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Updated: Jul 3, 2026
Administration of Δ9-Tetrahydrocannabinol (THC) in Adolescent and Adult Mice
Published on: August 1, 2025
Sensitivity to delta9-tetrahydrocannabinol is selectively enhanced in beta-arrestin2 -/- mice
Christopher S Breivogel1, Jonathan M Lambert, Steven Gerfin
1Department of Pharmaceutical Sciences, Campbell University School of Pharmacy Buies Creek, North Carolina 27506, USA. breivogel@campbell.edu
Abstract:
Little is known about the roles of beta-arrestins in the regulation of brain CB1 cannabinoid receptors. This study investigated the role of beta-arrestin2 in cannabinoid behavioral effects using beta-arrestin2 -/- mice and their wild-type counterparts. A variety of cannabinoid ligands from different chemical classes that exhibit a variety of efficacies for activation of CB1 receptors were investigated, including Delta-tetrahydrocannabinol, CP55940, methanandamide, JWH-073, and O-1812. Delta-tetrahydrocannabinol produced both greater antinociception and greater decreases in body temperature in beta-arrestin2 -/- compared with beta-arrestin2 +/+ mice. No significant differences were, however, present in either assay for the other CB1 agonists. Antagonist radioligand binding indicated no difference in the density of cannabinoid CB1 receptors in the cerebellum, cortex, or hippocampus of beta-arrestin2 +/+ and -/- mice. These data demonstrate that beta-arrestin2 may regulate cannabinoid CB1 receptor sensitivity in an agonist-specific manner.
Insights
Beta-arrestin2 influences cannabinoid CB1 receptor sensitivity, but only for certain agonists like Delta-tetrahydrocannabinol. This protein impacts cannabinoid behavioral effects and body temperature regulation.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Beta-arrestins are critical in G protein-coupled receptor regulation.
- The specific role of beta-arrestin2 in brain cannabinoid CB1 receptor (CB1R) function remains largely uncharacterized.
- Understanding these interactions is key to deciphering cannabinoid signaling pathways.
Purpose of the Study:
- To investigate the role of beta-arrestin2 in mediating the behavioral effects of various CB1R agonists.
- To determine if beta-arrestin2 influences CB1R sensitivity in a ligand-dependent manner.
Main Methods:
- Utilized beta-arrestin2 knockout mice (-/-) and their wild-type littermates (+/+).
- Administered diverse CB1R agonists including Delta-tetrahydrocannabinol, CP55940, methanandamide, JWH-073, and O-1812.
- Assessed behavioral outcomes (antinociception, hypothermia) and performed radioligand binding assays.
Main Results:
- Delta-tetrahydrocannabinol induced significantly greater antinociception and hypothermia in beta-arrestin2 -/- mice compared to wild-type.
- No significant differences in antinociception or hypothermia were observed for other tested CB1R agonists.
- CB1R density in key brain regions (cerebellum, cortex, hippocampus) was unaffected by the absence of beta-arrestin2.
Conclusions:
- Beta-arrestin2 plays a crucial role in modulating CB1R-mediated antinociception and hypothermia.
- This regulatory role is agonist-specific, highlighting differential signaling pathways for various CB1R ligands.
- Beta-arrestin2 influences CB1R sensitivity rather than receptor expression levels.
