L-dopa is the major treatment for
Parkinson's disease (PD), but its efficacy is limited by the presence of
dyskinesia. The
dyskinesia develops over a period of exposure to
L-dopa and is related to the dosage, therefore, the cause may involve inductive changes that produce toxic levels of metabolites, interfering with
dopamine (DA) neurotransmission. Chronic
L-dopa induces
catechol-O-methyltransferase (COMT) and
methionine adenosyl
transferase (MAT),
enzymes involved in the methylation of
catecholamines (CA). In addition, high levels of
3-O-methyl-dopa have been reported in the plasma of dyskinetic PD patients, treated with
L-dopa, as compared to non-dyskinetic patients, therefore, the methyl metabolites of CA may be increased during
L-dopa therapy and may be involved in the
dyskinesia. Since large amounts of DA are produced from
L-dopa, and DA is extensively methylated, the methyl metabolites of DA,
3-methoxytyramine (3-MT) and 3,4-dimethoxyphenylethylamine (DIMPEA), may be also involved. The first step in knowing this, is to assess the behavioral and DA-receptor activities of 3-MT and DIMPEA. In the rat, the
intraventricular injection of 0.5 micromol of DIMPEA increased the total distance traveled (TD) by over 100%, the number of movement (NM) made by 40% and the time spent moving (MT) by about 36%. Identical doses of 3-MT decreased the TD by 42%, NM by 22% and MT by 39%. DIMPEA (1 mM) increased the binding of DA with brain membranes by 44.7%, whereas 3-MT decreased it by 15.8%. The results show that 3-MT and DIMPEA are behaviorally active, and in parallel, they interact with the binding sites for DA, consequently, they may contribute to the side effects of
L-dopa.
L-dopa produces high levels of DA and induces MAT and COMT. It is proposed, therefore, that DA will be methylated to 3-MT and 3-MT to DIMPEA. At threshold level each product will inhibit, allosterically, its
enzyme of methylation, causing sequential and rhythmic up and down regulation of its concentration. At peak levels these hydrophobic metabolites will modulate the actions of DA on synaptic membranes, causing
abnormal movements, at times, resembling the "on-off effects".