Background and purpose. The purpose of this study was to evaluate the effects of CBD on the behavioural and gene expression changes induced by a new animal model of spontaneous cocaine withdrawal. Experimental approach. Six hours after cessation of progressive increase of cocaine administration for 12 days (15 mg·kg-1·day-1 to 60 mg·kg-1·day-1, i.p.), spontaneous cocaine withdrawal was evaluated in male mice. The effects of CBD (10, 20 and 40 mg·kg-1, i.p.) were evaluated on cocaine withdrawal-induced alterations in motor activity, somatic signs and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens were analysed by real-time PCR. Key results. Mice exposed to the spontaneous cocaine withdrawal model showed increased motor activity, somatic withdrawal signs and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal. In addition, the administration of CBD modulated the cocaine withdrawal-induced decrease of CNR1 and induced an additional up-regulation of CNR2 gene expression. Conclusions and implications. These results show behavioural and gene expression alterations in mice exposed to a new model of spontaneous cocaine withdrawal. Interestingly, CBD alleviates cocaine withdrawal-induced behavioural and gene expression alterations suggesting potential for the management of cocaine withdrawal.
Background and purpose. This study evaluated the effects of cannabidiol (CBD) and/or sertraline (STR) on behavioural and gene expression alterations induced by a new chronic animal model of post-traumatic stress disorder (PTSD). Experimental approach. C57BL/6J male mice were repeatedly exposed to physical and psychogenic alternate and unpredictable stressful stimuli. Fear-related memory and anxiety-like behaviours were evaluated. The effects of the administration of CBD (20 mg·kg-1, i.p.) and/or STR (10 mg·kg-1, p.o.) were analysed on behavioural and gene expressions changes induced by the model of PTSD. Gene expression changes of targets related with stress regulation, endocannabinoid and serotonergic systems were analysed by real-time PCR. Key results. Mice exposed to the animal model of PTSD showed increased and long-lasting fear-related memory and anxiety-like behaviours. CBD improved fear extinction and anxiety-like behaviour in PTSD animals significantly potentiated when combined with STR. Gene expression analyses revealed a long-term increase of corticotropin releasing factor (CRF) that was significantly normalized with the combination CBD plus STR. Cannabinoid receptors (CB1r and CB2r) were up regulated in PTSD mice whereas the serotonin transporter (5HTT) was reduced. Interestingly, CBD and STR alone or combined induced a significant and marked increase of 5HTT gene expression. Conclusions and implications. These results reveal the synergistic action of the combination CBD plus STR to enhance fear extinction and reduce anxiety-like behaviours, and to normalize gene expression alterations in the long-lasting animal model of PTSD. Taken together, CBD or the combination with STR deserves to be explored for the treatment of PTSD patients.