BACKGROUND AND PURPOSEIt has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ 9 -tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study was to investigate whether CBD modulated the functional effects and c-Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. EXPERIMENTAL APPROACHMale C57BL/6 mice were treated with vehicle, CBD, THC or a combination of CBD and THC (10 mg·kg À1 i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety-related behaviour, body temperature and brain c-Fos expression (a marker of neuronal activation). KEY RESULTSCBD potentiated THC-induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c-Fos expression in 11 of the 35 brain regions studied. CBD co-administration suppressed THC-induced c-Fos expression in six of these brain regions. This effect was most pronounced in the medial preoptic nucleus and lateral periaqueductal gray. Treatment with CBD alone diminished c-Fos expression only in the central nucleus of the amygdala compared with vehicle. CONCLUSIONS AND IMPLICATIONSThese data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC. AbbreviationsBNST, bed nucleus of the stria terminalis; CBD, cannabidiol; PAG, periaqueductal gray; PVH, paraventricular hypothalamic nucleus; THC, Δ 9 -tetrahydrocannabinol BJP IntroductionCannabis is a complex mixture of approximately 100 different cannabinoids that may modulate the effects of Δ 9 -tetrahydrocannabinol (THC), the main psychoactive constituent of the plant (Elsohly and Slade, 2005;Radwan et al., 2008). A number of studies now support the view that cannabidiol (CBD) may reduce the negative psychotropic effects of THC while enhancing its positive therapeutic actions (Russo, 2011;Niesink and van Laar, 2013). In naturalistic human studies where cannabinoid content in smoked material or the user's hair is compared with the subjective effects of cannabis, it has been inferred that CBD attenuates some effects of THC, such as memory impairment, attentional bias to drug-related stimuli, appetite stimulation, anxiety and psychotic-like states (Morgan and Curran, 2008;Niesink and van Laar, 2013). Controlled human laboratory studies administering known doses of CBD and THC largely agree with the results of the naturalistic studies, with CBD decreasing the psychoactive and physiological effects of THC. Specifically, CBD was shown to reduce the effects of THC on anxiety (Zuardi et al., 1982), hippocampus-dependent episodic memory, psy...

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Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET) and wild-type (WT) mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.