Dopamine Receptors and Levodopa-Induced Dyskinesia

Abstract

This chapter reviews preclinical and relevant clinical studies investigating the role and contribution of dopamine (DA) receptor subtypes in the pathophysiology of L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID) in parkinsonian patients and animal models. Altered dopaminergic neurotransmission in the basal ganglia are observed in LID. Two conditions are necessary for their appearance: (1) loss of DA in nigrostriatal pathway and (2) treatment with l-DOPA or DA agonists, the basis of replacement therapy. LID are clearly more complex than a hypersensitivity due to a simple increase in the density of striatal DA receptors. The development and expression of LID are related to increases in the activity of D1, D2, and D3 receptors, while the contribution of the activity of D4 and D5 receptors remains unexplored. In clinical trials with PD patients, some factors have been identified to increase the risk of developing LID such as high doses of l-DOPA or DA agonist treatment, abnormal and pulsatile stimulation of DA receptors, activation of a specific DA receptor subtype (D1 vs. D2/D3), and polymorphisms of the DA receptor subtypes (D1, D2). DA receptors interact with receptors of several other neurotransmitters. The implications of these interactions in the development and expression of LID in PD patients and animal models need further investigation to find novel drug targets.