British Journal of Pharmacology

Volume 159, Issue 1 p. 122-128

RESEARCH PAPER

Free Access

Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT_1A receptors

TV Zanelati,

TV Zanelati

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil,

These authors contributed equally to this work.

Search for more papers by this author

C Biojone,

C Biojone

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil,

These authors contributed equally to this work.

Search for more papers by this author

FA Moreira,

FA Moreira

Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte-MG, Brazil, and

Search for more papers by this author

FS Guimarães,

FS Guimarães

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil,

Search for more papers by this author

SRL Joca,

Corresponding Author

SRL Joca

Laboratory of Pharmacology, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, SP, Brazil

Dr Sâmia R. L. Joca, Laboratory of Pharmacology, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, 14040-903, Brazil. E-mail: [email protected]Search for more papers by this author

TV Zanelati,

TV Zanelati

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil,

These authors contributed equally to this work.

Search for more papers by this author

C Biojone,

C Biojone

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil,

These authors contributed equally to this work.

Search for more papers by this author

FA Moreira,

FA Moreira

Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte-MG, Brazil, and

Search for more papers by this author

FS Guimarães,

FS Guimarães

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil,

Search for more papers by this author

SRL Joca,

Corresponding Author

SRL Joca

Laboratory of Pharmacology, Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, SP, Brazil

First published: 19 January 2010

https://doi.org/10.1111/j.1476-5381.2009.00521.x

Citations: 275

About

Sections

PDF

Tools

Share a link

Email
Facebook
Twitter
LinkedIn
Reddit
Wechat

Abstract

Background and purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT_1A receptors. As 5-HT_1A receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT_1A receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).

Experimental approach: Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg·kg⁻¹), imipramine (30 mg·kg⁻¹) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg·kg⁻¹, i.p.), a 5-HT_1A receptor antagonist, before CBD (30 mg·kg⁻¹) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg·kg⁻¹) and submitted to the forced swimming test.

Key results: CBD (30 mg·kg⁻¹) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg·kg⁻¹) treatment did not change hippocampal BDNF levels.

Conclusion and implications: CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT_1A receptors.

Abbreviations:

CBD: cannabidiol
BDNF: brain derived neurotrophic factor
Δ⁹-THC: Δ⁹-tetrahydrocannabinol

Introduction

Extracts of the Cannabis sativa plant elicit in humans a complex subjective experience that includes euphoria, heightened sensitivity to external stimuli and relaxation (Johns, 2001). This plant contains more than 400 different compounds, of which 66 are termed cannabinoids. Δ⁹-tetrahydrocannabinol (Δ⁹-THC), one of the major constituents of C. sativa extracts (Mechoulam, 1970), is thought to account for most of the effects of cannabis through the activation of cannabinoid CB₁ receptors in the brain (Huestis et al., 2001; nomenclature follows Alexander et al., 2008). The major endogenous agonists of the CB₁ receptor are anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids (Piomelli, 2003). Anandamide is removed from the synaptic space by a putative neuronal uptake mechanism (Alger, 2004) and is inactivated intracellularly by the enzyme fatty acid amide hydrolase (Di Marzo et al., 1999).

It has recently been suggested that the endocannabinoid system may be involved in the pathophysiology of depression (Hill and Gorzalka, 2005). This is supported by several pieces of evidence showing that endocannabinoids and CB₁ receptors are widely distributed in brain areas that are often related to affective disorders (Devane, 1988) and that their expression is regulated by antidepressant drugs (Hill et al., 2008). Moreover, administration of inhibitors of anandamide uptake or metabolism, as well as CB₁ receptor agonists induces antidepressant-like effects in different animal models (Hill and Gorzalka, 2005; Adamczyk et al., 2008). In accordance with these preclinical results, many patients report benefits from cannabis use in depressive syndromes (Gruber et al., 1996; Ware et al., 2005), although clinical trials of its use in affective disorders have yielded mixed results (Robson, 2001; Degenhardt et al., 2003).

Cannabidiol (CBD) is another major component of C. sativa that exhibits a somewhat different pharmacology compared with that of Δ⁹-THC (Mechoulam et al., 2007). CBD is usually described as a non-psychoactive compound that inhibits some behavioural effects of Δ⁹-THC, such as catalepsy in rats (Formukong et al., 1988) and psychotomimetic and anxiogenic effects in humans (Zuardi et al., 1982). CBD, however, has been shown to induce antipsychotic- and anxiolytic-like activity in preclinical and clinical studies (Zuardi et al., 1982; 2006; Guimarães et al., 1990; Resstel et al., 2006). More recently, our group showed that systemic administration of CBD was able to attenuate the development of stress-induced behavioural consequences (Resstel et al., 2009), raising the possibility that CBD could also be useful for treating psychiatric disorders thought to involve impairment of stress-coping mechanisms, such as depression.

