN in dyskinetic animals have been evaluated. This study provides evidence of a high implication of the LC in levodopa-induced dyskinesia. First, LC basal electrophysiological properties are altered under dyskinetic conditions. Surprisingly, LC neuron electrophysiological properties perfectly correlated with all types of levodopa-induced dyskinesia but with the locomotive behaviour. Moreover, when the LC was destroyed in dyskinetic animals, an increase of the dyskinetic movements was observed. As for the DRN, no important changes are observed in dyskinetic conditions. The administration of levodopa does not change any electrophysiological characteristic in dyskinetic animals either. However, in these animals, fluoxetine produces lower effect sixty minutes after the levodopa administration indicating a likely desensitization of 5-HT1A receptors in DRN neurons. Additionally, in this study changes in the expression of FosB/¿FosB in cingulate cortex are observed in dyskinetic animals. In conclusion, in this study it has been verified that the LC and DRN are highly implied in PD and in levodopa-induced dyskinesia in rats.