Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors
Introduction
Cannabinoid compounds have been used by different cultures to improve mood since ancient times. For this reason, the study of the endocannabinoid system and cannabinoid derivatives has gained a great interest in anxiety/depression research (Bambico et al., 2007, Hill and Gorzalka, 2005, McLaughlin et al., 2007, Shearman et al., 2003).
In this regard, cannabidiol (CBD), the main non-psychotomimetic component of marijuana (Mechoulam et al., 2002), has shown anxiolytic properties both in humans and rodents (Bergamaschi et al., 2011, Guimaraes et al., 1990) after acute or chronic administration (Campos and Guimaraes, 2008, Campos et al., 2013b, Resstel et al., 2009). Nevertheless, little is known about its potential for treating depression. It was proposed as a putative novel antidepressant as it displayed positive responses in the forced swimming test (FST) (El-Alfy et al., 2010, Zanelati et al., 2010) and also in the novelty suppressed feeding test (NSF) under chronic stress conditions (Campos et al., 2013b). Furthermore, CBD exerts a positive impact on some neuroplasticity markers of antidepressant effects, such as increased brain-derived neurotrophic factor levels (Magen et al., 2010). It also restores the impaired neuroproliferation of chronically stressed animals (Campos et al., 2013b), and presents anti-inflammatory and immunomodulatory effects (Esposito et al., 2011, Malfait et al., 2000).
The mechanism of action of CBD has been extensively scrutinized (McPartland et al., 2015). This multifaceted drug produces different pharmacological actions modulating several receptors in the central nervous system (CNS) (CB1, CB2, 5-HT1A, TRPV1 and PPARγ receptors, among others) (Campos et al., 2013a, Campos et al., 2013b, Casarotto et al., 2010, Costa et al., 2004, Do Monte et al., 2013, Esposito et al., 2011, Pazos et al., 2013, Soares Vde et al., 2010, Thomas et al., 2007). Given the crosstalk among systems involved in mood control, the ability of CBD to modulate some of them, could result advantageous for the treatment of complex diseases like depression. Among all the above highlighted mechanisms, the CB1 and 5-HT1A receptors seem to be the most strongly implicated in the regulatory effects of CBD upon mood. CBD has been reported to act as an antagonist/inverse agonist of CB1 receptors (Thomas et al., 2007) and also to increase anandamide (AEA) levels (Bisogno et al., 2001, Leweke et al., 2012). It also exerts a positive allosteric modulation of 5-HT1A receptors rather than a direct agonism (Rock et al., 2012), a fact that could explain the unexpected key role of these serotonergic receptors in many of the effects of CBD. Pharmacological approaches with selective receptor antagonists showed that the acute anxiolytic-like and panicolytic-like properties of CBD are predominantly mediated by 5-HT1A receptors (Campos et al., 2013a, Campos and Guimaraes, 2008, Resstel et al., 2009, Soares Vde et al., 2010, Zanelati et al., 2010), whereas the anxiolytic-like effects induced by its chronic administration involving neurogenic actions, seem to be CB1-receptor dependent (Campos et al., 2013b).
Classical antidepressants act through serotonergic potentiation whereas the effects of fast-acting agents seem to be mediated by glutamatergic signalling (Du et al., 2006). However, there is scarce knowledge about the impact of CBD's administration on serotonergic and glutamatergic pathways. In this regard, 5-HT1A receptor is expressed within dorsal raphe nucleus (DRN) on 5-HTergic neurons and local GABAergic interneurons, where it controls 5-HT neuronal firing (Celada et al., 2001). They are also located in cortical interneurons and pyramidal cells modulating neurotransmitters efflux (Santana et al., 2004). In addition, endocannabinoid system is also strongly implicated in the control of 5-HT and glutamate release at different locations (Bambico et al., 2007, Bisogno et al., 2001, Brown et al., 2003, McLaughlin et al., 2012, Mendiguren and Pineda, 2009, Navarrete and Araque, 2008). Thus, the study of CBD's effects upon these pattern of neurotransmitter release would shed light on the mechanistic basis of the behavioural actions of CBD.