The mechanism of action of CBD is not fully understood. This compound has a low affinity for CB receptors (Petitet et al., 1998; Thomas et al., 1998), although it may block the reuptake of anandamide (Bisogno et al., 2001) and inhibit fatty acid amide hydrolase (Watanabe et al., 1998). Moreover, Russo and colleagues (2005) reported that CBD may exhibit agonist properties at 5-HT_1A receptors. In fact, recent work has shown that several CBD effects can be blocked by pretreatment with 5-HT_1A receptor antagonists (Hayakawa et al., 2007; Campos and Guimarães, 2008; Resstel et al., 2009).

Although activation of 5-HT_1A receptors has been consistently related to the therapeutic effect of antidepressant drugs (Savitz et al., 2009), a link between these receptors and antidepressant-like effect of CBD has not yet been investigated. Therefore, the aim of this work was to test the hypothesis that CBD would induce antidepressant-like effects in mice submitted to the forced swimming test and that this effect would involve the activation of 5-HT_1A receptors. In addition, considering the recent pieces of evidence relating the effects of antidepressant drugs with increased hippocampal expression of brain derived neurotrophic factor (BDNF) (see Saaralainen et al., 2003; Duman and Monteggia, 2006) and that activation of 5-HT_1A receptors regulates antidepressant-induced hippocampal BDNF expression (Ivy et al., 2003), we also investigated if CBD-induced behavioural effects in the forced swimming test would be associated with changes in BDNF expression in the hippocampus.

Methods

Animals

All animal care was in conformity with the Brazilian Society of Neuroscience and Behavior guidelines for the care and use of laboratory animals, which are in compliance with international laws. The experimental protocols were approved by the local Ethical Committee of the School of Medicine of Ribeirão Preto, University of Sao Paulo. Male Swiss mice (20–25 g) were provided by our local animal farm facility. After arriving at the Animal Care Unit of the Department of Pharmacology, School of Medicine of Ribeirão Preto, University of Sao Paulo, the animals were housed in groups of 6–10 animals per cage (570 cm²), in a temperature-controlled room (24 ± 1°C) under standard laboratory conditions with free access to food and water and a 12 h light/12 h dark cycle (lights on at 06:30h).

Forced swimming test

The forced swimming test was performed as described by Porsolt et al. (1977) with minor modifications. Mice were placed individually into glass cylinders (height 25 cm, diameter 17 cm) containing 10 cm of water maintained at 23–25°C. The animals were left in the cylinder for 6 min and the total duration of immobility was measured during the last 4 min period. Mice were considered to be immobile when they remained floating passively, performing only slow movements to keep their head above the water. The water was changed after each trial to avoid the influence of alarm substances (Abel and Bilitzke 1990). All experiments were videotaped and the immobility time was subsequently scored by an observer unaware of the treatments.

Exploratory activity

The test was performed according to Moreira and Guimarães (2005). Briefly, the animals were placed in a circular open field arena (40 cm in diameter with a 50 cm high Plexiglas wall) where the exploratory activity was videotaped during 6 min. The behaviour was analysed with the help of the Ethovision software (version 1.9; Noldus, the Netherlands). This software detects the position of the animal in the open field arena and calculates the distance moved.

Protein extraction and BDNF measurements

Immediately after the forced swimming test, mice were deeply anaesthetized (urethane 25%, 5 mL·kg⁻¹), killed by decapitation and their hippocampi removed. The left and right hippocampus were homogenized in lysis buffer (NaCl 137 mM; Tris-HCl 20 mM pH 7.6; glycerol 10%) containing protease inhibitor cocktail (Sigma, St. Louis, MO, USA) and, after centrifugation (5600×g, 15 min), the supernatant was stored at −80°C. Hippocampal BDNF was measured by ELISA (BDNF Emax^® ImmunoAssay System kit, Promega, Madison, WI, USA) according to the manufacture's instructions. Total proteins levels were measured by the Bradford method (Bradford 1976; Sapan et al. 1999) and used to normalize the samples.

Experimental design

Experiment 1. Mice received i.p. injections of CBD (3, 10, 30, 100 mg·kg⁻¹), imipramine or vehicles and were submitted to the forced swimming test. Independent groups of mice received CBD at the same doses or its vehicle and were submitted to the open field arena.

Experiment 2. Mice received i.p. injections of WAY100635 or saline followed, 30 min later, by a second injection of CBD (30 mg·kg⁻¹) or vehicle and they were exposed to the forced swimming test, 30 min later.

