Sex and estrous cycle-linked differences in the effect of cannabidiol on panic-like responding in rats and mice

Clinical and preclinical studies point towards anxiolytic actions of cannabidiol (CBD), but its effect in panic disorder has been less explored and few studies consider effects in females. We here compared the effect of CBD on the response of male and female rats and mice to a panicogenic challenge; exposure to low O₂ (rats) or high CO₂ (mice) paying attention in females to possible effects of estrous cycle phase. Male and female Sprague-Dawley rats and C57BL/6 J mice were exposed to 7% O₂ for 5 min (rats) or 20% CO₂ (mice) and escape behaviour, which has been associated with panic attacks, was quantified as undirected jumps towards the gas chamber's ceiling. The effect of pretreatment with CBD (1-10 mg kg^-1 i.p. in rats or 10-60 mg kg^-1 i.p. in mice) was tested. The results showed that low O₂ (rats) or high CO₂ (mice) evoked escape in both sexes. In female rats the response was estrous cycle-sensitive: females in late diestrus made significantly more jumps than females in proestrus. In female mice escape was not influenced by estrous cycle phase and CBD was panicolytic. In female rats CBD attenuated escape behaviour in late diestrus phase but not in proestrus. In male rats and mice CBD had no effect on escape behaviour. Therefore, CBD is panicolytic in female rats and mice but not in males. In rats the effect is estrous cycle-sensitive: rats were most responsive to CBD in late diestrus. In mice higher doses were required to elicit effects and estrous cycle had no effect.