title: Cannabinoids increase type 1 cannabinoid receptor expression in a cell culture model of striatal neurons: implications for Huntington's disease.
abstract: The type 1 cannabinoid receptor (CB1) is a G protein-coupled receptor that is expressed at high levels in the striatum. Activation of CB1 increases expression of neuronal trophic factors and inhibits neurotransmitter release from GABA-ergic striatal neurons. CB1 mRNA levels can be elevated by treatment with cannabinoids in non-neuronal cells. We wanted to determine whether cannabinoid treatment could induce CB1 expression in a cell culture model of striatal neurons and, if possible, determine the molecular mechanism by which this occurred. We found that treatment of STHdh(7/7) cells with the cannabinoids ACEA, mAEA, and AEA produced a CB1receptor-dependent increase in CB1 promoter activity, mRNA, and protein expression. This response was Akt- and NF-κB-dependent. Because decreased CB1 expression is thought to contribute to the pathogenesis of Huntington's disease (HD), we wanted to determine whether cannabinoids could increase CB1 expression in STHdh(7/111) and (111/111) cells expressing the mutant huntingtin protein. We observed that cannabinoid treatment increased CB1 mRNA levels approximately 10-fold in STHdh(7/111) and (111/111) cells, compared to vehicle treatment. Importantly, cannabinoid treatment improved ATP production, increased the expression of the trophic factor BDNF-2, and the mitochondrial regulator PGC1α, and reduced spontaneous GABA release, in HD cells. Therefore, cannabinoid-mediated increases in CB1 levels could reduce the severity of some molecular pathologies observed in HD.
authors.affiliation: Rm 6E Sir Charles Tupper Medical Bldg, Department of Pharmacology, Dalhousie University, 5850 College St., Halifax, NS, Canada B3H 4R2. robert.laprairie@dal.ca
authors.forename: Robert B
authors.initials: RB
authors.lastname: Laprairie
authors.forename: Melanie E M
authors.initials: ME
authors.lastname: Kelly
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Denovan-Wright
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D000071058:Huntingtin Protein; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D011714:Pyrans / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C508712:(6aR,10aR)-3-(1-methansulfonylamino-4-hexyn-6-yl)6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo(b,d)pyran; D002186:Cannabinoids; D004791:Enzyme Inhibitors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009025:Morpholines; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011714:Pyrans; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; D000255:Adenosine Triphosphate; C109925:AM 281