Experiment 3. Independent groups of mice received i.p. injections of CBD (30 mg·kg⁻¹), imipramine (30 mg·kg⁻¹) or vehicle and were submitted to the forced swimming test as described above. Immediately afterwards, the animals were anaesthetized and killed. Their hippocampi were removed and processed for ELISA measurements of BDNF content. This time point was chosen for BDNF measurements as an attempt to correlate BDNF levels at the moment of the test with the behavioural effects induced by the drug treatments (Takeda et al., 2006; Rantamäki et al., 2007; Shieh et al., 2008).

In all experiments the animals were submitted to the behavioural test 30 min after the last drug injection.

Data analysis

The Kolmogorov-Smirnov and Levene tests were initially employed to ensure that the data satisfied the criteria for carrying out anova. The behavioural data were expressed as means ± SEM. The immobility time in the first and third experiments was analysed using one-way anova followed by Duncan's post hoc test. The distance moved in the open field arena was analysed by repeated measure analysis of variance with time (1–6 min) as the within-subjects factor and drug as the between-subjects factor. Box's epsilon function was employed to correct the degree of freedom of the repeated factors. Experiment two was analysed by two-way anova using the first (WAY100635 or saline) and the second (CBD or vehicle) injections as main factors. In case of significant interaction between factors the treatment groups were compared using a one-way anova followed by Duncan's post hoc test. For experiment three, BDNF levels were normalized to the total protein content and expressed as mean ± SEM. The results were compared using one-way anova. The significance level was set at P < 0.05.

Materials

CBD (kindly supplied by THC-Pharma, Frankfurt, Germany): 3, 10, 30, 100 mg·kg⁻¹; imipramine hydrochloride (Sigma, St. Louis, MO, USA): 30 mg·kg⁻¹ (dose based on Poleszak et al., 2005); WAY100635 (WAY, Sigma, St. Louis, MO, USA): 0.1 mg·kg⁻¹ (dose based on Kaster et al., 2005). Imipramine and WAY100635 were dissolved in sterile isotonic saline solution and CBD was suspended in polyoxyethylenesorbitan monooleate (Tween 80) 2%-saline. The solutions were prepared immediately before use and injected i.p. in a volume of 10 mL·kg⁻¹.

Results

Effects of CBD or imipramine treatment in the forced swimming test and in the open field arena

There was a significant treatment effect in the forced swimming test (F_6,59= 3.89, P < 0.01), with imipramine and CBD (30 mg·kg⁻¹) significantly reducing the immobility time compared with the vehicle group (n= 8–12, Duncan P < 0.05; Figure 1).

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Cannabidiol (CBD, 30 mg·kg⁻¹) and imipramine (IMP, 15 mg·kg⁻¹) reduced immobility time in the forced swimming test. Mice (8–12/group) received i.p. injections of CBD (3–100 mg·kg⁻¹) or imipramine (IMP) and 30 min later were submitted to the forced swim. Data represent the mean ± SEM. * indicates P < 0.05 compared with vehicle group (anova followed by Duncan).

In the open field arena the distance travelled decreased over time (F_1,42= 49.12, P < 0.005), but there was no difference between drug treatment and vehicle at any dose tested (n= 8 per group; F_5,42= 0.59, P > 0.05). Also, no interaction was observed between time and treatment effects (F_5,42= 0.54, P > 0.05; Figure 2).

Effects of CBD (30 mg·kg⁻¹), alone or in combination with WAY100635, in the forced swimming test

There was a significant interaction between the first and second injections (F_1,48= 5.67, P= 0.02). Confirming results from the first experiment, saline + CBD (30 mg·kg⁻¹, n= 11) treatment reduced immobility time in the forced swimming test when compared with the saline + vehicle group (n= 16; Duncan P < 0.05). Effects of CBD were prevented by pre-treatment with WAY100635 (n= 8, WAY100635 + CBD vs. saline + CBD: Duncan P < 0.05). WAY100635 + vehicle (n= 17) treatment did not induce significant changes in immobility time when compared with saline + vehicle group (Duncan, P > 0.05). See Figure 3.

Effects of CBD (30 mg·kg⁻¹) or imipramine on hippocampal BDNF levels

As observed in the previous experiments, CBD (30 mg·kg⁻¹) and imipramine reduced the immobility time in the forced swimming test (F_2,19= 5.91, P < 0.05; Figure 4A). However, these treatments failed to change hippocampal BDNF levels (F_2,19= 0.013, P > 0.05; Figure 4B). Moreover, there was no correlation between immobility time and hippocampal BDNF levels (Pearson correlation, r= 0.33, n= 22, P > 0.05, data not shown).

