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Reversal of delta 9-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors

Caroline E Bass1, Sandra P Welch, Billy R Martin

  • 1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980613, MCV Station, Richmond, VA 23298-0613, USA.

European Journal of Pharmacology
|August 4, 2004
PubMed

Insights

Tolerance to Delta-9-tetrahydrocannabinol (THC) involves specific signaling pathways. Protein kinase A (PKA) activity is crucial for reversing tolerance to multiple THC-induced behaviors, suggesting varied pathways for THC

Area of Science:

  • Neuropharmacology
  • Cannabinoid Research
  • Molecular Biology

Background:

  • Repetitive administration of Delta-9-tetrahydrocannabinol (THC) leads to tolerance.
  • The specific signaling pathways underlying tolerance to THC's behavioral effects remain largely unknown.

Purpose of the Study:

  • To investigate the role of specific kinases in the development and expression of tolerance to THC.
  • To identify which signaling pathways are involved in mediating tolerance to various THC-induced behaviors.

Main Methods:

  • Utilized specific kinase inhibitors targeting PKA, PKG, PKC, and src tyrosine kinase.
  • Administered inhibitors to assess the reversal of established tolerance to four distinct THC-induced behaviors in a preclinical model.

Main Results:

  • Inhibition of PKG and PKC did not reverse THC tolerance across any tested behaviors.
  • Src tyrosine kinase inhibition only reversed tolerance to THC-induced hypoactivity.
  • Inhibition of PKA effectively reversed tolerance to all tested THC-induced behaviors, though dose and timing varied.

Conclusions:

  • PKA signaling is a major contributor to the development of tolerance to multiple THC effects.
  • THC appears to exert its diverse pharmacological actions through distinct intracellular signaling pathways.

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