Background: Accumulating evidence suggests that cannabidiol (CBD) may be an effective and safe anxiolytic agent and potentially also an antidepressant. Aim: The objective of this study was to further examine these properties of CBD using the ‘depressive-like' Wistar-Kyoto (WKY) rat, focusing on the drug's effect on anhedonia-like behaviors. Methods: Forty-eight WKY and 48 control Wistar adult male rats were pretreated orally with CBD (15, 30 and 45 mg/kg) or vehicle. The saccharin preference test (SPT), the elevated plus maze (EPM) test and the novel object exploration (NOE) test were used. Results: CBD showed a prohedonic effect on the WKY rats at 30 mg/kg in the SPT. In the NOE, CBD increased exploration of the novel object and locomotion at 45 mg/kg and increased locomotion at 15 mg/kg, indicating an improvement in the characteristically low motivation of WKY rats to explore. There was no similar effect at any dose in the EPM or in open-field behavior in the habituation to the NOE. Conclusions: These findings extend the limited knowledge on the antidepressant effect of CBD, now shown for the first time in a genetic animal model of depression. These results suggest that CBD may be beneficial for the treatment of clinical depression and other states with prominent anhedonia.

Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW: Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 1990;100:558-559.
Moreira FA, Guimaraes FS: Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 2005;512:199-205.
Resstel LB, Joca SR, Moreira FA, Correa FM, Guimaraes FS: Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res 2006;172:294-298.
Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS: 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 2009;156:181-188.
Campos AC, Ortega Z, Palazuelos J, Fogaca MV, Aguiar DC, Diaz-Alonso J, et al: The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 2013;16:1407-1419.
ElBatsh MM, Assareh N, Marsden CA, Kendall DA: Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology (Berl) 2012;221:239-247.
Crippa JA, Zuardi AW, Martin-Santos R, Bhattacharyya S, Atakan Z, McGuire P, et al: Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol 2009;24:515-523.
Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al: Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 2011;36:1219-1226.
Vinod KY, Hungund BL: Role of the endocannabinoid system in depression and suicide. Trends Pharmacol Sci 2006;27:539-545.
Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR: Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 2010;159:122-128.
El-Alfy AT, Ivey K, Robinson K, Ahmed S, Radwan M, Slade D, et al: Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacol Biochem Behav 2010;95:434-442.
Malkesman O, Weller A: Two different putative genetic animal models of childhood depression - a review. Prog Neurobiol 2009;88:153-169.
Overstreet DH: Modeling depression in animal models. Methods Mol Biol 2012;829:125-144.
Dugovic C, Solberg LC, Redei E, Van RO, Turek FW: Sleep in the Wistar-Kyoto rat, a putative genetic animal model for depression. Neuroreport 2000;11:627-631.
Castagne V, Moser P, Roux S, Porsolt RD: Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci 2011;8:8.10A.
Beck KD, Jiao X, Pang KC, Servatius RJ: Vulnerability factors in anxiety determined through differences in active-avoidance behavior. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:852-860.
McAuley JD, Stewart AL, Webber ES, Cromwell HC, Servatius RJ, Pang KC: Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis. Behav Brain Res 2009;204:162-168.
Vinod KY, Xie S, Psychoyos D, Hungund BL, Cooper TB, Tejani-Butt SM: Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats. PLoS One 2012;7:e36743.
Jennings EM, Okine BN, Olango WM, Roche M, Finn DP: Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains. Prog Neuropsychopharmacol Biol Psychiatry 2016;64:181-189.
Malkesman O, Braw Y, Maayan R, Weizman A, Overstreet DH, Shabat-Simon M, et al: Two different putative genetic animal models of childhood depression. Biol Psychiatry 2006;59:17-23.
Hales CA, Stuart SA, Anderson MH, Robinson ES: Modelling cognitive affective biases in major depressive disorder using rodents. Br J Pharmacol 2014;171:4524-4538.
Gaoni Y, Mechoulam R: The isolation and structure of δ-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc 1971;93:217-224.
Pellow S, Chopin P, File SE, Briley M: Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985;14:149-167.
Goodwin GA, Yacko H: Emergence of the exploratory motive in rats. Dev Psychobiol 2004;45:34-48.
Cuthbert BN: The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry 2014;13:28-35.
Bedwell JS, Gooding DC, Chan CC, Trachik BJ: Anhedonia in the age of RDoC. Schizophr Res 2014;160:226-227.
Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, et al: Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl) 2012;219:859-873.
Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al: Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2012;2:e94.
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