Simultaneous in vivo measurement of the cerebral type 1 cannabinoid receptor and endocannabinoid levels in transgenic rats of Huntington's disease.

Huntingtons disease (HD) is a progressive neurodegenerative disorder, without effective therapy. The endocannabinoid system is dysregulated in HD. Ex vivo studies point towards a role of the type 1 cannabinoid receptor (CB1-R) in the pathogenesis and symptom development. We recently investigated brain CB1-R availability in vivo in symptomatic HD patients, and in an acute experimental model using PET. In HD patients, we found that substantial cortical and subcortical decreases in CB1-R are present, irrespective of disease stage, disease duration, CAG repeats, motor symptoms or patient age. These findings are compatible with a disturbance of CB1-R expression by mutant-huntingtin. This is in accordance with in vitro studies indicating that nuclear accumulation of mutant htt interferes in a length-dependent way with the transcription factor SP1, inducing alterations of downstream protein expression (Dunah et al., 2002), and that the CB1-R gene is among those genes where transcription failure has been most prominently noticed in HD (McCaw et al., 2004). We thus assume that decreased CB1-R binding is also present in the presymptomatic stage, preceding motor and/or behavioral symptoms. Tracking the evolution of CB1-R levels in the presymptomatic stage may provide a biomarker for the earliest subclinical disease changes. In this project, we wish to simultaneously measure (1) CB1-Rs and (2) cerebral endocannabinoids levels of the striatum in vivo in the first transgenic rat model of Huntington's disease to identify potential targets for drug therapy. A combined in vivo measurement of endogenous cannabinoid levels and brain receptor availability is essential to correctly interpret disease-related changes in receptor binding in light of therapy.

Keywords:Type 1 cannabinoid receptor, Cerebral, Huntington's disease

Disciplines:Medical imaging and therapy