Discussion

The present results show that CBD reduces immobility time in the forced swimming test to a similar extent as a prototype antidepressant, imipramine. Thus, this work is the first to suggest that CBD has a favourable profile in a model predictive of antidepressant-like activity (Porsolt et al., 1977). CBD, however, was effective only at the 30 mg·kg⁻¹ dose, with smaller or higher doses producing no effect.

Considering that the forced swimming test is a paradigm based on evaluation of motor activity, drugs that induce changes in this parameter could confound data interpretation. In the present study, none of the CBD doses tested modified the distance moved in the open field arena. This datum is in agreement with previous reports showing that, at the doses tested, CBD does not induce significant motor changes (Guimarães et al., 1990; Moreira and Guimarães, 2005). This indicates that the antidepressant-like effect of CBD is not secondary to changes in motor behaviour. The present results, therefore, suggest that, in addition to anxiolytic, hypnotic and antipsychotic effects (Zuardi et al., 1982; Guimarães et al., 1990; Resstel et al., 2006), CBD could also have antidepressant properties.

The precise mechanisms underlying the effects of CBD are not well understood. CBD has a low affinity for cannabinoid CB₁ receptors (Petitet et al., 1998; Thomas et al., 1998), but may indirectly affect the endocannabinoid system by blocking anandamide reuptake (Bisogno et al., 2001) and inhibiting its enzymatic hydrolysis (Watanabe et al., 1998). It has recently been proposed, in addition, that CBD could act as an agonist at 5-HT_1A receptors (Russo et al., 2005). These receptors have been consistently related to the neurobiology of depression and to the mechanism of action of antidepressant drugs (Graeff et al., 1996; Joca et al., 2003; Savitz et al., 2009).

In accordance with the proposed activity of CBD on 5-HT_1A receptors, the present study showed that the antidepressant-like effect of CBD is inhibited by pre-treatment with WAY100635, a selective 5-HT_1A receptor antagonist (Kaster et al., 2005), at a dose that did not produce any effect by itself. This suggests that CBD effects in the forced swimming test depend on activation of 5-HT_1A receptors. This is consistent with previous observation that neuroprotective (Hayakawa et al., 2007) and anxiolytic (Campos and Guimarães, 2008; Resstel et al., 2009) effects induced by CBD are sensitive to 5-HT_1A receptor antagonists.

The mechanisms by which 5-HT_1A receptors mediate adaptation to stress and induce antidepressant-like effects are not completely understood. 5-HT_1A receptors are located presynaptically (somatodendritic autoreceptors) in 5-hydroxytryptaminergic cell bodies in the raphe nuclei of the brain stem and post-synaptically, predominantly in limbic structures such as the hippocampus, hypothalamus, prefrontal cortex and amygdala (Chalmers and Watson, 1991). It has been suggested that stress and/or genetic factors might impair post-synaptic 5-HT_1A-mediated effects in limbic regions, such as the hippocampus, and predispose individuals to stress-induced behavioural consequences (Graeff et al., 1996). In fact, several studies have found reduced number and/or affinity of post-synaptic 5-HT_1A receptors in the brains of depressed individuals (Sargent et al., 2000; Szewczyk et al., 2009) and of animals submitted to stress (Flugge, 1995; van Riedel et al., 2003). On the other hand, the number of 5-HT inhibitory autoreceptors is increased (Stockmeier et al., 1998). In agreement with the proposed hypothesis, chronic antidepressant treatment is shown to facilitate post-synaptic 5-HT_1A receptor-mediated function (Haddjeri et al., 1998) and administration of 5-HT_1A receptor agonists into the hippocampus induces antidepressant-like effects in animal models, most likely by attenuating the emotional impact of aversive stimuli (Graeff et al., 1996; Joca et al., 2003; 2007). However, the mechanisms involved in 5-HT_1A receptor-mediated antidepressant effect are still a matter of debate. One possibility is that activation of 5-HT_1A receptors attenuates limbic hyperactivity, an effect that can be observed in stressed rats (Shumake et al., 2002) and depressed humans (Mayberg et al., 2000; Goldapple et al., 2004). This effect could involve attenuation of local glutamate release (Strosznajder et al., 1996).

