Abstract
Fatigue is a non-motor symptom of Parkinson's disease (PD). Adenosine 2A receptor (A2AR) and compromised dopamine neurotransmission are linked to fatigue. Studies demonstrate that A2AR antagonism potentiates dopamine transmission via dopamine receptor D2 (D2R). However, the heterodimer form of A2AR-D2R in the striatum prompted questions about the therapeutic targets for PD patients. This study investigates the effects of caffeine (A2AR non-selective antagonist) plus haloperidol (D2R selective antagonist) treatment in the fatigue induced by the reserpine model of PD. Reserpinized mice showed impaired motor control in the open field test (p < 0.05) and fatigue in the grip strength meter test (p < 0.05). L-DOPA and caffeine plus haloperidol similarly increased motor control (p < 0.05) and mitigated fatigue (p < 0.05). Our results support the A2AR-D2R heterodimer participation in the central fatigue of PD, and highlight the potential of A2AR-D2R antagonism in the management of PD.