Dopamine modulates the susceptibility of striatal neurons to 3-nitropropionic acid in the rat model of Huntington's disease.
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. The striatum is the primary site of neuronal loss in HD; however, neither the mechanism of neurodegeneration nor the underlying cause of the selectivity for the striatum is understood. Chronic systemic injection of 3-nitropropionic acid (3-NP) into rats induces bilateral striatal lesions with many neuropathological features of HD and is widely used as a model of HD. In this study we examine the role striatal dopamine plays in 3-NP-induced striatal toxicity. The effect of elevated striatal dopamine levels on 3-NP toxicity was examined by using acute administration of methamphetamine. After 7 d of 3-NP treatment, a single low dose of methamphetamine markedly increased the frequency of striatal lesion formation. This effect was mediated via dopamine receptors because it could be blocked by the administration of dopamine receptor antagonists. The effect of decreased striatal dopamine on 3-NP toxicity was examined by lesioning the nigrostriatal dopamine input to one striatum 7 d before 3-NP treatment was started. Removal of the dopamine input protected the denervated striatum from the neurotoxic effects of systemic 3-NP but did not prevent the formation of lesions in the intact striatum. Thus the formation of 3-NP lesions is critically dependent on an intact dopamine input. Our data show that dopamine plays an important role in the formation of 3-NP lesions. We suggest that modulation of the dopaminergic system should be reevaluated as a potential drug target in the treatment for HD.
Reynolds
D S
DS
Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, United Kingdom.
Carter
R J
RJ
Morton
A J
AJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006816:Huntington Disease / Q000503:physiopathology*; D008694:Methamphetamine / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009574:Nitro Compounds; D016627:Oxidopamine; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000737:chemistry / Q000503:physiopathology; D013565:Sympatholytics; D013566:Sympathomimetics / Q000494:pharmacology
D000959:Antihypertensive Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D009574:Nitro Compounds; D011422:Propionates; D013565:Sympatholytics; D013566:Sympathomimetics; D008694:Methamphetamine; D016627:Oxidopamine; C015392:3-nitropropionic acid; D004298:Dopamine