Cannabidiol enhancement of serotonergic and glutamatergic signalling in a mouse model of depression induces fast and maintained antidepressant actions : implication of 5-HT 1 A receptors

Cannabidiol (CBD), the main non-psychomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated CBD effects following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following CBD treatment. We also assayed the pharmacological antagonism of CBD effects to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that CBD administration significantly enhanced serotonin and glutamate release in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters release occurring immediately after the first injection of CBD might underlie the fast antidepressantlike actions in OBX mice. Both antidepressant-like effect and enhanced 5HT/glutamate cortical release induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in preand post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism.