PKC regulates behavioral sensitivity, binding and tolerance to the CB1 receptor agonist WIN55,212-2

Melisa J. Wallace, Philip M. Newton, Thomas McMahon, Jacklyn Connolly, Anne Huibers, Jennifer Whistler, Robert O. Messing

Research output: Contribution to journalArticle

11 Scopus citations

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 (PKC) 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 PKC-/- mice compared with PKC+/+ 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 PKC -/- mice compared with PKC mice. These results indicate that PKC selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.

Original languageEnglish (US)
Pages (from-to)1733-1742
Number of pages10
JournalNeuropsychopharmacology
Volume34
Issue number7
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Keywords

  • Cannabinoid
  • CB1 receptor
  • G protein
  • Protein kinase C epsilon
  • Tolerance
  • WIN55,212-2

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    Wallace, M. J., Newton, P. M., McMahon, T., Connolly, J., Huibers, A., Whistler, J., & Messing, R. O. (2009). PKC regulates behavioral sensitivity, binding and tolerance to the CB1 receptor agonist WIN55,212-2. Neuropsychopharmacology, 34(7), 1733-1742. https://doi.org/10.1038/npp.2008.230