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Levodopa Therapy Of Parkinson's Disease: A Mechanism Potentially Explaining Major Side Effects

French National Institute for Health and Medical Research (INSERM)

Long-term treatment of Parkinson's disease with levodopa is very often associated with highly troublesome side effects such as involuntary movements and psychological disorders. The team headed by Pierre Sokoloff and Regis Bordet (INSERM Unit 109, directed by Professor Jean-Charles Schwartz in Paris) have found that an increase in dopamine D3 receptors in certain brain regions may be behind these adverse effects of levodopa. The paper they have published in PNAS shows that newly synthesized D3 receptor could alter the balance between two neuropeptides involved in motor control.

Parkinson's disease, a slowly progressive neurological condition, causes three main motor disorders: tremor at rest, stiffness and akinesia (diminished and slowed movements). It is due to the degeneration of neurons that produce and release dopamine in the substantia nigra. The best treatment is chronic administration of levodopa, the precursor of dopamine. Levodopa therapy leads to a marked improvement in all three motor disorders, but involuntary movements (dyskinesia) and psychological problems (especially hallucinations) frequently arise after many years of treatment. The nature of these adverse effects points to an excessive response (sensitization) to dopamine.

Despite extensive research the mechanisms underlying dopamine sensitization have remained elusive. For example, no change in dopamine D1 or D2 receptor expression has been found(1) The team at INSERM Unit 109 focused on the possible involvement of D3 dopamine receptors, whose expression is dependent on intact dopaminergic innervation, Parkinson's disease being due to degeneration of the dopaminergic pathway. They did so by comparing the brains of untreated "parkinsonian" rats and similar rats treated with levodopa; the latter become sensitized to dopamine, leading to an amplified motor action.

Sensitization was accompanied by a marked, gradual increase in D3 receptor synthesis in the damaged hemisphere. In addition, the receptor is increased in the nucleus accumbens in which it is naturally present but also and unexpectedly in the caudate-putamen in which it is normally absent. The caudate-putamen is strongly involved in motor control, while the nucleus accumbens is involved in the control of emotions. Sensitization was found to occur concomitantly with the emergence of new D3 receptors. When levodopa therapy was stopped, the motor effect diminished and D3 receptors disappeared simultaneously from the caudate-putamen and nucleus accumbens. Sensitization was the direct result of new D3 receptor synthesis, as a specific D3 receptor antagonist prevented the signs of excessive motor action.

Furthermore, the appearance of new D3 receptors and the sensitization process were accompanied by an imbalance in the synthesis of two neuropeptides (2) involved in motor control. The INSERM team suspect that this disequilibrium, generated by increased D3 receptor expression, underlies the increased motor action, i.e. behavioral sensitization, that occurs during the course of levodopa therapy.

The question is whether dopamine sensitization during levodopa therapy is also accompanied by D3 receptor overexpression in parkinsonian patients. A "knock-out" mouse model lacking D3 receptors should enable the involvement of this receptor in the sensitization phenomenon to be confirmed. If this is indeed the case, the use of specific D3 receptor antagonists might improve the treatment of Parkinson's disease. Molecules of this type are already undergoing animal trials as adjuncts to levodopa therapy.

(1) Five dopamine receptors, D1 to D5, have been identified

(2) dynoprhin and substance P

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References

Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa

Proceedings National Academy of Science (PNAS), april 1997, vol 94, pp 3363-3367

R. Bordet , S. Ridray , S. Carboni , J. Diaz , P. Sokoloff , and J.C.Schwartz

Laboratory of physiology, University René Descartes, Paris
INSERM Unit 109 3 Neurobiology and pharmacology 2, Paris


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