Abstract
Schizophrenia is considered a debilitating neurodevelopmental psychiatric disorder and its pharmacotherapy remains problematic without recent major advances. The development of interventions able to prevent the emergence of schizophrenia would therefore represent an enormous progress. Here, we investigated whether treatment with cannabidiol (CBD – a compound of Cannabis sativa that presents an antipsychotic profile in animals and humans) during peri-adolescence would prevent schizophrenia-like behavioral abnormalities in an animal model of schizophrenia: the spontaneously hypertensive rat (SHR) strain. Wistar rats and SHRs were treated with vehicle or CBD from 30 to 60 post-natal days. In experiment 1, schizophrenia-like behaviors (locomotor activity, social interaction, prepulse inhibition of startle and contextual fear conditioning) were assessed on post-natal day 90. Side effects commonly associated with antipsychotic treatment were also evaluated: body weight gain and catalepsy throughout the treatment, and oral dyskinesia 48 h after treatment interruption and on post-natal day 90. In experiment 2, serum levels of triglycerides and glycemia were assessed on post-natal day 61. In experiment 3, levels of BDNF, monoamines, and their metabolites were evaluated on post-natal days 61 and 90 in the prefrontal cortex and striatum. Treatment with CBD prevented the emergence of SHRs’ hyperlocomotor activity (a model for the positive symptoms of schizophrenia) and deficits in prepulse inhibition of startle and contextual fear conditioning (cognitive impairments). CBD did not induce any of the potential motor or metabolic side effects evaluated. Treatment with CBD increased the prefrontal cortex 5-HIAA/serotonin ratio and the levels of 5-HIAA on post-natal days 61 and 90, respectively. Our data provide pre-clinical evidence for a safe and beneficial effect of peripubertal and treatment with CBD on preventing positive and cognitive symptoms of schizophrenia, and suggest the involvement of the serotoninergic system on this effect.
Highlights
Schizophrenia is a debilitating psychiatric disorder whose pharmacotherapy remains unable to treat all core symptoms
There was no interaction effect, post hoc analysis revealed that only spontaneously hypertensive rat (SHR) treated with 0.5 mg/kg CBD displayed decreased locomotor activity when compared to VEH-treated SHRs
Treatment with CBD 0.5 mg/kg prevented the development of hyperlocomotion in SHRs (Figure 2A)
Summary
Schizophrenia is a debilitating psychiatric disorder whose pharmacotherapy remains unable to treat all core symptoms. Individuals with prodromal signs or recent functional decline associated with genetic risk are considered at ultra-high risk for developing schizophrenia (Gee and Cannon, 2011). It has been suggested that pharmacological intervention during the prodromal stage might retard or even detain the emergence of full-blown psychosis (Piras et al, 2014). It is noteworthy that only 30–40% of ultra-high risk individuals convert to full psychotic state (Gee and Cannon, 2011). Preventive strategies must be effective on halting schizophrenia symptoms and safe for the ultra-high risk individuals who will not convert. In this scenario, pre-clinical researches play a fundamental role in the development of more effective and non-detrimental strategies
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