Herein, we have evaluated the behavioural and neurochemical actions of CBD in the olfactory bulbectomy mouse model of depression (OBX) (Linge et al., 2013), since its antidepressant efficacy under pathological conditions has not been investigated yet. Firstly, we assayed the behavioural effects induced by acute and chronic administration of CBD, and in parallel we performed microdialysis studies to assess the effects of CBD on the serotonin (5-HT) and glutamate dialysate output in the ventromedial prefrontal cortex (vmPFCx), a pivotal area for the behavioural outcome depending on the emotional status. In addition, the 5-HT1A receptor functionality ([35S]GTPγS autoradiography) following chronic administration of CBD was analysed in different brain areas, given their role in the mechanism of action of antidepressants. Finally, pharmacological antagonism studies were performed to determine the receptor implicated in the behavioural and neurochemical actions of CBD.
Section snippets
Animals and OBX surgery
Experiments were conducted with 3 month old male C57BL6 mice weighing 25–30 g. All procedures were carried out with the previous approval of the Animal Care Committee of the University of Cantabria and according to the Spanish legislation (RD 53/2013) and the European Communities Council Directive (2010/63/UE) on “Protection of Animals Used in Experimental and Other Scientific Purposes. All efforts were made to minimise animal suffering, to reduce the number of animals used, and to utilise
Results
Different regimes of administration were initially assayed to choose the most appropriate. The first dose of CBD evaluated (10 mg/kg/day, i.p.) produced a significant reversal of OBX-induced hyperactivity after 2 weeks of treatment (Supplementary Fig. S1). As shown later (Section 3.1.2; Fig. 2A), a higher dose of CBD (50 mg/kg/day, i.p.) induced a sustained hyperactivity reversal from the first injection but it significantly decreased sucrose consumption in half of sham animals, and a trend was
Discussion
In this paper we demonstrate for the first time that CBD exerts rapid antidepressant-like effects as evidenced by the reversal of OBX-induced hyperactivity immediately after the first injection. Moreover, its efficacy is maintained and improved with the repeated administration, as the anhedonia was completely relieved after one week of treatment. The dose adjustment appears to be particularly important for the fast antidepressant effects of CBD. Hence, we found that 10 mg/kg of CBD exerts
Conclusions
This work evidences that CBD could represent a novel drug for treating depressive disorders in a very fast manner, acting via the enhancement of serotonergic and glutamatergic transmission through the modulation of 5-HT1A receptors. The fast onset of antidepressant action of CBD and the simultaneous anxiolytic effect would solve some of the main limitations of the current antidepressant therapies. Furthermore, the broad range for therapeutic dosage and the lack of psychotomimetic effects
Author contributors
The bulk of the experimental work, data analysis and interpretation, and the draft of the paper was carried out by Raquel Linge. Laura Jiménez-Sánchez equally contributed to the microdyalisis experiments performance and related data analysis and interpretation. Leticia Campa analysed microdyalisis samples in the HLPC. Fuencisla Pilar-Cuéllar and Rebeca Vidal participated in autoradiography and behavioural protocols development and in data interpretation. Angel Pazos contributed to the study
Disclosure
The authors declare no conflict of interest.
Acknowledgments
This research was supported by Spanish Ministry of Economy and Competitiveness (SAF2011-25020), Instituto de Salud Carlos III (FIS Grant PI13-00038) co-funded by the European Regional Development Fund (‘A way to build Europe’) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). Raquel Linge Méndez is a recipient of a predoctoral research contract of the Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) and Laura Jiménez-Sánchez a predoctoral fellowship from the
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- 1
Present address: Departamento de Fisiología y Farmacología, Universidad de Cantabria, Spain.
- 2
Present address: Departamento de Pediatría y Neonatología, FIB, Puerta de Hierro.
- 3
Present address: Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), 39011 Santander, Spain.
- 4
Present address: Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.