Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

Abstract

L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson′s disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub- anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured locomotor and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, high-dose priming triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed under the low-dose procedure despite clear evidence of LID, indicating that 80- Hz oscillations are not an exclusive signature of LID. Instead, the low-dose procedure resulted in the weeks-long gradual emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L- DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID, but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine′s therapeutic effects are region specific. Our findings also have clinical implications as we are the first to report novel oscillatory signatures associated with the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD, and as we identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia

“…In agreement with reports using a higher dose of L-DOPA (12-15 mg/kg) [15,16,[18][19][20] NBG oscillations were detected in the motor cortex of the lesioned hemisphere in all rats as well as in the striatum and GPe, whereas the detection rate in the SNr was limited. In contrast, a recent study did not find an increase in NBG oscillations in 6-OHDA-lesioned rats after treatment with 7 mg/kg L-DOPA in a 3-week priming paradigm, despite clear dyskinetic behaviour [56]. The discrepancy with our data could depend on differences in the methods of spectral analysis, where the use of IRASA in the current study (see the "Time-Frequency Analysis of LFP Power" section) allowed the isolation of true oscillatory phenomena [42].…”