title: Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.
abstract: Cannabidiol (CBD), the main non-psychotomimetic 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 the effects of CBD 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 treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD 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 the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and 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.
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Linge
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain; Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, IDIBAPS, 08036, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Jiménez-Sánchez
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain; Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, IDIBAPS, 08036, Barcelona, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Campa
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Pilar-Cuéllar
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Pazos
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain; Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, IDIBAPS, 08036, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Adell
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain. Electronic address: alvaro.diaz@unican.es.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Díaz
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D002185:Cannabidiol / Q000008:administration & dosage*; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009830:Olfactory Bulb / Q000601:surgery; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D044282:Receptor, Serotonin, 5-HT1A; D002185:Cannabidiol; D012701:Serotonin; D018698:Glutamic Acid
keywords: (−)Cannabidiol (PubChem CID: 12302390); 5-HT(1A) receptor; AM251 (PubChem CID: 2125); Antidepressant; Cannabidiol; Glutamate; Olfactory bulbectomy; Serotonin; WAY-100635 maleate salt (PubChem CID: 11957721)