In addition, antidepressant treatment may increase hippocampal neurogenesis and BDNF expression (see Duman and Monteggia, 2006), effects that are necessary for some of their behavioural effects (Santarelli et al., 2003; Saaralainen et al., 2003). However, it remains controversial whether their effects on stress-coping in the forced swimming test occur in parallel with increased BDNF expression. 5-HT_1A receptors are thought to mediate some of the trophic actions attributed to 5-HT, such as increased neurogenesis (Brezun and Daszuta, 1999; Radley and Jacobs, 2002) and BDNF release (Ivy et al., 2003). Thus, we tested whether imipramine and CBD would increase hippocampal BDNF. However, the present study failed to detect any effect of CBD or imipramine on this variable. Despite these results, BDNF involvement in imipramine- and CBD-induced effects may not be ruled out as, even if acute effects of antidepressants on BDNF-mediated transmission have already been described (Saaralainen et al., 2003; Rantamäki et al., 2007; Dzitoyeva et al., 2008; Shieh et al., 2008), several studies have shown increased hippocampal BDNF expression only after subchronic or chronic antidepressant treatments (Castrén et al., 2007). Experimental differences between studies, other than the treatment duration, might also have contributed to the observed results. For example, the use of extracts of the whole hippocampus could have masked treatment effects on BDNF levels, as molecular and functional differences among hippocampal subregions have been described (Bannerman et al., 2004; Datson et al., 2009). Moreover, the use of tissue homogenates impairs the distinction between intracellular and released BDNF pools and it is possible that only a small and local release of BDNF is required to cause behavioural effects (Saaralainen et al., 2003).

The antidepressant-like effects of CBD were only evident at the dose of 30 mg·kg⁻¹, with smaller or higher doses producing no effect. This inverted U-shape profile has been observed in several previous studies with CBD (Guimarães et al., 1990; Moreira et al., 2006) and is often observed with drugs that modulate the endocannabinoid system (Viveros et al., 2005). The mechanisms for this effect are not yet understood, but probably reflect the complex pharmacology of this compound. Among the possible mechanisms there is an interaction with TRPV1 vanilloid receptors. CBD can activate these receptors in µM concentrations (Bisogno et al., 2001) and they are expressed in several brain areas related to emotional responses such as the amygdala, hippocampus, prefrontal cortex and periaqueductal gray (Cristino et al., 2006). TRPV1 receptors can facilitate glutamate release (Palazzo et al. 2002) and glutamate receptor antagonists have been shown to induce antidepressant-like effects (Joca et al., 2007). Corroborating this possibility, activation of TRPV1 receptors has recently been implicated in the bell-shaped dose–response curve observed with the endocannabinoid anandamide, microinjected into the prefrontal cortex (Rubino et al., 2008).

In conclusion, the results of the present study showed that CBD induces antidepressant-like effects in the forced swimming test, suggesting for the first time that this compound may possess antidepressant properties. Moreover, this work also suggests that CBD-induced effects are probably mediated by facilitation of 5-HT_1A receptor-mediated neurotransmission.

Acknowledgements

The authors wish to thank J.C. Aguiar and E.L.T. Gomes for technical support and FAPESP and CNPq for financial support. We also thank THC-Pharma for the kind supply of CBD.

Conflicts of interest

The authors declare no conflicts of interest.

References

Abel EL, Bilitzke PJ (1990). A possible alarm substance in the forced swimming test. Physiol Behav 48: 233–239.
10.1016/0031-9384(90)90306-O
CASPubMedWeb of Science®Google Scholar
Adamczyk P, Gołda A, McCreary AC, Filip M, Przegaliński E (2008). Activation of endocannabinoid transmission induces antidepressant-like effects in rats. J Physiol Pharmacol 59 (2): 217–228.

CASPubMedWeb of Science®Google Scholar
Alexander SPH, Mathie A, Peters JA (2008). Guide to Receptors and Channels (GRAC), 3rd edition (2008 revision). Br J Pharmacol 153 (Suppl. 2): S1–S209.
10.1038/sj.bjp.0707746
PubMedWeb of Science®Google Scholar
Alger BE (2004). Endocannabinoids: getting the message across. Proc Natl Acad Sci USA 101: 8512–8513.
10.1073/pnas.0402935101
CASPubMedWeb of Science®Google Scholar
Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T et al. (2004). Regional dissociations within the hippocampus–memory and anxiety. Neurosci Biobehav Rev 28 (3): 273–283.
10.1016/j.neubiorev.2004.03.004
CASPubMedWeb of Science®Google Scholar
Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I et al. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134: 845–852.
10.1038/sj.bjp.0704327
CASPubMedWeb of Science®Google Scholar
Bradford MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254.
10.1016/0003-2697(76)90527-3
CASPubMedWeb of Science®Google Scholar
Brezun JM, Daszuta A (1999). Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89: 999–1002.
10.1016/S0306-4522(98)00693-9
CASPubMedWeb of Science®Google Scholar
Campos AC, Guimarães FS (2008). Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 199 (2): 223–230.
10.1007/s00213-008-1168-x
CASPubMedWeb of Science®Google Scholar
Castrén E, Võikar V, Rantamäki T (2007). Role of neurotrophic factors in depression. Curr Opin Pharmacol 7 (1): 18–21.
10.1016/j.coph.2006.08.009
CASPubMedWeb of Science®Google Scholar
Chalmers DT, Watson SJ (1991). Comparative anatomical distribution of 5-HT1A receptor mRNA and 5-HT1A binding in rat brain–a combined in situ hybridisation/in vitro receptor autoradiographic study. Brain Res 561: 51–60.
10.1016/0006-8993(91)90748-K
CASPubMedWeb of Science®Google Scholar
Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V (2006). Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139: 1405–1415.
10.1016/j.neuroscience.2006.02.074
CASPubMedWeb of Science®Google Scholar
Datson NA, Morsink MC, Steenbergen PJ, Aubert Y, Schlumbohm C, Fuchs E et al. (2009). A molecular blueprint of gene expression in hippocampal subregions CA1, CA3, and DG is conserved in the brain of the common marmoset. Hippocampus 19 (8): 739–752.
10.1002/hipo.20555
CASPubMedWeb of Science®Google Scholar
Degenhardt L, Hall W, Lynskey M (2003). Exploring the association between cannabis use and depression. Addiction 98: 1493–1504.
10.1046/j.1360-0443.2003.00437.x
CASPubMedWeb of Science®Google Scholar
Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34: 605–613.

