Dopamine and Huntington’s disease

Abstract

Huntington’s disease (HD) is an incurable, inherited, progressive neurodegenerative disorder that is defined by a combination of motor, cognitive and psychiatric features. Pre-clinical and clinical studies have demonstrated an important role for the dopamine (DA) system in HD with dopaminergic dysfunction at the level of both DA release and DA receptors. It is, therefore, not surprising that the drug treatments most commonly used in HD are anti-dopaminergic agents. Their use is based primarily on the belief that the characteristic motor impairments are a result of overactivation of the central dopaminergic pathways. While this is a useful starting place, it is clear that the behavior of the central dopaminergic pathways is not fully understood in this condition and may change as a function of disease stage. In addition, how abnormalities in dopaminergic systems may underlie some of the non-motor features of HD has also been poorly investigated and this is especially important given the greater burden these place on the patients’ and families’ quality of life. In this review, we discuss what is known about central dopaminergic pathways in HD and how this informs us about the mechanisms of action of the dopaminergic therapies used to treat it. By doing so, we will highlight some of the paradoxes that exist and how solving them may reveal new insights for improved treatment of this currently incurable condition, including the possibility that such drugs may even have effects on disease progression and pathogenesis.

Keywords:

• dopamine
• dopamine receptor
• Huntington’s disease
• motor disorder
• striatum

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Erratum

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Key issues

• Alterations in the dopaminergic system have been reported in Huntington’s disease (HD) and associated with both motor and cognitive features of the condition.

• There are many techniques to measure dopamine (DA) levels and turnover along with DA receptor expression in animal models of HD. However, in humans, techniques are limited to PET scanning and more sophisticated and dynamic techniques are needed.

• DA receptors are reduced both in patients and animal models of HD and this has been found early in the disease course (often ahead of overt manifest disease) and correlated in some studies with some aspects of executive dysfunction. However, exactly how DA abnormalities map on to the cognitive problems of HD is unclear.

• DA levels seem to follow a biphasic pattern with increased levels in the early stages and decreased concentrations in the later stages of the disease progression.

• Treatments targeting the dopaminergic system have been tested in animals models and patients with HD and found to have effects primarily on chorea and other motor symptoms, although this largely is a result of seeing HD as being a movement disorder rather than a complex neuropsychiatric condition.

• A new type of drug stabilizing the dopaminergic synapse is now being trialed with some success.

• Treatments depleting or blocking DA receptors may also have disease-modifying effects, although this is currently unproven.

• The future development of more selective DA receptor drugs may not only help better treat HD, but may also have disease-modifying effects.

Notes