Antidepressant-like effects of Δ9-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression

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Abstract

The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB1 receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ9-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression.

As expected, OB rats were hyperactive in the open field. Repeated THC (2 mg/kg, i.p. once every 48 h for 21 days) and rimonabant (5 mg/kg, i.p. once every 48 h for 21 days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs1/2) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK1/2 expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats.

These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.

Highlights

► Antidepressant-like behavioural properties of both THC and rimonabant in OB rats. ► In intact rats THC increased BDNF but rimonabant had no effect. ► In intact rats rimonabant and THC increased the levels of p-ERKs1/2. ► Neither THC nor rimonabant altered expression of BDNF or pERK in the OB rats.

Introduction

It is estimated by the WHO that depression will be the most important cause of disability in the world by the year 2020 (Murray and Lopez, 1997). The current treatments for depression are only partially effective (Post et al., 2010), necessitating the development of alternative pharmacotherapies. Retrospective studies in cannabis users and small clinical trials have suggested possible therapeutic benefit of cannabinoid use in depression (Gruber et al., 1996). However, other previous studies have suggested that cannabis use may be a contributory cause of depression and suicidal behaviours (Bovasso, 2001). These human findings have their counterpart in animal studies, but the situation is complicated by reports of cannabinoid receptor agonists and antagonists displaying both anxiolytic- and anxiogenic-like effects in rodent models of anxiety and depression (Bambico et al., 2007, Berrendero and Maldonado, 2002, Griebel et al., 2005, Jiang et al., 2005, Viveros et al., 2005). Rimonabant can be classified as a CB1 antagonist but its inverse agonist properties have been well documented by in vitro pharmacological experiments (Howlett et al., 2002). Thus, its biochemical or behavioural effects generally are opposite in direction to effects produced by Δ9-THC or other CB1 agonists. Rimonabant has been investigated mainly for the treatment of obesity and associated metabolic dysregulation; however, clinical trials showed an increased incidence of psychiatric side effects, mainly anxiety and depression-like states, in obese patients which resulted in rimonabant being withdrawn from the market (Leite et al., 2009).

The involvement of the endocannabinoid system in depression is supported by pre-clinical studies such as that of Hill et al. (2008a) showing increased CB1 receptor expression and decreased endocannabinoid content in different brain regions in the chronic mild unpredictable stress model; effects that were generally reversed by chronic antidepressant administration. In transgenic animals lacking the cannabinoid CB1 receptor, there are enhanced behavioural signs of anxiety and depression and an amplified sensitivity to stressful stimuli (Aso et al., 2008). In clinical investigations, Hill et al. (2008b) demonstrated that circulating levels of endocannabinoids were significantly reduced in a population with major clinical depression. Together, these data are consistent with the hypothesis that an endogenous endocannabinoid system operates to maintain an appropriate affective state. They are also consistent with the traditional mood-elevating properties of cannabinoids and, perhaps, the anxiety and depression experienced by some patients prescribed the CB1 receptor antagonist rimonabant as an adjunct for weight reduction (Hill and Gorzalka, 2009).

Animal models of psychiatric disorders represent valuable tools for invasively studying molecular changes in brain tissue which cannot be done in patients (Licinio and Wong, 2004). Thus, olfactory bulbectomy (OB) in rodents has been proposed as a model with high predictive validity for chronic psychomotor agitated depression (Harkin et al., 2003, Kelly et al., 1997). The bilateral removal of the olfactory bulbs creates chronic behavioural, endocrine, neurotransmitter and immunological changes that are qualitatively similar to those occurring in depressed patients (Song et al., 1994a, Song et al., 1994b, van Riezen and Leonard, 1990). Moreover, in the context of the neurogenesis hypothesis of depression (Duman and Monteggia, 2006), some studies have reported that impaired cell proliferation and/or neuronal degeneration observed following olfactory bulbectomy are reduced by some antidepressants (Jaako-Movits et al., 2006, Jarosik et al., 2007, Keilhoff et al., 2006).

The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive plant cannabinoid, and the CB1 receptor antagonist rimonabant on intact and OB rats (as a model of depression). Our working hypothesis was that THC would show antidepressant-like activity whilst rimonabant might reflect its clinical side effects and exacerbate the effects of bulbectomy.

Section snippets

Animals

Male Lister hooded rats (n = 8–10 per group; Charles River UK) weighing 180–300 g were housed four per cage and acclimatised to the laboratory conditions for one week before the experiment. Rats were kept in a temperature-regulated (22 ± 2 °C) room and artificial lighting was provided from 0700 h to 1900 h. Food and water were available ad libitum and each animal was handled daily through the first week. Experimental testing began seven days after the acclimatisation period and was performed during the

Effect of ∆9-THC on spontaneous locomotor activity

In intact rats, chronic administration of ∆9-THC (2 mg/kg, i.p.) significantly decreased total locomotor activity (Fig. 1). Chronic treatment with the CB1 receptor antagonist rimonabant (5 mg/kg, i.p.) significantly increased total locomotor activity compared with vehicle-treated rats. Pre-treatment with rimonabant prevented the THC-induced decrease in locomotor activity. Acute administration (30 min) of THC or rimonabant had no significant effect on spontaneous locomotor activity (data not shown).

Discussion

In the present study, acute administration of THC (2.0 mg/kg) failed to affect total locomotor activity in intact animals. However, chronic THC treatment (2.0 mg/kg) in intact animals inhibited spontaneous locomotor activity and this effect was completely reversed by the cannabinoid CB1 antagonist rimonabant, perhaps indicating a role for CB1 receptors in modulating motor behaviours as previously reported (Barg et al., 1995), although a CB receptor-independent physiological antagonism due to the

Disclosure/Conflict of interest

The authors have no conflicts of interest to disclose.

Acknowledgements

The authors are grateful for the support of the Menoufia University (Egypt) and the University of Nottingham (UK) and to Clare Spicer, Liaque Latif and Stacey Knapp for technical assistance.

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