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

June 18, 1997

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

For more information :


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

French National Institute for Health and Medical Research (INSERM)

Related Dopamine Articles from Brightsurf:

Dopamine surge reveals how even for mice, 'there's no place like home'
''There's no place like home,'' has its roots deep in the brain.

New dopamine sensors could help unlock the mysteries of brain chemistry
In 2018, Tian Lab at UC Davis Health developed dLight1, a single fluorescent protein-based biosensor.

Highly sensitive dopamine detector uses 2D materials
A supersensitive dopamine detector can help in the early diagnosis of several disorders that result in too much or too little dopamine, according to a group led by Penn State and including Rensselaer Polytechnic Institute and universities in China and Japan.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Viewing dopamine receptors in their native habitat
A new study led by UT Southwestern researchers reveals the structure of the active form of one type of dopamine receptor, known as D2, embedded in a phospholipid membrane.

Significant differences exist among neurons expressing dopamine receptors
An international collaboration, which included the involvement of the research team from the Institut de Neurociències of the UAB (INC-UAB), has shown that neurons expressing dopamine D2 receptors have different molecular features and functions, depending on their anatomical localization within the striatum.

How dopamine drives brain activity
Using a specialized magnetic resonance imaging (MRI) sensor that can track dopamine levels, MIT neuroscientists have discovered how dopamine released deep within the brain influences distant brain regions.

Novelty speeds up learning thanks to dopamine activation
Brain scientists led by Sebastian Haesler (NERF, empowered by IMEC, KU Leuven and VIB) have identified a causal mechanism of how novel stimuli promote learning.

Evidence in mice that childhood asthma is influenced by the neurotransmitter dopamine
Neurons that produce the neurotransmitter dopamine communicate with T cells to enhance allergic inflammation in the lungs of young mice but not older mice, researchers report Nov.

Chronic adversity dampens dopamine production
People exposed to a lifetime of psychosocial adversity may have an impaired ability to produce the dopamine levels needed for coping with acutely stressful situations.

Read More: Dopamine News and Dopamine Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.