Learning to Have a Long‐Duration Response

Abstract

Dopamine-based therapies form the cornerstone of Parkinson's disease (PD) treatment. During chronic levodopa (LD) therapy, motor symptoms show a sustained improvement for up to 14 days after stopping therapy, 1 well beyond the clearance of LD from the body. This enduring effect, known as the longduration response (LDR), significantly contributes to the sustained-uniform response to LD in early PD. The loss of LDR is associated with emergence of motor fluctuations, making interventions aimed at maintaining LDR an attractive target. Dopamine plays a crucial role in movement, learning, and reward. 2 While exploring the mechanisms of LDR, Cheung and colleagues 3 discovered that dopamine-dependent motorlearning, even without explicit reward, underlies the LDR.In their study, mice underwent training on two distinct motor tasks without explicit reward. After unilateral dopamine-depletion with 6-hydroxydopamine, mice were re-exposed to one task. Motor deficits gradually emerged over four re-exposure sessions. However, when tested on the other task in session 5, no impairment was observed. This suggests that repetitive motor performance, in the context of dopamine-depletion, leads to task-specific motor impairment-an "unlearning effect" termed "parkinsonian decline" by the authors. Another group was trained twice a day both in the on and off states. Besides the immediate response to LD, cumulative positive effects gradually appeared in the off state over 5 days, persisting after a 3-day LD washout. This mirrors the LDR observed in patients after prolonged LD exposure. Paired with the observation of task-specific parkinsonian decline, it suggests that LDR is a form of dopamine-dependent motor-learning.Parkinsonian decline coincided with under-recruitment of direct pathway spiny projection neurons (dSPNs) and over-recruitment of indirect pathway SPNs (iSPNs). Pharmacological activation of (hypoactive) dSPNs led to an LDR-like similar to the one seen with LD. Simultaneously, D2 agonists, reducing activity of the (hyperactive) iSPNs, partially restored parkinsonian decline. The magnitude of acute therapeutic improvement predicted the magnitude of LDR-like response, irrespective of treatment strategy, suggesting a motor-learning effect. However, D1 agonists led to an over-recruitment of both dSPNs and iSPNs while D2 agonists led to reduction in both pathways' activation. The authors demonstrated that restoring the balance in dSPN:iSPN recruitment, irrespectively of absolute activity, was the best predictor of LDR maintenance.In vivo effects of D1/D2 acting-drugs are more complex than expected by rate-models. 4 Balancing "relative activity" of striatal pathways, more than modulating "absolute activity" can become a therapeutic strategy. Multiple combinations of D1 agonists and D2 agonists/antagonist can be tested to extend LDR. The authors showed that repeated motor-training in off state may lead to motor decline. This suggests that physical activity schedules should be optimized during good on states to maximized benefits in p...