bioRxiv : the preprint server for biology · 2025
Parkinsonian striatal acetylcholine dynamics are refractory to L-DOPA treatment.
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Potjer Eva V, Wu Xunhui, Kane Allison N, Parker Jones G
Аннотация
BACKGROUND: Fluctuations in striatal dopamine (DA) are interdependent with fluctuations in acetylcholine (ACh), both of which are thought to be important for motor function and dysfunction in Parkinson's disease (PD).
OBJECTIVES: Determine how ACh dynamics are altered by dopamine under normal and parkinsonian conditions following acute and chronic L-DOPA treatment.
METHODS: We used fiber photometry to record fluorescent DA and ACh sensors in the dorsomedial striatum (DMS) of normal mice treated with vehicle or amphetamine and in the dorsolateral striatum (DLS) of mice with unilateral substantia nigra (SNc) DA neuron lesions (using 6-OHDA) subjected to an L-DOPA-induced dyskinesia (LID) protocol.
RESULTS: Under normal conditions, ACh exhibited transient increases followed by pauses and fluctuated at ~1-Hz frequency in an anti-correlated manner to DA. Amphetamine treatment reduced the frequency of ACh fluctuations and amplitude of ACh transients while prolonging after-transient pauses. In 6-OHDA-lesioned mice, ACh dynamics oscillated at a higher frequency, and ACh events had reduced peaks and pauses. L-DOPA increased DA and, after repeated treatments, also reduced ACh. However, L-DOPA neither restored the anti-correlation between DA and ACh nor normalized the reduced ACh transient and pause amplitudes or the increased frequency of ACh fluctuations. In extended recordings during the transition to the L-DOPA OFF state, ACh remained low as DA diminished, and ACh transient and pause amplitudes remained suppressed, and the oscillatory frequency elevated.
CONCLUSIONS: Dopamine depletion transforms striatal ACh dynamics and L-DOPA fails to normalize these dynamics. Because these dynamics are unresponsive to treatment, new therapies targeting them may offer symptomatic improvements for PD and LID.
OBJECTIVES: Determine how ACh dynamics are altered by dopamine under normal and parkinsonian conditions following acute and chronic L-DOPA treatment.
METHODS: We used fiber photometry to record fluorescent DA and ACh sensors in the dorsomedial striatum (DMS) of normal mice treated with vehicle or amphetamine and in the dorsolateral striatum (DLS) of mice with unilateral substantia nigra (SNc) DA neuron lesions (using 6-OHDA) subjected to an L-DOPA-induced dyskinesia (LID) protocol.
RESULTS: Under normal conditions, ACh exhibited transient increases followed by pauses and fluctuated at ~1-Hz frequency in an anti-correlated manner to DA. Amphetamine treatment reduced the frequency of ACh fluctuations and amplitude of ACh transients while prolonging after-transient pauses. In 6-OHDA-lesioned mice, ACh dynamics oscillated at a higher frequency, and ACh events had reduced peaks and pauses. L-DOPA increased DA and, after repeated treatments, also reduced ACh. However, L-DOPA neither restored the anti-correlation between DA and ACh nor normalized the reduced ACh transient and pause amplitudes or the increased frequency of ACh fluctuations. In extended recordings during the transition to the L-DOPA OFF state, ACh remained low as DA diminished, and ACh transient and pause amplitudes remained suppressed, and the oscillatory frequency elevated.
CONCLUSIONS: Dopamine depletion transforms striatal ACh dynamics and L-DOPA fails to normalize these dynamics. Because these dynamics are unresponsive to treatment, new therapies targeting them may offer symptomatic improvements for PD and LID.