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Olfactory dysfunction is a common non-motor symptom associated with Parkinson's disease (PD). This condition usually appears before the onset of the cardinal motor symptoms and is still poorly understood. Here, we generated a mouse model of early-stage PD based on partial 6-hydroxydopamine (6-OHDA) lesion of the dorsal striatum to reproduce the olfactory deficit and associated cellular and electrophysiological anomalies observed in patients. Using this model, we investigated the effect of long-term, continuous administration of pramipexole, a dopamine D2/3 selective agonist, on olfactory dysfunction. We found that pramipexole reverted the impairment of odor discrimination displayed by the mouse model in the habituation/dishabituation test. In line with similar observations in PD patients, the mouse model showed an increase of dopamine cells paralleled by augmented levels of the dopamine marker, tyrosine hydroxylase, in the olfactory bulb (OB). These changes, which have been proposed to contribute to olfactory dysfunction, were abolished by oral administration of pramipexole. Local field potential recording in the OB of 6-OHDA lesion mice showed reduced oscillations in the beta frequency range, in comparison to healthy control mice. This abnormality, which is suggestive of defective long range OB transmission, was also counteracted by pramipexole. Altogether these findings indicate that prolonged pharmacological stimulation of dopamine D2-like receptors rescues olfactory discrimination observed in experimental parkinsonism. Moreover, they show that this protective effect is exerted in parallel to a normalization of dopamine neurons and beta band oscillations in the OB, providing information on the potential mechanisms involved in PD-related olfactory dysfunction.
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