The missing, the short, and the long: Levodopa responses and dopamine actions

Abstract

We attempt to correlate the clinical pharmacology of dopamine replacement therapy (DRT) in Parkinson Disease with known features of striatal dopamine actions. Despite its obvious impact, DRT does not normalize motor function, likely due to disrupted phasic dopaminergic signaling. The DRT Short Duration Response is likely a permissive-paracrine effect, possibly resulting from dopaminergic support of corticostriate synaptic plasticity. The DRT Long Duration Response may result from mimicry of tonic dopamine signaling regulation of movement vigor. Our understanding of dopamine actions does not explain important aspects of DRT clinical pharmacology. Reducing these knowledge gaps provides opportunities to improve understanding of dopamine actions and symptomatic treatment of Parkinson disease.

Figure 1

Clinical characteristics of the SDR and LDR effects. (A) Schematic representation of the SDR and LDR effects (adapted from Nutt et al., Short and long-duration responses to levodopa during the first year of therapy, Ann Neurology, 1997, Figure 1). Drug-naïve PD patients were given IV levodopa infusions, and motor function assessed with a finger-tapping task. After 4 days, a second infusion was given. Patients returned after one year and underwent the same protocol after PD medications were held overnight. The LDR is visible as the upward migration of motor performance immediately prior to the first IV levodopa infusion after one year of treatment. The SDR immediately follows IV levodopa infusions. (B) From Clissold et al., Longitudinal study of the motor response to levodopa in Parkinson’s disease, Mov Disord, 2006, Figure 5. Schematic of the progression of the magnitude of the short- (open boxes; SDR) and long- (solid boxes; LDR) duration responses to levodopa. The solid line represents disability in the untreated state and is a partial function of the magnitude of the LDR. With disease progression, the LDR wanes and the SDR becomes a relatively larger component of the levodopa response. Higher scores indicate increasing disability.

Figure 2

The natural history of LDR and SDR with disease progression in Kempster’s cohort. From Alty et al., Longitudinal study of the levodopa motor response in Parkinson’s disease: relationship between cognitive decline and motor function, Mov Disord, 2009, Figure 5. Modified Webster Scores of PD patients in the practical “off” state (tops of boxes) and 60–90 minutes after their usual levodopa dose (bottom of boxes) as a function of disease duration for non-demented (black boxes) and demented (MMSE < 24, white boxes) patients. The Modified Webster Score is a standardized assessment of motor function, with higher scores indicating worse function. Note the diminished magnitude of the SDR in demented vs non-demented patients.

Figure 3

Schematic diagram of the striatal “synaptic triad.” Cortical (and thalamic afferents) synapse on striatal projection neuron spine heads with dopaminergic terminals on spine necks. Dopaminergic synapses are well positioned to both modulate glutamatergic signaling onto medium spiny projection neurons and plasticity of corticostriate synapses.

Figure 4

Temporal difference model reward prediction error signaling. The red trace indicates actual state value; the blue trace indicates estimated state value; the black trace represents dopamine neuron firing rates (FR). In a hypothetical task, a cue predicts a reward and reward timing with 100% certainty. Note that the state value gradually increases after the predictive cue as the rewarding event moves closer. On trial 1 (top panel), the agent is unaware of the cue-reward association, so the state value estimate is low until the reward is delivered. This is reflected as a phasic increase in DA neuron firing at reward delivery. After many trials (“mid-session”), the agent associates the cue with reward according to the rules of temporal difference models, but is not yet certain of the 100% correspondence between cue and reward. Therefore, the state value estimate jumps twice, reflected in two smaller phasic DA firing increases. With more experience, the agent understands that the cue predicts reward with 100% certainty, and the phasic DA signal migrates entirely to the cue.

Figure 5

Schematic representation of varying opportunity cost of inaction (tonic dopamine signaling) on vigor. Optimal latency to initiate movement (as a surrogate for response vigor). Top – high tonic dopamine, bottom – low tonic dopamine. Black curves – cost of movement vigor, which is very high at short latencies and independent of tonic dopamine levels. Red lines – opportunity cost of the action relative to inaction, which has a higher slope at higher tonic dopamine levels. Blue curves – net action value as a function of latency (expected action value minus the cost of vigor and opportunity cost). The maximum net action value (optimum latency) is indicated with an asterisk. Note the optimal latency to maximize future rewards shifts to the right with decreasing tonic dopamine levels.

Figure 6

LDR-like effect of levodopa in MitoPark mice. Number of locomotor bout initiations (“progressions”, panel A) and maximal locomotor velocity (panel B) in MitoPark (MP) and wildtype (WT) mice moving freely in an open field. MitoPark mice initiated fewer locomotor bouts with lower peak velocities as their midbrain dopamine neurons degenerated (red lines). Once treated with levodopa, both measures of motor function returned to near baseline levels, but only with repeated dosing (dashed blue lines). Modified for formatting from Panigrahi et al, Dopamine is Required for the Neural Representation and Control of Movement Vigor, Cell, 2015, Figure 6).

Figure 7

(A) Proposed dopamine action “pyramid” as related to the clinical pharmacology of DRT. Phasic dopamine (DA) release acts on a very short time-scale and is responsible for “fine-tuning.” It is lost in early PD, explaining why dopamine replacement therapy cannot fully restore motor function. Dopamine supports normal corticostriatal synaptic plasticity, which operates on intermediate time scales (minutes to hours) and is responsible for the SDR. Tonic dopamine signaling indicates the average rate of reward over hours to weeks, and is responsible for the LDR. (B) Proposed changes in dopamine actions during progression of Parkinson Disease. In the “honeymoon period,” the LDR allows infrequent dosing of dopamine replacement therapy to provide stable motor function. As the LDR wanes, motor fluctuations and dyskinesias emerge, but the preserved SDR allows at least temporary restoration of motor function with DRT. With continued disease progression, pathology spreads to cortex and cortical afferents become dysfunctional or degenerate, reducing the SDR. In many patients, SDR decline is paralleled by other extrastriatal pathologies that contribute to disability.