Objective: We implement a pharmacological approach for eliciting dopamine deprivation using transient blockage of dopamine signaling to replicate core parkinsonian motor symptoms.

Background: Parkinson’s disease (PD) represents a prototypical neuronal circuit disease with impaired cortico-basal ganglia network signaling, which is thought to underpin the characteristic motor manifestations such as tremor, rigidity and brady/hypokinesia. Genetic and toxin-based strategies in mice can be used to induce a dopamine-deficient state resembling PD. The unilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) lesions the medial forebrain bundle (MFB) and is widely implemented as it replicates adult-onset, severe dopaminergic denervation, replicating well-characterized behavioral phenotypes that mimic parkinsonian hypokinesia. However, 6-OHDA model requires extensive histological verification steps and is not always associated with a strong locomotor phenotype. This justifies complementary approaches, particularly when combined with targeted viral-based manipulations of distinct neuronal subsets.

Method: We implement a pharmacological approach for dopamine deprivation using transient inhibition of dopamine signaling to replicate key motor symptoms. Pharmacological strategies may evoke an acute and robust parkinsonian motor phenotype without extensive histological validation. This approach allows to probe within a single behavioral session both the effects of dopamine-deprived state and subsequent viral-based manipulations of neuronal subsets. Dopamine-deficient signaling in mice was induced by either dopamine D1 receptor antagonist (SCH23390) or dopamine D2 receptor antagonists (haloperidol)  in a dose-response setup. Motor behavior analysis was performed using the ANYmaze software (Stoelting) and marker less tracking with deep learning tools (e.g DeepLabCut).

Results: Our behavioral analysis revealed a strong attenuation of locomotor response with clear hypokinesia and immobility upon treatment with either dopamine D1 or D2 receptor antagonists.

Conclusion: We aim to identify a large-scale repertoire of motor behavior metrics in both naïve and challenged mice upon a pharmacologically-induced dopamine-deficient state. We develop a viable pharmacological model that will enable us to probe distinct cortico-basal ganglia circuit components significance for motor restoration in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evoking-parkinsonism-in-mice-by-a-pharmacological-approach-combined-with-targeted-viral-based-manipulations-of-neuronal-ensembles/