Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington's disease transgenic mice.
Early loss of CB1 receptors is a hallmark of human Huntington's disease. Data from rodent studies suggest that preservation and activation of CB1 receptors may be protective against disease progression. R6/1 transgenic mice are considered to be a model of early pathogenic changes in Huntington's disease. We have shown previously that levels of CB1 in R6/1 mice prior to the onset of motor symptoms (12 weeks of age) remain high enough to justify commencement of cannabinoid drug treatment. Eight weeks of daily treatment with the cannabinoid agonists HU210 (0.01 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 10.00 mg/kg), or the inhibitor of endocannabinoid metabolism URB597 (0.30 mg/kg), did not alter the progressive deterioration of performance observed in motor behavioural testing. HU210-treated R6/1 mice experienced a significant increase in seizure events suggesting that this therapy may lower the seizure threshold and cautioning against highly efficacious agonists as potential therapy in this disease. Molecular characterisation of brains at the end of the study showed that there were no significant effects of HU210 or THC treatment on the ligand binding of cannabinoid CB1, dopamine D1, D2, serotonin 5HT2A or GABA(A) receptors, nor CB1 or fatty acid amide hydrolase (FAAH) mRNA expression in R6/1 mice. Intriguingly, a significant increase in the number of ubiquitinated aggregates was observed in the striatum with HU210 treatment, indicating an influence of CB1 on the disease process. Chronic URB597 treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration.
Dowie
M J
MJ
Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Howard
M L
ML
Nicholson
L F B
LF
Faull
R L M
RL
Hannan
A J
AJ
Glass
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002186:Cannabinoids / Q000008:administration & dosage*; D015331:Cohort Studies; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011897:Random Allocation; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol; C062018:HU 211