Male and female rats differ in brain cannabinoid CB1 receptor density and function and in behavioural traits predisposing to drug addiction: effect of ovarian hormones.

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 [(3)H]CP55940 and CP55940-stimulated [(35)S]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 [(35)S]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.

Baclofen prevents drug-induced reinstatement of extinguished nicotine-seeking behaviour and nicotine place preference in rodents.

The gamma-aminobutyric acid(GABA)-B receptor agonist baclofen is known to reduce drug intake in both animals and humans and to prevent reinstatement of cocaine-, opioid-, and alcohol-seeking in rats after a period of extinction, but its effect on nicotine reinstatement is unknown. This study investigated the effect of baclofen on nicotine-seeking reinstatement both using the extinction/reinstatement model of nicotine self-administration and conditioned place preference (CPP). Results showed that in rats previously trained to intravenously self-administer nicotine (30 microg/kg/inf) under a FR-1 schedule of reinforcement, acute nicotine (0.15 mg/kg) priming effectively reinstates nicotine-seeking behaviour following extinction. At doses used in this study (up to 2.5 mg/kg) baclofen alone did not affect locomotor activity and did not reinstate responding. However, baclofen dose-dependently attenuated drug-induced reinstatement of nicotine-seeking in rats. Moreover, baclofen (1.25 mg/kg) completely blocked nicotine-induced reinstatement of extinguished nicotine (0.3 mg/kg) CPP in mice. Altogether, our results showed that baclofen is able to antagonise reinstatement of nicotine-seeking and CPP triggered by nicotine primings, suggesting its potential clinical utility as an anti-relapse agent.