Effects of cannabidiol plus sertraline on behavioural and gene
expression alterations in a long-lasting animal model of post-traumatic
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.