SCH 23390 enhances exogenous L-DOPA decarboxylation in nigrostriatal neurons

Exogenous L-DOPA enhances dopamine metabolism in the intact and denervated striatum, and is the treatment of choice for Parkinsonism. Aromatic L-amino acid decarboxylase (AAAD) converts L-DOPA to dopamine. Blockade of dopamine D1-like receptors increases the activity of AAAD in both intact and denervated striatum. A single dose of SCH 23390, a dopamine D1-like receptor antagonist, increases the activity of AAAD in the striatum and midbrain and induces small changes in dopamine metabolism. When L-DOPA is administered after SCH 23390, there is a significant increase in the formation of 3,4-dihydroxyphenylacetic acid and dopamine turnover in striatum and midbrain compared to L-DOPA alone, suggesting further enhancement of dopamine metabolism. When the studies are repeated in the MPTP mouse model of Parkinson's disease, there is significantly more dopamine metabolism in the striatum of lesioned mice pretreated with SCH 23390 than in a comparison group treated with L-DOPA alone. These studies suggest that it may be possible to enhance the conversion of L-DOPA to dopamine in Parkinson's disease patients by administering substances that augment brain AAAD.