Sex-dependent differences are frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. We recently demonstrated a modulating effect of sex and oestrous cycle on cannabinoid-taking and seeking behaviours. Here, we investigated the influence of sex and oestrogen in the regulation of cannabinoid CB1 receptor density and function, measured by [³H]CP55940 and CP55940-stimulated [³⁵S]GTPγS binding autoradiography, respectively, in the prefrontal cortex (Cg1 and Cg3), caudate- putamen, nucleus accumbens, amygdala and hippocampus of male and cycling female rats, as well as ovariectomised (OVX) rats and OVX rats primed with oestradiol (10 µg/rat) (OVX+E). CB1 receptor density was significantly lower in the prefrontal cortex and amygdala of cycling females than in males and in OVX females, a difference that appeared to be oestradiol-dependent, because it was no more evident in the OVX+E group. CP55940-stimulated [³⁵S]GTPγS binding was significantly higher in the Cg3 of OVX rats relative to cycling and OVX+E rats. No difference was observed in CB1 receptor density or function in any of the other brain areas analysed. Finally, sex and oestradiol were also found to affect motor activity, social behaviour and sensorimotor gating in rats tested in locomotor activity boxes, social interaction and prepulse inhibition tasks, respectively. Our findings provide biochemical evidence for sex- and hormone- dependent differences in the density and function of CB1 receptors in selected brain regions, and in behaviours associated with greater vulnerability to drug addiction, revealing a more vulnerable behavioural phenotype in female than in male rats.

Background and purpose:  Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food‐seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation.Experimental approach:  A standard fasted protocol and a novel long‐term home‐cage observation system with free‐feeding animals were used to assess the feeding behaviour of mice treated with the CB₁ antagonist AM251. Similarly, the effects of the phytocannabinoid Δ⁹‐tetrahydrocannabivarin (Δ⁹‐THCV), which behaves like a CB₁ antagonist, were also determined in free‐feeding animals.Key results:  AM251 suppressed food intake and weight gain in fasted and non‐fasted animals. The suppression of food intake by AM251 (10 mg·kg⁻¹) endured for a period of 6–8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Δ⁹‐THCV also induced hypophagia and weight reduction at doses as low as 3 mg·kg⁻¹. No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Δ⁹‐THCV‐rich cannabis‐extract failed to suppress food intake and weight gain, possibly due to residual Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC) in the extract. This Δ⁹‐THC effect was overcome by the co‐administration of cannabidiol.Conclusions and implications:  The data strongly suggest (i) the long‐term home‐cage observation system is a sensitive and obesity‐relevant tool, and (ii) the phytocannabinoid Δ⁹‐THCV is a novel compound with hypophagic properties and a potential treatment for obesity.