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Several pre-clinical and human-based studies have shown that acutely administered cannabidiol (CBD) can produce anxiolytic-like effects The present study investigated the effects of chronic administration of CBD on rat behaviour and on the expression of brain proteins. Male Lister-hooded rats (150–200 g, n = 8 per group) received daily injections of CBD (10 mg/kg, i.p.) for 14 days. The rats were subjected to two behavioural tests: locomotor activity and conditioned emotional response (CER). The expression of brain-derived neurotrophic factor (BDNF), its receptor tyrosine kinase B (Trk B), extracellular signal-regulated kinases (ERK1/2) and phospho-ERK1/2 and the transcription factor cyclic AMP response element binding protein activation (CREB) and phospho-CREB were determined in brain regions such as the frontal cortex and hippocampus using Western immunoblotting. CBD significantly increased the time spent freezing in the CER test with no effect on locomotor activity. CBD significantly reduced BDNF expression in the hippocampus and frontal cortex with no change in the striatum. In addition, CBD significantly reduced TrkB expression in the hippocampus with a strong trend towards reduction in the striatum but had no effect in the frontal cortex. In the hippocampus, CBD had no effect on ERK1/2 or phospho-ERK2, but in the frontal cortex, CBD significantly reduced phospho-ERK1/2 expression without affecting total ERK. Chronic administration of CBD produced an anxiogenic-like effect in clear opposition to the acute anxiolytic profile previously reported. In addition, CBD decreased the expression of proteins that have been shown to be enhanced by chronic treatment with antidepressant/anxiolytic drugs.

In reply to Dr. Gururajan's comments on our manuscript (Elbatsh et al. 2012) about the anxiogenic-like effects of chronic cannabidiol administration in rats, we accept that the use of a wider ranging dose/response design would have been desirable. We emphasised the need for additional longterm multi-dose studies of the drug in models of affective disease in the discussion which present constraints of finance and time have not allowed. Moreover, given that cannabidiol (CBD) is being reported almost as a panacea, we consider it of value to show, even if only at a single dose, that CBD can provoke potentially deleterious behavioural responses. Secondly, in terms of the behavioural changes in the context of anxiety, not only total distance travelled was reported in the activity boxes, but also rearing and grooming as possible markers of anxiety-related behaviour. Locomotor activity in a neutral environment was measured to detect any hypoactivity associated with CBD treatment that could have interfered with the interpretation of behavioural changes in the conditioned emotional response (CER). We used the CER test which had previously been used to show anxiolytic effects of acute CBD (Bitencourt et al. 2008; Resstel et al. 2006), but we agree that the elevated plus maze could also be an appropriate test, given that it would be useful to find converging effects in a number of anxiety test procedures. Maha Elbatsh for the authors