Immediate-early gene response to methamphetamine, haloperidol, and quinolinic acid is not impaired in Huntington's disease transgenic mice.
Striatal neurons in symptomatic Huntington's disease (HD) transgenic mice are resistant to a variety of toxic insults, including quinolinic acid (QA), kainic acid and 3-nitropropionic acid. The basis for this resistance is currently unknown. To investigate the possibility that the immediate-early gene (IEG) response is defective in symptomatic HD mice leading to a lack of response to these compounds, we examined the expression of c-Fos and Krox 24 after administration of the indirect dopamine agonist methamphetamine, the dopamine D(2) receptor antagonist haloperidol and the neurotoxin QA in 5- and 10-week-old R6/2 transgenic HD and wild-type mice. Unlike wild-type and pre-symptomatic R6/2 transgenic HD mice, 10-week-old symptomatic HD mice were resistant to methamphetamine-induced gliosis and QA lesion. There was, however, no difference in the number or distribution of c-Fos-immunoreactive nuclei 2 hr after single injections of methamphetamine or haloperidol among 5- and 10-week-old wild-type mice and 5- and 10-week-old R6/2 HD mice. Similarly, despite their resistance to QA-induced lesioning and lower basal levels of krox-24 mRNA, the symptomatic R6/2 mice had equivalent increases in the amount of c-fos and krox-24 mRNA compared to wild-type and pre-symptomatic R6/2 HD mice as determined by in situ hybridization and densitometry 2 hr after QA administration. These data demonstrate that the c-Fos and Krox 24 IEG response to dopamine agonists, dopamine antagonists and neurotoxic insult is functional in symptomatic R6/2 HD mice. Resistance to toxic insult in R6/2 mice may be conferred by interactions of mutant huntingtin with proteins or transcriptional processes further along the toxic cascade.
MacGibbon
G A
GA
Laboratory of Molecular Neuroscience, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Hamilton
L C
LC
Crocker
S F
SF
Costain
W J
WJ
Murphy
K M
KM
Robertson
H A
HA
Denovan-Wright
E M
EM
D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D051766:Early Growth Response Protein 1; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017874:Immediate-Early Proteins; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018726:Anti-Dyskinesia Agents; D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D008694:Methamphetamine; D017378:Quinolinic Acid; D006220:Haloperidol