A behavioural comparison of acute and chronic D9-tetrahydrocannabinol and cannabidiol in
Leonora E. Long, Rose Chesworth, Xu-Feng Huang, Iain S. McGregor, Jonathon C. Arnold and Tim Karl
International Journal of Neuropsychopharmacology, 2010, 13, 861–876.
doi : 10.1017/S1461145709990605
Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent D9 tetrahydro-cannabinol (D9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, D9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). D9-THC produced the classic cannabinoid CB1 receptormediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, D9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light–dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light–dark test at a low dose (1 mg/kg). Acute and chronic D9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with D9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic D9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.
Key words : Antipsychotic, anxiolytic, cannabidiol, mouse, D9-tetrahydrocannabinol.
The population risk for schizophrenia is increased by cannabis use (Henquet et al. 2005; Moore et al. 2007). This increase is reported to be greater in people with a predisposition to psychosis (Henquet et al. 2005). D9-tetrahydrocannabinol (D9-THC), the most abundant of the >70 cannabis constituents, produces the euphoric effects sought by recreational users, and produces psychotomimetic symptoms such as altered perception and disrupted working memory. Schizophrenia patients show increased susceptibility to these effects (D’Souza et al. 2005). D9-THC has partial agonist efficacy at cannabinoid CB1 and CB2 receptors and exerts many of its central effects via inhibition of neurotransmitter release by presynaptic CB1 receptors. Cannabidiol (CBD), another cannabis constituent, does not produce the psychotropic effects of D9-THC and antagonizes the effects of CB1/CB2 receptor agonists (Pertwee, 2008). Interestingly, consumption of cannabis with little or no CBD content is associated with increased incidence of psychotic symptoms (Morgan & Curran, 2008; Rottanburg et al. 1982), suggesting that CBD may partially attenuate the psychotomimetic effects of D9-THC or other cannabis constituents. The therapeutic potential for CBD is supported by observations of its antipsychotic-like (Leweke et al. 2000; Zuardi et al. 2006a) and anxiolytic-like effects (Crippa et al. 2004, 2009) after acute oral administration in healthy volunteers. While preliminary data in treatment-resistant schizophrenia patients suggest that CBD monotherapy is not effective (Zuardi et al. 2006b), regular oral CBD administration reduces psychotic symptoms in Parkinson’s disease sufferers (Zuardi et al. 2008).
Reports of CBD effects in rodents are currently restricted to acute studies: CBD exerts anxiolytic-like (Campos & Guimaraes, 2008; Guimaraes et al. 1994; Moreira et al. 2006; Onaivi et al. 1990; Resstel et al. 2006) and antipsychotic-like (Long et al. 2006; Moreira & Guimaraes, 2005; Zuardi et al. 1991) effects in mice (Swiss, ICR) and rats (Wistar). Interestingly, CBD induces c-fos expression in the rat nucleus accumbens but not the dorsal striatum, in a pattern similar to that of clozapine (Guimaraes et al. 2004). To accurately model the effects of regular cannabis use in humans and to determine the potential for lasting clinical efficacy of cannabinoids such as CBD, chronic rodent behavioural studies are necessary. Furthermore, since a majority of mutant mouse models are generated on a C57BL/6J or mixed C57BL/6Jr129SvJ genetic background, studies in C57BL/6J mice are crucial for further research.
This study therefore aimed to directly compare the acute and chronic effects of D9-THC and CBD in
C57BL/6J mice using a multi-tiered battery of schizophrenia- and anxiety-relevant behavioural tests. CBD effects were compared to the well-characterized effects of D9-THC in the classic cannabinoid CB1 receptor agonist ‘tetrad’. Following this, mice were assessed using a comprehensive multi-tiered battery of behavioural models relevant to positive (spontaneous hyperactivity), negative (social withdrawal, anxiety) and cognitive (disrupted learning and working memory, impaired sensorimotor gating) symptoms of schizophrenia during repeated treatment with D9-THC or CBD. The antipsychotic effect of chronic CBD on druginduced psychotomimetic behaviour was assessed using acute challenges with the non-competitive NMDA antagonist MK-801 and the catecholaminergic stimulant dexamphetamine (Dex). To enable comparison of the effects of repeated treatment, a followup study on acute anxiolytic and potentially antipsychotic- like effects of CBD was conducted, using doses that were behaviourally active in the chronic study.