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Mechanism of action of dopaminergic agents in Parkinson's disease

From the Department of Neurology (Dr. Koller), University of Kansas Medical Center, Kansas City, KS, and Centro de Especialidades Neurologicas(Dr. Rueda), Bogota, Colombia.

Address correspondence and reprint requests to Dr. William C. Koller, Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7314.

Abstract.

As the substantia nigra degenerates in Parkinson's disease (PD), the nigrostriatal pathway is disrupted, reducing striatal dopamine and producing PD symptoms. Although dopamine does not readily cross the blood-brain barrier, its precursor, levodopa, does. Levodopa is absorbed in the small bowel and is rapidly catabolized by aromatic-L-amino-acid decarboxylase(AADC) and catechol-O-methyltransferase (COMT). Because gastric AADC and COMT degrade levodopa, the drug is given with inhibitors of AADC(carbidopa or benserazide), and inhibitors of COMT will also enter clinical use. Although the exact site of decarboxylation of exogenous levodopa to dopamine in the brain is unknown, most striatal AADC is located in nigrostriatal dopaminergic nerve terminals. Newly synthesized dopamine is stored in the terminals and then released, stimulating postsynaptic dopamine receptors and mediating the antiparkinsonian action of levodopa. Dopamine agonists act directly on postsynaptic dopamine receptors, thus obviating the need for metabolic conversion, storage, and release. How the actions of dopaminergic drugs produce side effects and how these side effects should be managed are discussed.