Abstract
The cannabinoid CB1 receptor (CB1) is one of the most abundant G protein-coupled receptors in the brain, but little is known about the mechanisms that modulate CB1 receptor signaling. Here, we show that inhibition or null mutation of the epsilon isozyme of protein kinase C (PKCɛ) selectively enhances behavioral responses to the CB1 agonist WIN55,212-2 in mice, but not to the structurally unrelated CB1 agonist CP55,940. Binding affinity for [3H] WIN55,212-2 was increased in brain membranes from PKCɛ−/− mice compared with PKCɛ+/+ mice. There was no difference in binding of the inverse agonist [3H] SR141716A. In addition, repeated administration of WIN55,212-2 produced greater analgesic and thermal tolerance in PKCɛ−/− mice compared with PKCɛ+/+mice. These results indicate that PKCɛ selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.
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Acknowledgements
These studies were supported by fellowship DA019308 from the NIDA to MJW, and by grant AA013588 from the NIAAA and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California to ROM.
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Wallace, M., Newton, P., McMahon, T. et al. PKCɛ Regulates Behavioral Sensitivity, Binding and Tolerance to the CB1 Receptor Agonist WIN55,212-2. Neuropsychopharmacol 34, 1733–1742 (2009). https://doi.org/10.1038/npp.2008.230
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DOI: https://doi.org/10.1038/npp.2008.230
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