Author: Espa E, Song L, Skovgård K, Fanni S, Cenci MA.

Abstract:

Background: Current models of L-DOPA-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-DOPA. However, patients with LID receive combination therapies that often include dopamine agonists. 

Objective: Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses. 

Methods: Different regimens of L-DOPA monotreatment and L-DOPA-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-DOPA monotreatment or L-DOPA combined with ropinirole.

Results: We defined chronic regimens of L-DOPA monotreatment and L-DOPA-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared to the monotreatment group, animals receiving the L-DOPA-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced following L-DOPA-ropinirole cotreatment vs L-DOPA monotreatment. Significant group differences were moreover detected upon comparing the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-DOPA-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-DOPA-ropinirole cotreated animals.

Conclusions: Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms candidate interventions in both clinical and experimental settings. 

Link: https://pubmed.ncbi.nlm.nih.gov/36656044/

The abstract submission deadline and early-bird registration time has been prolonged to January 31st 2023.

We are happy to announce that Kjell Fuxe and Wolfram Schultz were elected as honorary members of SWEBAGS.

They will give their honorary lecture early 2023 , we will announce the date and time in the event calendar as soon as we have this confirmed.

EBRAINS will arrange a Satellite event @ FENS, Friday July 8, from 8:30AM to 5:30PM CEST at the INSPE, Paris (lunch included).

It will highlight the connections between basic and clinical neuroscience and computational neuroscience. The program is structured around four sessions on why, what, how and where to integrate multi-resolution and multi-scale data for neuroscience research. More info and free registration.

Improving well-being and survival in the 6-OHDA lesion model of Parkinson´s disease in mice: Literature review and step-by-step protocol

Authors

Adriane Guillaumin, Bianca Vicek & Åsa Wallén-Mackenzie

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative motor disorder and primarily affects movement control but also a range of non-motor functions. With unknown etiology and lack of cure, much research is dedicated to unravel pathological mechanisms and improve clinical prospects for symptom alleviation, prevention and treatment. To achieve these goals, animal models intended to represent symptoms similar to those observed in the complex clinical display of PD play a key role. It is important to bear in mind that, in any studies with laboratory animals, it is crucial to take the 3Rs principle (Refine, Reduce, Replace) into account. The main pathology of PD includes degeneration of dopamine neurons in the substantia nigra pars compacta (SNc). The 6-hydroxydopamine (6-OHDA) lesion model, in which dopaminergic neurons are chemically destroyed, is often favored as a laboratory model of PD in both rodents and primates. However, while reproducing several features of clinical PD, mice exposed to 6-OHDA frequently experience systemic dysfunction causing premature death. To avoid suffering and unnecessary deaths of laboratory mice, there is a need for improved experimental protocols in accordance with the 3Rs principle. Based on current literature and our own previous experiments, we decided to test the effect of three parameters: 1) reduced dose of the 6-OHDA toxin; 2) daily post-operative care to avoid hypothermia and energy loss; 3) shortened interval from surgical injection of toxin to time of sacrifice. 

By implementing a 6-OHDA lesion protocol using a lower dose of toxin than commonly seen in the literature alongside careful post-operative care and decreased time post-injection, a fully recovered weight post-surgery and high survival rate was obtained. This was achieved despite full expression of the 6-OHDA-induced locomotor phenotype.  A step-by-step protocol was formulated. Validation using histological analysis confirmed toxin-induced degeneration of midbrain dopamine neurons with concomitant loss of dopaminergic projections in the lesioned hemisphere. Notably, while SNc dopamine neurons were drastically reduced, those located in the ventral tegmental area (VTA) were less affected in a medial^{high survival} to lateral^{low survival} manner.

The Refine and Reduce parameters of the 3Rs principle in experimental animal welfare were specifically addressed which allowed us to improve well-being and survival of mice while maintaining characteristic parkinsonian features in the 6-OHDA lesion model. A table summarizing current literature on the 6-OHDA model in rodents as well as our validated step-by-step experimental protocol is provided.

Link

http://sjlas.org/index.php/SJLAS/article/view/1105

Umeå University has 2 open postdoc positions

Postdoctor in Integrative Neurophysiology
– With a focus on data analyses
or
– With a focus on physiological recordings of brain activity in behaving animals

Deadline for both positions: April 15.

For more information, please contact Associate Professor Per Petersson, e-mail: [email protected], Department of Integrative Medical Biology, Umeå University.