Cannabinoids increase type 1 cannabinoid receptor expression in a cell culture model of striatal neurons: Implications for Huntington's disease

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• 作者：Robert B. Laprairie ; Melanie E.M. Kelly ; Eileen M. Denovan-Wright
• 关键词：Type 1 cannabinoid receptor (CB1) ; Cannabinoids ; Gene expression ; Akt ; NF-¦ÊB ; Huntington's disease
• 刊名：Neuropharmacology
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：72
• 期：Complete
• 页码：47-57
• 全文大小：2403 K

文摘

The type 1 cannabinoid receptor (CB<sub>1sub>) is a G protein-coupled receptor that is expressed at high levels in the striatum. Activation of CB<sub>1sub> increases expression of neuronal trophic factors and inhibits neurotransmitter release from GABA-ergic striatal neurons. CB<sub>1sub> mRNA levels can be elevated by treatment with cannabinoids in non-neuronal cells. We wanted to determine whether cannabinoid treatment could induce CB<sub>1sub> 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<sup>7/7sup> cells with the cannabinoids ACEA, mAEA, and AEA produced a CB<sub>1sub>receptor-dependent increase in CB<sub>1sub> promoter activity, mRNA, and protein expression. This response was Akt- and NF-¦ÊB-dependent. Because decreased CB<sub>1sub> expression is thought to contribute to the pathogenesis of Huntington's disease (HD), we wanted to determine whether cannabinoids could increase CB<sub>1sub> expression in STHdh<sup>7/111sup> and <sup>111/111sup> cells expressing the mutant huntingtin protein. We observed that cannabinoid treatment increased CB<sub>1sub> mRNA levels approximately 10-fold in STHdh<sup>7/111sup> and <sup>111/111sup> cells, compared to vehicle treatment. Importantly, cannabinoid treatment improved ATP production, increased the expression of the trophic factor BDNF-2, and the mitochondrial regulator PGC1¦Á, and reduced spontaneous GABA release, in HD cells. Therefore, cannabinoid-mediated increases in CB<sub>1sub> levels could reduce the severity of some molecular pathologies observed in HD.