Florida State University
Objective: Our objective was to assess reduction or elimination of behaviors following chronic administration of cannabidiol (CBD) using a newly found mouse model (Kv1.3-/- mice) that exhibits anxiety and attention deficit-like behaviors. We hypothesized that CBD isolate (antagonist) and WIN 55, 212-2-mesylate (WIN), an agonist for CB1 and CB2, might be anxiolytic. To test the mouse model, we examined dose-responsiveness, sex-dependency, route of delivery, and also metabolically phenotyped mice using a comprehensive lab animal monitoring system.
Methods: Two-month-old Kv1.3-/- or wildtype mice were phenotyped for anxiety behaviors using the elevated plus maze (EPM), the light-dark box (LDB), and the marble burying test. Mice were dosed daily, 30 minutes prior to performing a behavioral test. Mice of both sexes were separated into cohorts in which they were designated to receive an intraperitoneal injection of either drug (WIN = 1 mg/kg; CBD = 5 mg/kg) or vehicle solution at equivalent volume. Acute cohorts received daily dosage for 5 days and chronic cohorts received 20 doses over a 30 day interval.
Results: Without drug treatment, both genotypes exhibited anxiety-like behaviors in the LDB and EPM, preferring dark side or closed arms of the apparatuses, respectively. With acute WIN treatment, Kv1.3-/- mice showed lessened anxiety in the LDB. Following chronic WIN treatment, they showed no change in LDB behavior. Acute and chronic WIN treatment in Kv1.3-/- mice mitigated anxiety in the EPM, but showed no effect on anxiety for wildtype mice if acutely administered and heightened anxiety following chronic treatment. For cohorts treated acutely with CBD, Kv1.3-/- mice showed enhanced anxiety behaviors in the LDB. Mice of both genotypes showed enhanced anxiety behaviors in the EPM following acute CBD treatment.
Conclusion: In conclusion, our data showed that CBD may act as an anxiogenic drug in both wildtype and Kv1.3-/- mice. WIN acted as an anxiolytic drug for mice with trait anxiety (Kv1.3-/-), which was ineffective in these mice long-term, and ineffective acutely in wildtype mice exposed to state anxiety. We have collected and are analyzing chronic effects of WIN and CBD on body weight, energy expenditure, fuel utilization, and locomotor activity.
Co-authors: Brigitte Cochan1, Camilla May1, Claudia Silver1, Nicholas Maykut1, Claudia Cedeno Laya1, Debra Ann Fadool1
1Florida State University