https://doi.org/10.1177/0269881118784877 Journal of Psychopharmacology 1–10 © The Author(s) 2018 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881118784877 journals.sagepub.com/home/jop Introduction The plant Cannabis sativa has been widely used throughout his- tory for recreational purposes due to its wide-range of psychoac- tive effects that include relaxation and reflexive state (Johns, 2001). Additionally, the therapeutic interest in the plant, as well as in its isolated compounds, has grown after the identification of its active components and the discovery of the endocannabinoid system (Mechoulam and Parker, 2013). Δ 9 -THC is the primary responsible for the herb psychoactive effects whereas cannabid- iol (CBD) is a non-psychotomimetic compound whose therapeu- tic potential has been explored in clinical and preclinical studies (Hill et al., 2012). CBD has been the focus of intense scientific investigation due to its tolerability, security, and lack of addictive properties (Izzo et al., 2009). Preclinical evidence indicates that CBD can be useful in a variety of disorders affecting the central nervous system (CNS), such as Alzheimer's disease, schizophre- nia, anxiety, and depression (Guimarães et al., 1990; Martín- moreno et al., 2011; Moreira and Guimarães, 2005; Zanelati et al., 2010; Zuardi et al., 1993, 1995). The antidepressant-like effect induced by systemic adminis- tration of CBD was initially demonstrated by our group in mice exposed to the forced swim test (FST; Zanelati et al., 2010), an effect later confirmed by others (El-Alfy et al., 2010; Linge et al., 2016; Réus et al., 2011; Schiavon et al., 2016; Shoval et al., 2016). More recently, we demonstrated that local administration of CBD into the ventromedial prefrontal cortex (PFC) induced antidepressant-like effects (Sartim et al., 2016), thus implicating Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test Ariandra G Sartim 1 , Amanda J Sales 2 , Francisco S Guimarães 2,3,5 and Sâmia R. L. Joca 1,3,4,5 Abstract Background: Cannabidiol is a non-psychotomimetic compound with antidepressant-like effects. However, the mechanisms and brain regions involved in cannabidiol effects are not yet completely understood. Brain-derived neurotrophic factor/tropomyosin-receptor kinase B/mammalian target of rapamycin (BDNF-TrkB-mTOR) signaling, especially in limbic structures, seems to play a central role in mediating the effects of antidepressant drugs. Aim: Since it is not yet known if BDNF-TrkB-mTOR signaling in the hippocampus is critical to the antidepressant-like effects of cannabidiol, we investigated the effects produced by cannabidiol (10/30/60 nmol/0.2 μL) micro-injection into the hippocampus of mice submitted to the forced swim test and to the open field test. Methods: Independent groups received intra-hippocampal injections of rapamycin (mTOR inhibitor, 0.2 nmol/0.2 μL) or K252 (Trk antagonist, 0.01 nmol/0.2 μL), before the systemic (10 mg/kg) or hippocampal (10 nmol/0.2μL) injection of cannabidiol, and were submitted to the same tests. BDNF levels were analyzed in the hippocampus of animals treated with cannabidiol (10 mg/kg). Results: Systemic cannabidiol administration induced antidepressant-like effects and increased BDNF levels in the dorsal hippocampus. Rapamycin, but not K252a, injection into the dorsal hippocampus prevented the antidepressant-like effect induced by systemic cannabidiol treatment (10 mg/ kg). Differently, hippocampal administration of cannabidiol (10 nmol/0.2 μL) reduced immobility time, an effect that was blocked by both rapamycin and K252a local microinjection. Conclusion: Altogether, our data suggest that the hippocampal BDNF-TrkB-mTOR pathway is vital for cannabidiol-induced antidepressant-like effect when the drug is locally administered. However, other brain regions may also be involved in cannabidiol-induced antidepressant effect upon systemic administration. Keywords Cannabidiol, forced swim test, antidepressant, hippocampus, mammalian target of rapamycin signaling, stress 1 Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil 2 Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil 3 Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil 4 Translational Neuropsychiatry Unit (TNU), Aarhus University, Denmark 5 National Institute of Science and Translational Medicine, (INCT), Ribeirão Preto, Brazil Corresponding author: Sâmia Joca, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP), Café Av, s/n, 14040-903, Ribeirão Preto, SP, Brazil. Email: samia@usp.br 784877JOP 0 0 10.1177/0269881118784877Journal of PsychopharmacologySartim et al. research-article 2018 Original Article