The Research On Eltoprazine Modulated γ Oscillations In Cortico-striatal Projection Ameliorating Manifestation Of L-dopa-induced Dyskinesia Rats

Parkinson’s disease(PD)is one of the most pervasive neurodegenerative disease,characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta(SNc)combined with aberrant cortico-basal ganglia-thalamic(CBT)neural circuit neural activity.As a result,the striatum(Str)is innervated by dopaminergic neurons,resulting in the disorder of the basal ganglia circuit and a series of symptoms such as tremors,rigidity,bradykinesia,and non-motor symptoms.Dopamine(DA)replacement therapy is the backbone of PD treatment.However,long-term levodopa(L-dopa)administration can lead to the decline of its clinical efficacy and a series of adverse secondary effects.Levodopa-induced dyskinesia(LID)is the major and severe disabled motor complication of chronic L-dopa intake.The incidence of LID seriously impacts life quality of patients and brings great burden to patients’ family and whole society.However,its pathophysiological mechanism is obscure,and lacking standard and effective therapeutic schedules.The disequilibrium of excitatory and inhibitory activities based on neural networks is considered to be one of the reasons for LID occurrence.Numerous researches have demonstrated that the pathogenesis of LID is related to not only dopaminergic receptors but also nondopaminergic receptors,such as serotonergic receptors,and various nondopaminergic medications are applied to manage such complications.It has been proved that the dysfunction of serotonergic(5-HT)neurons is involved in the pathophysiological process of PD and LID,leading to motor and non-motor symptoms in PD and LID patients.Eltoprazine,a 5-HT1A/B autoreceptor agonist,inhibits dopamine release from 5-HT neurons and has been shown to effectively ameliorate dyskinesia in rats and patients with LID.Although eltoprazine has been shown to alleviate LID efficiently in a dose-dependent manner,the changes in neural electrophysiology level during its administration remain to be explored,and the underlying mechanisms for its therapeutic effect remain obscure.The purpose of this study was to investigate the accumulative effect of L-dopa on neural oscillation in the cortico-striatal projection and explore neural electrophysiological alterations occurring after eltoprazine intervention.To better understand the pathological mechanism underlying LID at the electrophysiological level,we investigated the effect of L-dopa on γ oscillation in the primary motor cortex(M1)-dorsolateral striatum(DLS)and the factors influencing γ oscillations power.We also examined the electrophysiological alterations occurring after eltoprazine intervention in rats with LID.γ activities were spatially dependent,with different characteristics and influencing factors in distinct regions;γ oscillations were narrowband in the M1 and broadband in the DLS.The exaggerated aperiodic-adjusted γ activities power correlated positively with the aperiodic-corrected power of β rhythm in M1,while striatal γ oscillations were modulated by enhanced θ-γ phase-amplitude coupling in the DLS.L-dopa administration increased γ-band coherence and PL Vs.Eltoprazine regulated the aberrant neural activities elicited by L-dopa injection,ameliorating dyskinetic symptoms,reducing AIMs score and extending response times to L-dopa administration.