5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats

Leonardo B.M. Resstel, Rodrigo F. Tavares, Sabrina F.S. Lisboa, Sâmia R.L. Joca, Fernando M.A. Corrêa and Francisco S. Guimarães

British Journal of Pharmacology, 2009, 156, 181–188;

doi : 10.1111/j.1476-5381.2008.00046.x

Background and purpose : Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa which induces anxiolytic- and antipsychotic-like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5-HT1A receptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5-HT1A receptors.

Experimental approach : Male Wistar rats received i.p. injections of vehicle or CBD (1, 10 or 20 mg kg-1) and 30 min later were submitted to 60 min of restraint where their cardiovascular responses were recorded. The protocol of the second experiment was similar to the first one except that animals received i.p. injections of the 5-HT1A receptor antagonist WAY100635 (0.1 mg kg-1) before CBD treatment and exposure to restraint. 24 h later they were also tested in the elevated plus-maze (EPM), an animal model of anxiety.

Key results : Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD. WAY100635 by itself did not change the cardiovascular and anxiogenic response to RS, but blocked the effects of CBD.

Conclusion and implications : The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT1A receptor-mediated neurotransmission.

Keywords : cannabinoids; cardiovascular system; elevated plus-maze; 5-HT1A receptor

Abbreviations : CBD, cannabidiol; EPM, elevated plus-maze; HR, heart rate; MAP, mean arterial pressure; THC, D9-tetrahydrocannabinol

Introduction

Marijuana (from Cannabis sativa) is one of the most widely abused drugs in the world. In humans, it elicits subjective changes that include euphoria, heightened sensitivity to external stimuli and relaxation (Martin et al., 1991; Compton et al., 1992; Johns, 2001). The major constituent of cannabis is D9-tetrahydrocannabinol (THC) and this is thought to be the main ingredient responsible for its psychoactive properties (Mechoulam, 1970; Mechoulam et al., 1970; Ilan et al., 2005). The discovery of specific binding sites for THC led to the discovery of the cannabinoid receptors (Devane et al., 1988; Matsuda et al., 1990; Munro et al., 1993) and, so far, two sub-types of the cannabinoid receptor have been identified,

CB1 and CB2 (Pertwee, 2005; nomenclature follows Alexander et al., 2008). The activation of CB1 receptors by THC is thought to account for most of the central effects of cannabis (Huestis et al., 2001). Anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids, are the major endogenous agonists of the CB1 receptor (Di Marzo et al., 1998; Piomelli, 2003).

Cannabidiol (CBD), another cannabinoid generally found in relatively high concentrations in cannabis, exhibits a somewhat different pharmacology compared with THC (Mechoulam et al., 2002). CBD attenuates the psychotomimetic and anxiogenic effects of THC in humans (Karniol et al., 1974; Zuardi et al., 1982). Moreover, systemic administration of CBD induced antipsychotic (Zuardi et al., 1991; Zuardi et al., 2006) and anxiolytic-like effects (Guimaraes et al., 1990; Resstel et al., 2006).

The mechanism of action of CBD is not fully understood. It has a low affinity for cannabinoid receptors (Petitet et al., 1998; Thomas et al., 1998) but can block the reuptake of anandamide (Bisogno et al., 2001) and its metabolism by the enzyme, fatty acid amide hydrolase (FAAH), (Watanabe et al., 1998; Di Marzo et al., 1999; Mechoulam and Hanus, 2002; Mechoulam et al., 2002). Moreover, CBD may possess agonistic properties at 5-HT1A receptors (Russo et al., 2005). Although there are contradictory results, several studies indicate that activation of these receptors can induce anxiolyticlike effects and mediate adaptation to stress (Blier and de Montigny, 1994; Blier and Ward, 2003; Joca et al., 2003; Joca et al., 2007).

Acute restraint is an uncontrollable stress situation that produces endocrine and autonomic responses characterized by increases in glucocorticoids levels, blood pressure and heart rate (HR) (Tavares and Correa, 2006; Hsu et al., 2007). These responses are accompanied by activation of several brain structures (Pacak and Palkovits, 2001). In addition to physiological responses, animals submitted to restraint also develop behavioural changes reflected, for example, in reduced exploratory activity in an open field 24 h after stress (Kennett et al., 1985a; 1987; Mechiel Korte and De Boer, 2003), increased immobility in a forced swimming test (Sevgi et al., 2006) and reduced exploration of the open arms of an elevated plus-maze (EPM) (Guimaraes et al., 1993; Padovan and Guimaraes, 2000). These stress-induced behavioural changes can be attenuated by systemic or intracerebral administration of anxiolytic and antidepressant drugs (Kennett et al., 1985a; 1987; Guimaraes et al., 1993; Padovan and Guimaraes, 2000; Mechiel Korte and De Boer, 2003). A possible effect of CBD on these changes, however, has not yet been investigated. Therefore, in the present work we tested the hypothesis that systemic administration of CBD would attenuate the acute physiological changes and the behavioural consequences of restraint stress. We also evaluated the involvement of 5-HT1A receptors in the effects of CBD in this model.

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