The role of dopamine in motor symptoms in the R6/2 transgenic mouse model of Huntington's disease.
In both Huntington's disease (HD) patients and genetic mouse models of HD, there is a pre-symptomatic loss of dopamine (DA) receptors, suggesting that dysfunctional dopaminergic neurotransmission may be involved in early HD presentation. However, the role of DA in HD symptoms is not fully understood. In this study, we examined the possibility that dysfunctional dopaminergic neurotransmission contributes to the progressive decline in motor function of a transgenic mouse model of HD (R6/2 line). We found that R6/2 mice display an age-dependent abnormal behavioural response to (+)-methamphetamine (METH) and a dose-dependent increase in sensitivity to METH toxicity compared with wild-type (WT) mice. R6/2 mice also showed an attenuated response to cocaine, indicating that DA release may be compromised. Striatal DA levels were reduced in R6/2 mice by 9 weeks of age. Replacement of DA by chronic treatment with laevodopa (L-DOPA, administered as Sinemet) caused short-term improvements in activity and rearing behaviour, and abolished abnormal spontaneous hindlimb grooming. However, long-term treatment with L-DOPA had deleterious effects on survival and rotarod performance of R6/2 mice. These results suggest that dysfunctional DA neurotransmission contributes to phenotype development in R6/2 mice and thus also may be important in symptom progression in HD.
Hickey
Miriam A
MA
Department of Pharmacology, University of Cambridge, UK.
Reynolds
Gavin P
GP
Morton
A Jennifer
AJ
D000375:Aging / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005951:Glucose Tolerance Test; D006816:Huntington Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D007980:Levodopa / Q000494:pharmacology*; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects; D015996:Survival Rate
D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D008694:Methamphetamine; D007980:Levodopa; D003042:Cocaine; D004298:Dopamine