Revisiting the complex influences of cannabinoids on motor functions unravels pharmacodynamic differences between cannabinoid agonists

While numerous cannabinoid ligands were historically characterized using the tetrad test (hypomobility, catalepsy, hypothermia, analgesia), only few studies have extensively compared HU 210 and CP 55,940 which are nowadays classically used as reference agonists. Therefore, we herein re-examined the acute and the sustained changes in motor activities mediated by these two agonists in adult rats. As expected for cannabinoid agonists, exposure to either HU 210 or CP 55,940 induced a marked reduction in spontaneous locomotion. This reduction observed as early as 15 min after injection was correlated with the typical rearing and cataleptic responses, and was reversed by co-administration of the CB1 cannabinoid receptor antagonist SR 141716A. Nevertheless, HU 210, but not CP 55,940, was found to induce persistent responses, lasting for at least 24 h. Also suggesting the involvement of additional targets for HU 210, 10 mg/kg SR 141716A failed to reverse the persistent HU 210-mediated decline in locomotion and rearing, while 1 mg/kg was sufficient to completely abolish the behavioural responses measured 6 h after the injection. Beside pharmacokinetic differences, these data therefore denote distinct pharmacodynamic profiles for HU 210 and CP 55,940. Together, these results suggest that HU 210 displays multicomponent responses that should be taken into account when interpreting data from in vivo/ex vivo studies.