Therapeutic Potential of Cannabidiol and WIN 55, 212‐2‐mesylate for Treatment of Anxiety

Abstract

As the medicalization of marijuana occurs across the United States, the psychoactive component of the cannabis plant, Delta9-Tetrahydrocannabinol (THC), has gained recognition for its therapeutic potential. Meanwhile, its non-psychoactive counterpart, cannabidiol (CBD), has been marketed to treat Parkinson's disease, Chron's disease, dystonia, attention-deficit hyperactivity disorder (ADHD), inflammation, depression, fibromyalgia, epilepsy, and most commonly, anxiety. Given the over the counter accessibility of CBD and the fact that anxiety disorders are the most common type of mental illness in the United States, our objective was to access the therapeutic potential of cannabinoid receptor agonists and antagonists for treatment of anxiety. We hypothesized that CBD might be anxiolytic when chronically administered to a newly found mouse model of anxiety and attention deficit (Kv1.3-/- mice). Similarly to THC, WIN 55, 212-2-mesylate (WIN) is an agonist for the cannabinoid receptors CB1 and CB2, but it is not known to have any psychoactive properties. CBD is an antagonist for CB1 and CB2 receptors, and we used a CBD isolate to ensure purity. Our methods employed two-month-old Kv1.3-/- or wildtype mice that were phenotyped for anxiety behaviors using three assays, namely 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 (WIN55 = 1 mg/kg; CBD = 5 mg/kg) or vehicle solution at equivalent volume. Acute cohorts were defined as daily dosage for 5 days and chronic cohorts were treated with 20 doses over a 30 day interval. Without drug treatment, both genotypes exhibited anxiety-like behaviors in the LDB and EPM tasks, preferring dark side or closed arms of the apparatuses, respectively. For acute WIN treatment, Kv1.3-/- mice showed lessened anxiety in the LDB (increased time in light, decreased time in dark), however, following chronic WIN treatment, they showed no change in LDB behavior. In contrast, in wildtype mice, neither acute nor chronic WIN treatment changed LDB behaviors. Both acute and chronic WIN treatment in Kv1.3-/- mice mitigated anxiety in the EPM test (mice decreased time in the closed arms), whereas the same in wildtype mice showed no effect of anxiety if acutely administered and heightened anxiety following chronic treatment (mice increased time in closed arms). For cohorts treated acutely with CBD, Kv1.3-/- mice showed enhanced anxiety behaviors in the LDB (mice decreased time in light and increased time in dark). Mice of both genotypes showed enhanced anxiety behaviors in the EPM (mice increased time in the closed arms) following acute CBD treatment.In conclusion, our data did not support our hypothesis and 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.