Cannabidiol potentiates pharmacological effects of Δ⁹-tetrahydrocannabinol via CB₁ receptor-dependent mechanism

Abstract

Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Δ⁹-tetrahydrocannabinol (Δ⁹-THC). However, such interactions have not sufficiently been clear and may have important implications for understanding the pharmacological effects of marijuana. In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Δ⁹-THC on locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory in the eight-arm radial maze task in mice. In addition, we measured expression level of cannabinoid CB₁ receptor at striatum, cortex, hippocampus and hypothalamus. Δ⁹-THC (1, 3, 6 and 10 mg/kg) induced hypoactivity, catalepsy-like immobilisation and hypothermia in a dose-dependent manner. In addition, Δ⁹-THC (1, 3 and 6 mg/kg) dose-dependently impaired spatial memory in eight-arm radial maze. On the other hand, cannabidiol (1, 3, 10, 25 and 50 mg/kg) did not affect locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory on its own. However, higher dose of cannabidiol (10 or 50 mg/kg) exacerbated pharmacological effects of lower dose of Δ⁹-THC, such as hypoactivity, hypothermia and impairment of spatial memory. Moreover, cannabidiol (50 mg/kg) with Δ⁹-THC (1 mg/kg) enhanced the expression level of CB₁ receptor expression in hippocampus and hypothalamus. Cannabidiol potentiated pharmacological effects of Δ⁹-THC via CB₁ receptor-dependent mechanism. These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.

Introduction

Cannabis contains about 60 different cannabinoids, including the psychoactive component, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), and other major non-psychoactive components, such as cannabidiol, cannabinol and cannabigerol. Δ⁹-THC has been demonstrated to produce hypothermia, learning and memory impairment, impairment of the prepulse inhibition of the startle reflex, catalepsy-like immobilisation, aggressive behaviour, analgesia and hypoactivity (Wiley and Martin, 2002, Martin et al., 1991, Fujiwara, 2001, Mishima et al., 2001, Nagai et al., 2006, Egashira et al., 2006). These effects are at least partly caused by binding to cannabinoid receptor 1 (CB₁ receptor) within the brain. On the other hand, cannabidiol, a non-psychoactive component of cannabis, has been found to be an anticonvulsant in animal models of epilepsy and in humans with epilepsy. Moreover, cannabidiol has been shown to exert cannabinoid-like effects against such conditions as spasm, anxiety, nausea and rheumatoid arthritis (Mecholam et al., 2002, Ashton et al., 2005). However, cannabidiol is generally known to have a very low affinity (in the micromolar range) for the cannabinoid CB₁ and CB₂ receptors, but also to have many pharmacological actions. These actions are thought to be dependent on a new cannabinoid receptor, such as an abnormal cannabidiol receptor, a non-CB₁ and non-CB₂ receptor, and G-protein-coupled receptor GPR55 (Begg et al., 2005, Baker et al., 2006). There are multiple cannabinoid receptors, most of them identified pharmacologically but yet to be cloned.

It has been suggested that coadministration of cannabidiol may alter the pharmacological effects of Δ⁹-THC, potentiating some therapeutic benefits of Δ⁹-THC, while attenuating some of its negative effects (Karniol et al., 1974, Russo and Guy, 2006, Zuardi et al., 1982). The potentially interesting modulatory effects of cannabidiol have been described in several reports. For example, the cataleptic effects of Δ⁹-THC were similarly reversed by equal doses of cannabidiol (Karniol and Carlini, 1973). Δ⁹-THC-induced hypothermia is potentiated by equal doses of cannabidiol (Fernandes et al., 1974), while higher doses of cannabidiol either antagonise (Borgen and Davis, 1974) or have no effect (Ham et al., 1975). In addition, the antinociceptive effects of Δ⁹-THC are adversely potentiated by a high dose of cannabidiol (i.e. 30 mg/kg) in mice (Varvel et al., 2006), while similar doses of cannabidiol have been found to antagonise the effects of Δ⁹-THC in a formic-acid-induced writhing test (Welburn et al., 1976). Moreover, administration of very high doses of cannabidiol have been shown to raise the Δ⁹-THC concentration in the blood and brain (Bornheim et al., 1995, Jones and Pertwee, 1972), an effect likely due to inhibition of hepatic microsomal Δ⁹-THC metabolism (Jaeger et al., 1996, Watanabe et al., 1987). This pharmacokinetic explanation may account for several potentiating effects, for which high doses of cannabidiol have been assessed. Therefore, it is important to assess the interaction between Δ⁹-THC and cannabidiol.

The present experiments were conducted to evaluate putative interactions between Δ⁹-THC and cannabidiol in behavioural tests, such as spontaneous locomotor activity, catalepsy-like immobilisation and rectal temperature. In addition, we assessed the potentiating effects of combining Δ⁹-THC with cannabidiol, compared to Δ⁹-THC alone, on spatial memory in the eight-arm radial maze task. Finally, we measured the expression levels of cannabinoid CB₁ receptor in the striatum, cortex, hippocampus and hypothalamus.