CASPubMedWeb of Science®Google Scholar
Di Marzo V, De Petrocellis L, Bisogno T, Melck D (1999). Metabolism of anandamide and 2-arachidonoylglycerol: an historical overview and some recent developments. Lipids 34: S319–S325.
10.1007/BF02562332
CASPubMedWeb of Science®Google Scholar
Duman RS, Monteggia LM (2006). A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59 (12): 1116–1127.
10.1016/j.biopsych.2006.02.013
CASPubMedWeb of Science®Google Scholar
Dzitoyeva S, Imbesi M, Uz T, Dimitrijevic N, Manev H, Manev R (2008). Caffeic acid attenuates the decrease of cortical BDNF transcript IV mRNA induced by swim stress in wild-type but not in 5-lipoxygenase-deficient mice. J Neural Trans 115 (6): 823–827.
10.1007/s00702-008-0034-7
CASPubMedWeb of Science®Google Scholar
Flugge G (1995). Dynamics of central nervous 5-HT1A receptors under psychosocial stress. J Neurosci 15 (11): 7132–7140.

PubMedWeb of Science®Google Scholar
Formukong EA, Evans AT, Evans FJ (1988). Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L. J Pharm Pharmacol 40: 132–134.
10.1111/j.2042-7158.1988.tb05198.x
CASPubMedWeb of Science®Google Scholar
Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S et al. (2004). Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 61 (1): 34–41.
10.1001/archpsyc.61.1.34
PubMedWeb of Science®Google Scholar
Graeff FG, Guimarães FS, Andrade GCS, Deakin JFW (1996). Role of 5-HT in stress, anxiety and depression. Pharmaco Biochem Behav 54 (1): 129–141.
10.1016/0091-3057(95)02135-3
CASPubMedWeb of Science®Google Scholar
Gruber AJ, Pope HG Jr, Brown ME (1996). Do patients use marijuana as an antidepressant? Depression 4: 77–80.
10.1002/(SICI)1522-7162(1996)4:2<77::AID-DEPR7>3.0.CO;2-C
CASPubMedGoogle Scholar
Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW (1990). Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100: 558–559.
10.1007/BF02244012
CASPubMedWeb of Science®Google Scholar
Haddjeri N, Blier P, De Montigny C (1998). Long term antidepressant treatments result in a tonic activation of forebrain 5HT1a receptors. J Neurosci 18 (23): 10150–10156.

