Serotonin and glutamate release in medial prefrontal cortex after cannabidiol treatment

Abstract

Cannabinoids constitute a family of compounds that have been used from ancient times to improve mood and therefore they have been proposed as a putative new treatment for emotional disorders. In this sense, Cannabidiol (CBD), the major non-psychotomimetic compound present in marihuana, has shown anxiolytic actions in humans and animals, both acute and chronically, and it also displays a positive response in acute antidepressant predictive paradigms such as the forced swimming test. Nevertheless, the mechanism of action of this promising drug remains unclear. Due to the strong implication of serotonin and glutamate systems in mood disorders, the study of CBD actions upon their release in brain areas crucial in emotional disorders, results of a great interest. In this work, we aimed to investigate the effect of CBD administration in serotonin (5-HT) and glutamate (Glu) release in the infralimbic medial prefrontal cortex (IL-mPFCx) after acute and chronic treatments, in the olfactory bulbectomy (OBX), an animal model of comorbid anxiety and depression. For this purpose, OBX or sham-operation was conducted in half of the animals and they were administered CBD or vehicle resulting in four experimental groups, and divided in two series for different duration treatments. Concentric dialysis probes were implanted in the IL-mPFCx under sodium pentobarbital anesthesia and neurotransmitters were determined by HPLC coupled to electrochemical (5-HT) and fluorimetric (Glu) detection. The results demonstrated that a single injection of CBD produced a significant increase in 5-HT release only in OBX animals, while no effect was observed in the sham counterparts. Glutamate dialysate levels were augmented after CBD, both in sham and OBX mice. Interestingly, chronic treatment with CBD produced an increment of 5-HT local efflux in OBX animals, but also in their sham counterparts. However, the Glu efflux increase in response to CBD injection was only preserved in OBX animals after chronic treatment. Taking together, these results indicate that one injection of CBD affects serotonin release in mPFCx under pathologic conditions, and that it modulates the serotonin system when chronically administered in sham animals. Regarding the glutamate system, CBD injection prompts immediate glutamate facilitation in all animals studied, although in chronic administration, sham animals probably adapt their system to counteract the continuous increment in glutamate, whereas OBX animals lack this ability of keeping brain glutamatergic homeostasis.