Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease.
Huntington's disease (HD) is an inherited neurodegenerative disease characterised by cell dysfunction and death in the basal ganglia and cortex. Currently there are no effective pharmacological treatments available. Loss of cannabinoid CB1 receptor ligand binding in key brain regions is detected early in HD in human postmortem tissue [Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience 97:505-519]. In HD transgenic mice environmental enrichment upregulates the CB1 receptors and slows disease progression [Glass M, van Dellen A, Blakemore C, Hannan AJ, Faull RL (2004) Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 123:207-212]. These findings, combined with data from lesion studies have led to the suggestion that activation of cannabinoid receptors may be protective. However, studies suggest that CB1 mRNA may be decreased early in the disease progression in HD mice, making this a poor drug target. We have therefore performed a detailed analysis of CB1 receptor ligand binding, protein, gene expression and levels of endocannabinoids just prior to motor symptom onset (12 weeks of age) in R6/1 transgenic mice. We demonstrate that R6/1 mice exhibit a 27% decrease in CB1 mRNA in the striatum compared to wild type (WT). Total protein levels, determined by immunohistochemistry, are not significantly different to WT in the striatum or globus pallidus, but are significantly decreased by 19% in the substantia nigra. CB1 receptor ligand binding demonstrates significant but small decreases (<20%) in all basal ganglia regions evaluated. The levels of the endocannabinoid 2-arachidonoyl glycerol are significantly increased in the cortex (147%) while anandamide is significantly decreased in the hippocampus to 67% of WT. Decreases are also apparent in the ligand binding of neuronal D1 and D2 dopamine receptors co-located with CB1, while there is no change in GABA(A) receptor ligand binding. These results suggest that in this R6/1 mouse colony at 12 weeks there are only very small changes in CB1 protein and receptors and thus this would be an appropriate time point to evaluate therapeutic interventions.
Dowie
M J
MJ
Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand.
Bradshaw
H B
HB
Howard
M L
ML
Nicholson
L F B
LF
Faull
R L M
RL
Hannan
A J
AJ
Glass
M
M
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D020820:Dyskinesias / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D011954:Receptors, Dopamine; C094503:glyceryl 2-arachidonate; C078814:anandamide