Dopamine Replacement Therapy, Learning and Reward Prediction in Parkinson's Disease: Implications for Rehabilitation

Abstract

The principal feature of Parkinson's disease (PD) is the impaired ability to acquire and express habitual-automatic actions due to the loss of dopamine in the dorsolateral striatum, the region of the basal ganglia associated with the control of habitual behavior. Dopamine replacement therapy (DRT) compensates for the lack of dopamine, representing the standard treatment for different motor symptoms of PD (such as rigidity, bradykinesia and resting tremor). On the other hand, rehabilitation treatments, exploiting the use of cognitive strategies, feedbacks and external cues, permit to "learn to bypass" the defective basal ganglia (using the dorsolateral area of the prefrontal cortex) allowing the patients to perform correct movements under executive-volitional control. Therefore, DRT and rehabilitation seem to be two complementary and synergistic approaches. Learning and reward are central in rehabilitation: both of these mechanisms are the basis for the success of any rehabilitative treatment. Anyway, it is known that "learning resources" and reward could be negatively influenced from dopaminergic drugs. Furthermore, DRT causes different well-known complications: among these, dyskinesias, motor fluctuations, and dopamine dysregulation syndrome (DDS) are intimately linked with the alteration in the learning and reward mechanisms and could impact seriously on the rehabilitative outcomes. These considerations highlight the need for careful titration of DRT to produce the desired improvement in motor symptoms while minimizing the associated detrimental effects. This is important in order to maximize the motor re-learning based on repetition, reward and practice during rehabilitation. In this scenario, we review the knowledge concerning the interactions between DRT, learning and reward, examine the most impactful DRT side effects and provide suggestions for optimizing rehabilitation in PD.

Keywords: DRT side effects; dopamine replacement therapy; learning; rehabilitation; reward prediction.

Figure 1

Dopaminergic pathways and the role of dopamine in reward, compulsive behavior and addiction. Although dopamine replacement therapy (DRT) successfully improves motor deficits in Parkinson’s disease (PD), its effects on cognitive and motivational processes are more equivocal. This is related to the effect that DRT exercises on the different dopaminergic pathways: the nigrostriatal pathway, responsible for voluntary movements, connects the substantia nigra with the dorsal striatum; the mesocorticolimbic pathways, associated with reward and motivation-related processes, connect the ventral tegmental area to the ventral striatum and the cerebral cortex (in particular the frontal lobes). In the early stages of PD the ventral striatal dopamine projections are relatively preserved, and the dopaminergic drugs lead to an “overflow” of dopamine in the ventral striatum and mesocorticolimbic system. This overflow is responsible for the problems in reward (due to disruption of the dopaminergic input to mesolimbic pathway), motivational-related processing and maladaptive decision-making (due to disruption of the dopaminergic input to mesocortical pathway), impaired ability to learn from negative consequences with compulsive behaviors and impulsivity (due to alteration of dopaminergic input to ventral striatum). Drug addiction, related to the disruption of the dopaminergic input to dorsal striatum represents a pathological shift form voluntary drug use to more habitual and compulsive drug intake. The alteration in the learning and reward mechanisms could impact seriously on the rehabilitative outcomes. Thus, it is necessary to titrate carefully DRT to produce the desired improvement in motor symptoms while minimizing the associated detrimental effects.