CASPubMedWeb of Science®Google Scholar
Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu AX et al. (2007). Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 52 (4): 1079–1087.
10.1016/j.neuropharm.2006.11.005
CASPubMedWeb of Science®Google Scholar
Hill MN, Gorzalka BB (2005). Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol 16 (5–6): 333–352.
10.1097/00008877-200509000-00006
CASPubMedWeb of Science®Google Scholar
Hill MN, Carrier EJ, McLaughlin RJ, Morrish AC, Meier SE, Hillard CJ et al. (2008). Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment. J Neurochem 106 (6): 2322–2336.
10.1111/j.1471-4159.2008.05567.x
CASPubMedWeb of Science®Google Scholar
Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET et al. (2001). Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58: 322–328.
10.1001/archpsyc.58.4.322
CASPubMedWeb of Science®Google Scholar
Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA (2003). Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav 75 (1): 81–88.
10.1016/S0091-3057(03)00044-3
CASPubMedWeb of Science®Google Scholar
Joca SR, Padovan CM, Guimarães FS (2003). Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus prevents learned helplessness development. Brain Res 978 (1–2): 177–184.
10.1016/S0006-8993(03)02943-3
CASPubMedWeb of Science®Google Scholar
Joca SR, Ferreira FR, Guimarães FS (2007). Modulation of stress consequences by hippocampal monoaminergic, glutamatergic and nitrergic neurotransmitter systems. Stress 10 (3): 227–249.
10.1080/10253890701223130
CASPubMedWeb of Science®Google Scholar
Johns A (2001). Psychiatric effects of cannabis. Br J Psychiatry 178: 116–122.
10.1192/bjp.178.2.116
CASPubMedWeb of Science®Google Scholar
Kaster MP, Santos AR, Rodrigues AL (2005). Involvement of 5-HT1A receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test. Brain Res Bull 67 (1–2): 53–61.
10.1016/j.brainresbull.2005.05.025
CASPubMedWeb of Science®Google Scholar
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S et al. (2000). Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48 (8): 830–843.
10.1016/S0006-3223(00)01036-2
CASPubMedWeb of Science®Google Scholar
Mechoulam R (1970). Marihuana chemistry. Science 168: 1159–1166.
10.1126/science.168.3936.1159
CASPubMedWeb of Science®Google Scholar
Mechoulam R, Petersa M, Murillo-Rodriguez E, Hanus LO (2007). Cannabidiol – recent advances. Chem Biodivers 4: 1678–1692.
10.1002/cbdv.200790147
PubMedWeb of Science®Google Scholar
Moreira FA, Guimarães FS (2005). Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512: 199–205.
10.1016/j.ejphar.2005.02.040
CASPubMedWeb of Science®Google Scholar
Moreira FA, Aguiar DC, Guimarães FS (2006). Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30 (8): 1466–1471.
10.1016/j.pnpbp.2006.06.004
CASPubMedWeb of Science®Google Scholar
Palazzo E, de Novellis V, Marabese I, Cuomo D, Rossi F, Berrino L et al. (2002). Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur J Pharmacol 439: 69–75.
10.1016/S0014-2999(02)01367-5
CASPubMedWeb of Science®Google Scholar
Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998). Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63: PL1–PL6.
10.1016/S0024-3205(98)00238-0
CASPubMedWeb of Science®Google Scholar
Piomelli D (2003). The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4: 873–884.
10.1038/nrn1247
CASPubMedWeb of Science®Google Scholar
Poleszak E, Wlaz P, Szewczyk B, Kedzierska E, Wyska E, Librowski T et al. (2005). Enhancement of antidepressant-like activity by joint administration of imipramine and magnesium in the forced swim test: Behavioral and pharmacokinetic studies in mice. Pharmacol Biochem Behav 81 (3): 524–529.
10.1016/j.pbb.2005.03.017
CASPubMedWeb of Science®Google Scholar
Porsolt RD, Le Pichon M, Jalfre M (1977). Depression: a new animal model sensitive to antidepressant treatment. Nature 266: 730–732.
10.1038/266730a0
CASPubMedWeb of Science®Google Scholar
Radley JJ, Jacobs BL (2002). 5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus. Brain Res 955 (1–2): 264–267.
10.1016/S0006-8993(02)03477-7
CASPubMedWeb of Science®Google Scholar
Rantamäki T, Hendolin P, Kankaanpää A, Mijatovic J, Piepponen P, Domenici E et al. (2007). Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 32 (10): 2152–2162.
10.1038/sj.npp.1301345
CASPubMedWeb of Science®Google Scholar
Resstel LB, Joca SR, Moreira FA, Correa FM, Guimarães FS (2006). Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res 172 (2): 294–298.
10.1016/j.bbr.2006.05.016
PubMedWeb of Science®Google Scholar
Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (2009). 5-HT_1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156 (1): 181–188.
10.1111/j.1476-5381.2008.00046.x
CASPubMedWeb of Science®Google Scholar
van Riedel E, Meijer OC, Steebergen PJ, Joels M (2003). Chronic unpredictable stress causes attenuation of serotonin responses in cornu ammonis 1 pyramidal neurons. Neuroscience 120: 649–658.
10.1016/S0306-4522(03)00355-5
CASPubMedWeb of Science®Google Scholar
Robson P (2001). Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 178: 107–115.
10.1192/bjp.178.2.107
CASPubMedWeb of Science®Google Scholar
Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E et al. (2008). Role in Anxiety Behavior of the Endocannabinoid System in the Prefrontal Cortex. Cereb Cortex 18 (6): 1292–1301.
10.1093/cercor/bhm161
CASPubMedWeb of Science®Google Scholar
Russo EB, Burnett A, Hall B, Parker KK (2005). Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30: 1037–1043.
10.1007/s11064-005-6978-1
CASPubMedWeb of Science®Google Scholar
Saaralainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E et al. (2003). Activation of the trkB neurotrophin receptor is induced by antidepressant drugs and requires for antidepressant-induced behavioural effects. J Neurosci 23 (1): 349–357.

