Differential behavioural effects of intra-infralimbic and intra-DRN infusion of cannabidiol : unravelling the molecular mechanisms
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Rationale. Systemic administration of cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is able to induce a rapid and maintained antidepressant effect. Both the medial prefrontal cortex (mPFCx) and and more specifically the infralimbic cortex (IL), the dorsal raphe nucleus (DRN) have been related to the actions of antidepressants. However, the contribution of each particular area to CBD actions and the underlying molecular mechanisms remain to be elucidated. Objectives. (1) To compare the acute behavioural effects of the local infusion of CBD (60 nm) in the mPFCx (bilateral injection in IL region) and in the DRN of rats, using the open field (OF) and forced swimming (FST) paradigms. (2) To investigate the effect of CBD on the expression of those neuroplasticity biomarkers in the mPFCx that are reported to be associated to fast antidepressant actions, using western blot techniques. (3) To assess the molecular interaction of CBD with those 5-HT1A receptors located in postsynaptic (mPFCx) and presynaptic (DRN) areas, using [35S]GTPγS techniques Results. Intra-IL, but not intra-DRN, infusion of CBD reduced immobility in the FST, mainly by increasing the swimming behaviour. No significant changes were observed in the different parameters evaluated in the OF (total distance, central activity). This behavioural outcome induced by intra-IL infusion of CBD was associated with an increased BDNF and mTOR signalling in the mPFCx. [35S]GTPγS studies revealed the positive allosteric modulation of CBD upon cortical 5-HT1A heteroreceptors, but not 5-HT1A autoreceptors. Conclusion. These results show that the IL prefrontal cortex appears to be the preferential brain area involved in the antidepressant effect of CBD. Intra-IL, but not intra-DRN, was followed by an increased expression of those neuroplasticity proteins that are associated to fast antidepressant actions. In addition, CBD appears to exhibit a positive allosteric modulation upon 5-HT1A heteroreceptors.