Effects of dopamine metabolites on locomotor activities and on the bindingof dopamine: Relevance to the side effects of L-dopa

L-dopa is the major treatment for Parkinson's disease (PD), but its efficac y 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 c ause 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 (MA T), enzymes involved in the methylation of catecholamines (CA). In addition , high levels of 3-O-methyl-dopa have been reported in the plasma of dyskin etic PD patients, treated with L-dopa, as compared to non-dyskinetic patien ts, 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 ar e produced from L-dopa, and DA is extensively methylated, the methyl metabo lites of DA, 3-methoxytyramine (3-MT) and 3,4-dimethoxyphenylethylamine (DI MPEA), may be also involved. The first step in knowing this, is to assess t he behavioral and DA-receptor activities of 3-MT and DIMPEA. In the rat, th e intraventricular injection of 0.5 mu mol of DIMPEA increased the total di stance 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 decrea sed the TD by 42%, NM by 22% and MT by 39%. DIMPEA (1 mM) increased the bin ding 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 pa rallel, they interact with the binding sites for Dq consequently they may c ontribute 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 methyl ated to 3-MT and 3-MT to DIMPEA. At threshold level each product will inhib it, allosterically, its enzyme of methylation, causing sequential and rhyth mic up and down regulation of its concentration. At peak levels these hydro phobic metabolites will modulate the actions of DA on synaptic membranes, c ausing abnormal movements, at times, resembling the "on-off effects".