Parkinsonian striatal acetylcholine dynamics are refractory to L-DOPA treatment

Abstract

BackgroundFluctuations in striatal dopamine (DA) are interdependent with fluctuations in acetylcho- line (ACh), both of which are thought to be important for motor function and dysfunction in Parkinsons disease (PD). ObjectivesDetermine how ACh dynamics are altered by dopamine under normal and parkinsonian conditions following acute and chronic L-DOPA treatment. MethodsWe 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. ResultsUnder 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 tran- sition 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. ConclusionsDopamine 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/686401v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@705b66org.highwire.dtl.DTLVardef@80afd2org.highwire.dtl.DTLVardef@972c41org.highwire.dtl.DTLVardef@da91f8_HPS_FORMAT_FIGEXP M_FIG C_FIG We used dual-wavelength fiber photometry to simultaneously record dopamine and acetylcholine dynam- ics in the dorsal striatum. We recorded these dynamics in control mice before and after treatment with the dopamine releaser amphetamine and in hemiparkinsonian mice before after treatment with the dopamine pre-cursor L-DOPA. We asked how these experimental manipulations alter the bulk signaling of dopa- mine and acetylcholine, their temporal relationship, and the sub-second dynamics of acetylcholine signaling.