Objective:

The objective of this study is to determine Amantadine’s effects on striatal direct and indirect spiny projection neurons (dSPNs and iSPNs) in bradykinetic and dyskinetic states to gain insight into Amantadine's mechanism of action. 

Background:

Amantadine is a unique medication that improves both bradykinetic and dyskinetic movements, but its use is limited by serious side effects and its mechanism of action is unknown. Determining its mechanism of action may be useful for the development of new, improved treatments for Parkinson's disease.

Design/Methods:

We used two-photon calcium imaging to simultaneously record the firing activity of dSPNs and iSPNs in the dorsolateral striatum of mice as they ran on a wheel. We first recorded behavior and neural activity in the pre-lesion baseline state, then injected mice with 6-OHDA in the ipsilateral substantia nigra pars compacta (SNc) to induce unilateral dopamine depletion. We then recorded behavior and neural activity in dopamine depleted mice receiving the following intraperitoneal injections: Saline (vehicle control), Amantadine 60mg/kg, L-DOPA 10mg/kg, and L-DOPA 10mg/kg + Amantadine 60mg/kg.

Results:

In dopamine depleted mice, compared to Saline alone, Amantadine increased the maximum achieved running speed and mean dSPN calcium event rate per trial. Additionally, compared to L-DOPA 10mg/kg alone, Amantadine (when given with L-DOPA 10mg/kg) reduced the percentage of time mice spent having dyskinetic movements and increased the mean iSPN calcium event rate per trial.

Conclusions:

Amantadine improves bradykinesia and increases dSPN activity in dopamine depleted mice. Amantadine also reduces dyskinesias and increases iSPN activity in dopamine depleted mice given high-dose L-DOPA. This data suggests that increasing iSPN activity may be a useful strategy for treating dyskinesias. This could be used to guide the development of selective, novel treatments for dyskinesias with better side effect profiles than Amantadine.