title: The role of dopamine in Huntington's disease.
abstract: Alterations in dopamine (DA) neurotransmission in Parkinson's disease are well known and widely studied. Much less is known about DA changes that accompany and underlie some of the symptoms of Huntington's disease (HD), a dominant inherited neurodegenerative disorder characterized by chorea, cognitive deficits, and psychiatric disturbances. The cause is an expansion in CAG (glutamine) repeats in the HTT gene. The principal histopathology of HD is the loss of medium-sized spiny neurons (MSNs) and, to a lesser degree, neuronal loss in cerebral cortex, thalamus, hippocampus, and hypothalamus. Neurochemical, electrophysiological, and behavioral studies in HD patients and genetic mouse models suggest biphasic changes in DA neurotransmission. In the early stages, DA neurotransmission is increased leading to hyperkinetic movements that can be alleviated by depleting DA stores. In contrast, in the late stages, DA deficits produce hypokinesia that can be treated by increasing DA function. Alterations in DA neurotransmission affect glutamate receptor modulation and could contribute to excitotoxicity. The mechanisms of DA dysfunction, in particular the increased DA tone in the early stages of the disease, are presently unknown but may include initial upregulation of DA neuron activity caused by the genetic mutation, reduced inhibition resulting from striatal MSN loss, increased excitation from cortical inputs, and DA autoreceptor dysfunction. Targeting both DA and glutamate receptor dysfunction could be the best strategy to treat HD symptoms.
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors: Carlos
authors: C
authors: Cepeda
authors: Huntington's Disease Research Forum, Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, Buckinghamshire, UK.
authors: Kerry P S
authors: KP
authors: Murphy
authors: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Quebec City, QC, Canada.
authors: Martin
authors: M
authors: Parent
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: mlevine@mednet.ucla.edu.
authors: Michael S
authors: MS
authors: Levine
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D004298:Dopamine
keywords: Huntington's disease; dopamine; glutamate; medium-sized spiny neurons; neurotransmission; receptors