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The Dynamic Nature Of Type 1 Cannabinoid Receptor (Cb1) Gene Transcription

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The type 1 cannabinoid receptor (CB1) is an integral component of the endocannabinoid system that modulates several functions in the CNS and periphery. The majority of our knowledge of the endocannabinoid system involves ligand–receptor binding, mechanisms of signal transduction, and protein–protein interactions. In contrast, comparatively little is known about regulation of CB1 gene expression. The levels and anatomical distribution of CB1 mRNA and protein are developmental stage-specific and are dysregulated in several pathological conditions. Moreover, exposure to a variety of drugs, including cannabinoids themselves, alters CB1 gene expression and mRNA levels. As such, alterations in CB1 gene expression are likely to affect the optimal response to cannabinoid-based therapies, which are being developed to treat a growing number of conditions. Here, we will examine the regulation of CB1 mRNA levels and the therapeutic potential inherent in manipulating expression of this gene.

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Manipulation of CB1 expression may have wide ranging affects on physiological processes such as embryogenesis (Paria et al., 1995) and neural development (Fitzgerald et al., 2012). Given that CB1 gene expression is highest in many regions of the brain during early development and adolescence, and it is these areas of high expression where expression is often altered during disease progression, the effect of CB1 therapeutics on CB1 expression will depend on the existing level of CB1 expression. CB1 levels can be modulated pharmacologically by pro-inflammatory peptides, oestrogen, insulin, atypical antipsychotics, methamphetamine, ethanol, retinoic acid and, importantly, endogenous and exogenous cannabinoids (Figure 4). The observation that cannabinoids can induce CB1 mRNA expression in cell culture suggests that cannabinoid ligands could regulate CB1 levels. Although long-term treatment with THC in vivo is associated with tachyphylaxis (Corchero et al., 1999), other cannabinoids have not been examined; the extent of tachyphylaxis may vary in a ligand-specific manner (Hudson et al., 2010), as well as with the duration of exposure (Zhuang et al., 1998), half-life, efficacy, and potency of the cannabinoid. For instance, acute doses of less-potent agonists of CB1 (e.g. AEA relative to THC; Pertwee et al., 2010), or allosteric modulators of CB1 (Ahn et al., 2012) may induce CB1 expression in vivo, whereas chronic treatment with more-potent agonists may cause receptor desensitization. If this is the case, then cannabinoid-dependent manipulation of CB1 levels may represent a useful therapeutic strategy for diseases where reduced or elevated CB1 levels correlate with disease progression. Overall, the affect of cannabinoid-based therapies may depend upon their modulation of CB1 gene expression.

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