CB 1 receptor transgenic mice in the cannabinoid triad: a novel approach to assess in vivo efficacy of CB 1 ligands.

The abuse of structurally diverse synthetic cannabinoids has resulted in untoward effects in users and concomitant spike in emergency room visits, which signify a significant public health concern. Synthetic cannabinoids bind and activate cannabinoid CB1 receptors, which are responsible for the psychomimetic effects of the primary active constituent of marijuana, D 9 ‐tetrahydrocannabinol (THC). While THC is classified as a partial agonist, many of the synthetic cannabinoids have been identified as full agonists. While various in vitro methods assess CB 1 receptor efficacy (e.g. [ 35 S]GTPgS binding, cAMP production), only drug discrimination procedures are currently utilized to determine in vivo efficacy. Here, we assess efficacy utilizing a cumulative dose‐response procedure of several cannabinoids (WIN55,212‐2, CP55,940, CP47,497, and THC) on CB1 receptor‐mediated pharmacological effects (i.e., catalepsy, hypothermia, and thermal antinociception) in CB1 (+/+), (+/‐), and (‐/‐) mice. As expected, these compounds produced little or no effects in CB1 (‐/‐) mice, consistent with the premise that these effects are CB1 receptor mediated. Each of these compounds produced maximum effects in CB1 (+/+) mice, but (+/‐) mice displayed differential sensitivity to these CB1 receptor agonists that was positively associated with their in vitro efficacy. Analysis of potency ratios between CB1 (+/+) and (+/‐) mice revealed a rank order of efficacy (from highest to lowest) of WIN55,212‐2 > CP55,940 > CP47,497 > THC. Together, these experiments demonstrate a quick and accurate method to determine in vivo efficacy, and this design correlates well with prior in vitro efficacy determinations in [ 35 S]GTPgS binding assays.