Parkinson's disease causes degeneration and loss of dopaminergic neurons in a brain region called the substantia nigra. The resulting drop in levels of the neurotransmitter dopamine can be partially replenished by taking the dopamine agonist levodopa, but long-term treatment often results in unwelcome twitching, arm waving, and other uncontrolled movements that have been the focus of much research. Recent clinical trials showed that delivery of neurotrophic growth factors directly into the brain could reduce these involuntary movements (see ARF related news story), while other studies have suggested the possible benefits of drugs that target specific receptor subtypes (see ARF related news story). Now, Pierre Sokoloff and colleagues at the Victor Segalen University, Bordeaux, the Neurobiology and Molecular Pharmacology Unit of INSERM, Paris, and the Johann Wolfgang Goethe-University, Frankfurt, Germany, report that they can reduce levodopa-induced dyskinesia in a primate model of PD with dopamine agonists specific for D3 receptors.

As in a recent study on rats by Picconi et al. (see also Picconi section of ARF related news story), first author Erwan Bezard and colleagues found that Parkinsonian monkeys could be divided into two subtypes-those that exhibit dyskinesia after levodopa treatment and those that do not. To characterize these behaviors, the authors looked for differences in expression of dopamine receptors in regions of the brain that are known to be affected by the disease, including the caudate nucleus, the putamen, and the globus pallidus. They found that in all three regions, D3 receptor subtypes were ablated in monkeys without dyskinesia and in those that did not receive levodopa treatment. In contrast, in the dyskinetic group of animals, there was a marked and statistically significant upregulation of D3 receptors (about twofold higher in the putamen and about fivefold higher in the globus pallidus), suggesting that specific targeting of these receptors may attenuate levodopa-associated dyskinesia.

To test this hypothesis, Bezard et al. administered either the D3 partial agonist BP 897 or a placebo to animals that exhibited dyskinesia. Remarkably, the former elicited a 66 percent reduction in the severity of dyskinesia without affecting motor improvement resulting from levodopa treatment. The authors also developed and tested a D3 antagonist called ST 198, but while it did attenuate the dyskinesia, it was only effective over a small range of doses.

According to the authors, these experiments indicate "a new therapeutic approach based on the use, in combination with levodopa, of a D3 receptor partial agonist to avoid the expression of dyskinesia."-Tom Fagan.

Reference:
Bezard E, Ferry S, Mach U, Stark H, Leriche L, Boraud T, Gross C, Sokoloff P. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med. 2003 Jun;9(6):762-7. Abstract