PubMedWeb of Science®Google Scholar
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301 (5634): 805–809.
10.1126/science.1083328
CASPubMedWeb of Science®Google Scholar
Sapan CV, Lundblad RL, Price NC (1999). Colorimetric protein assay techniques. Biotechnol Appl Biochem 29 (Pt 2): 99–108.
10.1111/j.1470-8744.1999.tb00538.x
CASPubMedWeb of Science®Google Scholar
Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J et al. (2000). Brain serotonin1A receptor binding measured by positron emission topography with (11C) WAY100635. Arch Gen Psychiat 57: 174–180.
10.1001/archpsyc.57.2.174
CASPubMedWeb of Science®Google Scholar
Savitz J, Lucki I, Drevets WC (2009). 5-HT1A receptor function in major depressive disorder. Prog Neurobiol 88: 17–31.
10.1016/j.pneurobio.2009.01.009
CASPubMedWeb of Science®Google Scholar
Shieh CH, Hong CJ, Huang YH, Tsai SJ (2008). Potential antidepressant properties of cysteamine on hippocampal BDNF levels and behavioral despair in mice. Prog Neuropsychopharmacol Biol Psychiatry 32 (6): 1590–1594.
10.1016/j.pnpbp.2008.06.003
CASPubMedWeb of Science®Google Scholar
Shumake J, Edwards E, Gonzalez-Lima F (2002). Dissociation of septo-hippocampal metabolism in the congenitally helpless rat. Neuroscience 114 (2): 373–337.
10.1016/S0306-4522(02)00297-X
CASPubMedWeb of Science®Google Scholar
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G (1998). Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 18 (18): 7394–7401.

CASPubMedWeb of Science®Google Scholar
Strosznajder J, Chalimoniuk M, Samochocki M (1996). Activation of serotonergic 5-HT1A receptor reduces Ca(2+)- and glutamatergic receptor-evoked arachidonic acid and No/cGMP release in adult hippocampus. Neurochem Int 28 (4): 439–444.
10.1016/0197-0186(95)00103-4
CASPubMedWeb of Science®Google Scholar
Szewczyk B, Albert PR, Burns AM, Czesak M, Overholser JC, Jurjus GJ et al. (2009). Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder. Int J Neuropsychopharmacol 12 (2): 155–168.
10.1017/S1461145708009012
CASPubMedWeb of Science®Google Scholar
Takeda H, Tsuji M, Yamada T, Masuya J, Matsushita K, Tahara M et al. (2006). Caffeic acid attenuates the decrease in cortical BDNF mRNA expression induced by exposure to forced swimming stress in mice. Eur J Pharmacol 534 (1–3): 115–121.
10.1016/j.ejphar.2006.01.026
CASPubMedWeb of Science®Google Scholar
Thomas BF, Gilliam AF, Burch DF, Roche MJ, Seltzman HH (1998). Comparative receptor binding analyses of cannabinoid agonists and antagonists. J Pharmacol Exp Ther 285: 285–292.

CASPubMedWeb of Science®Google Scholar
Viveros MP, Marco EM, File SE (2005). Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81 (2): 331–342.
10.1016/j.pbb.2005.01.029
CASPubMedWeb of Science®Google Scholar
Ware MA, Adams H, Guy GW (2005). The medicinal use of cannabis in the UK: results of a nationwide survey. Int J Clin Pract 59: 291–295.
10.1111/j.1742-1241.2004.00271.x
CASPubMedWeb of Science®Google Scholar
Watanabe K, Ogi H, Nakamura S, Kayano Y, Matsunaga T, Yoshimura H et al. (1998). Distribution and characterization of anandamide amidohydrolase in mouse brain and liver. Life Sci 62 (14): 1223–1229.
10.1016/S0024-3205(98)00052-6
CASPubMedWeb of Science®Google Scholar
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982). Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl) 76: 245–250.
10.1007/BF00432554
CASPubMedWeb of Science®Google Scholar
Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS (2006). Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39 (4): 421–429.
10.1590/S0100-879X2006000400001
CASPubMedWeb of Science®Google Scholar

Citing Literature

Volume159, Issue1

Special Issue:Themed Section: QT Safety: Guest Editor: J‐P Valentin

January 2010

Pages 122-128

Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT_1A receptors