Dopamine release is severely compromised in the R6/2 mouse model of Huntington's disease

被引:107
作者
Johnson, MA
Rajan, V
Miller, CE
Wightman, RM
机构
[1] Univ N Carolina, Dept Chem, Venable & Kenan Labs, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Ctr Neurosci, Chapel Hill, NC 27599 USA
关键词
cocaine; dopamine; huntingtin; Huntington's disease; methamphetamine; voltammetry;
D O I
10.1111/j.1471-4159.2006.03762.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recently, alterations in dopamine signaling have been implicated in Huntington's disease. In this work, dopamine release and uptake was measured in striatal slices from the R6/2 transgenic mouse model of Huntington's disease using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Dopamine release in brain slices from 6-week-old R6/2 mice is substantially reduced (53% of wild type), while dopamine uptake is unaffected. In agreement with this, R6/2 mice injected with the dopamine uptake inhibitor cocaine exhibited a blunted motor activity response (54% of wild type). At 10 weeks of age, an even more dramatic motor activity decrease in response to cocaine injection (21% of wild type) was observed. Moreover, the pre-drug activity of 10-week-old R6/2 mice was significantly reduced (by 37%) compared with 6-week-old R6/2 mice. Striatal dopamine release decreased with age, indicating that progressive alterations in dopaminergic pathways may affect motor activity. The inhibition constants of cocaine and methamphetamine (METH) determined in brain slices differed little between genotype or age group, suggesting that the decreased responses to cocaine and METH arise from compromised dopamine release rather than differences in uptake or drug action. Collectively, these data demonstrate (i) a reduction in the ability of dopamine terminals to release dopamine and (ii) the importance of this attenuation of release on the motor symptoms of Huntington's disease.
引用
收藏
页码:737 / 746
页数:10
相关论文
共 59 条
[11]   Decreased striatal monoaminergic terminals in Huntington disease [J].
Bohnen, NI ;
Koeppe, RA ;
Meyer, P ;
Ficaro, E ;
Wernette, K ;
Kilbourn, MR ;
Kuhl, DE ;
Frey, KA ;
Albin, RL .
NEUROLOGY, 2000, 54 (09) :1753-1759
[12]   Early exploratory behavior abnormalities in R6/1 Huntington's disease transgenic mice [J].
Bolivar, VJ ;
Manley, K ;
Messer, A .
BRAIN RESEARCH, 2004, 1005 (1-2) :29-35
[13]   BIOCHEMICAL CORRELATES OF MOTOR CHANGES CAUSED BY THE MANIPULATION OF DOPAMINE FUNCTION IN THE SUBSTANTIA-NIGRA OF THE MOUSE [J].
BRADBURY, AJ ;
COSTALL, B ;
KELLY, ME ;
NAYLOR, RJ ;
SMITH, JA .
NEUROPHARMACOLOGY, 1985, 24 (12) :1155-1161
[14]   Methamphetamine rapidly decreases vesicular dopamine uptake [J].
Brown, JM ;
Hanson, GR ;
Fleckenstein, AE .
JOURNAL OF NEUROCHEMISTRY, 2000, 74 (05) :2221-2223
[15]   A single methamphetamine administration rapidly decreases vesicular dopamine uptake [J].
Brown, JM ;
Riddle, EL ;
Sandoval, V ;
Weston, RK ;
Hanson, JE ;
Crosby, MJ ;
Ugarte, YV ;
Gibb, JW ;
Hanson, GR ;
Fleckenstein, AE .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 302 (02) :497-501
[16]  
Carter RJ, 1999, J NEUROSCI, V19, P3248
[17]  
COOPER JR, 2003, BIOCH BASIS NEUROPHA, P405
[18]   TRINUCLEOTIDE REPEAT LENGTH INSTABILITY AND AGE-OF-ONSET IN HUNTINGTONS-DISEASE [J].
DUYAO, M ;
AMBROSE, C ;
MYERS, R ;
NOVELLETTO, A ;
PERSICHETTI, F ;
FRONTALI, M ;
FOLSTEIN, S ;
ROSS, C ;
FRANZ, M ;
ABBOTT, M ;
GRAY, J ;
CONNEALLY, P ;
YOUNG, A ;
PENNEY, J ;
HOLLINGSWORTH, Z ;
SHOULSON, I ;
LAZZARINI, A ;
FALEK, A ;
KOROSHETZ, W ;
SAX, D ;
BIRD, E ;
VONSATTEL, J ;
BONILLA, E ;
ALVIR, J ;
CONDE, JB ;
CHA, JH ;
DURE, L ;
GOMEZ, F ;
RAMOS, M ;
SANCHEZRAMOS, J ;
SNODGRASS, S ;
DEYOUNG, M ;
WEXLER, N ;
MOSCOWITZ, C ;
PENCHASZADEH, G ;
MACFARLANE, H ;
ANDERSON, M ;
JENKINS, B ;
SRINIDHI, J ;
BARNES, G ;
GUSELLA, J ;
MACDONALD, M .
NATURE GENETICS, 1993, 4 (04) :387-392
[19]   Expression of mutant huntingtin blocks exocytosis in PC12 cells by depletion of complexin II [J].
Edwardson, JM ;
Wang, CT ;
Gong, B ;
Wyttenbach, A ;
Bai, JH ;
Jackson, MB ;
Chapman, ER ;
Morton, AJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (33) :30849-30853
[20]   TYROSINE HYDROXYLASE-LIKE IMMUNOREACTIVITY IS DISTRIBUTED IN THE MATRIX COMPARTMENT OF NORMAL HUMAN AND HUNTINGTONS-DISEASE STRIATUM [J].
FERRANTE, RJ ;
KOWALL, NW .
BRAIN RESEARCH, 1987, 416 (01) :141-146