Female but not male rats show biphasic effects of low doses of Δ-tetrahydrocannabinol on anxiety: can cannabidiol interfere with these effects?

Δ-tetrahydrocannabinol (THC) is the main phytocannabinoid present in the Cannabis sativa. It can produce dose-dependent anxiolytic or anxiogenic effects in males. THC effects on anxiety have scarcely been studied in females, despite their higher prevalence of anxiety disorders. Cannabidiol, another phytocannabinoid, has been reported to attenuate anxiety and some THC-induced effects. The present study aimed to investigate the behavioral and neurochemical effects of THC administered alone or combined with CBD in naturally cycling female rats tested in the elevated plus-maze. Systemically administered THC produced biphasic effects in females, anxiolytic at low doses (0.075 or 0.1 mg/kg) and anxiogenic at a higher dose (1.0 mg/kg). No anxiety changes were observed in males treated with the same THC dose range. The anxiogenic effect of THC was prevented by co-administration of CBD (1.0 or 3.0 mg/kg). CBD (3.0 mg/kg) caused an anxiolytic effect. At a lower dose (1.0 mg/kg), it facilitated the anxiolytic effect of the low THC dose. The anxiogenic effect of THC was accompanied by increased dopamine levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). In contrast, its anxiolytic effect was associated with increased mPFC serotonin concentrations. The anxiolytic effect of CBD was accompanied by increased mPFC serotonin turnover. Together, these results indicate that female rats are susceptible to the biphasic effects of low THC doses on anxiety. These effects could depend on mPFC and NAc dopaminergic and serotoninergic neurotransmissions. CBD could minimize potential THC high-dose side effects whereas enhancing the anxiolytic action of its low doses in females.