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

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Parkinson disease (PD) is a common neurodegenerative disorder and the most common serious movement disorder. The defining clinical features of bradykinesia, rigidity, and resting tremor, accompanied by characteristic alterations of posture, gait, and voice quality, are among the most striking phenomena in neurology. Equally impressive is the marked improvement seen in many patients with dopamine replacement therapy (DRT). The discovery that dopamine is the primary neurotransmitter of the nigrostriatal projection, whose disruption causes the cardinal motor features of parkinsonism, focused attention on understanding striatal dopamine actions. The large literature in this field, although far from conclusive, indicates that striatal dopaminergic neurotransmission mediates important aspects of learning, motivation, and goal‐directed behaviors.
The complex basic science literature on striatal dopamine suggests several important components of its actions.1 Disruption of striatal dopaminergic signaling should manifest in complex ways, and it should be possible to correlate important features of the clinical response to DRT with basic aspects of striatal dopaminergic signaling. The goal of this Grand Rounds is to explore these potential correlations to assist identification of mechanisms relevant to the clinical actions of DRT. Similarly, failures of our present understanding of dopaminergic nigrostriatal signaling to explain important features of DRT clinical pharmacology point to important areas for future investigation. We suggest that disruption of 3 key functions of striatal dopaminergic signaling—phasic dopaminergic signaling, permissive‐paracrine dopaminergic modulation of corticostriate synaptic plasticity, and tonic dopaminergic signaling that estimates the background rate of reward—explain important features of DRT clinical pharmacology. These potential correlations expose significant gaps between DRT clinical pharmacology and our present knowledge of dopaminergic nigrostriatal signaling.
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