Cannabidiol Administered During Peri-Adolescence Prevents Behavioral Abnormalities in an Animal Model of Schizophrenia
Fernanda F. Peres, Mariana C. Diana, Raquel Levin, Mayra A. Suiama, Valéria Almeida, Ana M. Vendramini, Camila M. Santos, Antônio W. Zuardi, Jaime E. C. Hallak, José A. Crippa and Vanessa C. Abílio
Frontiers in Pharmacology, 2018, 9, article 901.
Doi : 10.3389/fphar.2018.00901
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 schizophrenialike 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.
Keywords : schizophrenia, cannabidiol, SHR strain, prevention, side effects, animal models, serotonin, BDNF
Schizophrenia is a debilitating psychiatric disorder whose pharmacotherapy remains unable to treat all core symptoms. In addition, currently available treatments are associated with high rates of treatment resistance and significant motor and metabolic side effects (Briles et al., 2012). The onset of schizophrenia occurs mainly between late adolescence and early adulthood and it is preceded by a prodromal phase. 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). In 2010, researchers predicted that prevention
strategies would be implemented on the following decades and could diminish first-episode psychosis (Insel, 2010; Tandon et al., 2010). Nonetheless, so far few studies have investigated potential preventive pharmacological interventions (Lambert et al., 2016). It is also noteworthy that only 30–40% of ultra high risk individuals convert to full psychotic state (Gee and Cannon, 2011). Therefore, preventive strategies must be effective on halting schizophrenia symptoms and also 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.
The spontaneously hypertensive rat (SHR) strain is suggested as an animal model to study several aspects of schizophrenia. When compared with Wistar rats (WRs), SHRs display schizophrenia-like behavioral abnormalities that are reversed by antipsychotic drugs and potentiated by pro-psychotic manipulations (Calzavara et al., 2009; Calzavara et al., 2011; Levin et al., 2011). Adult SHRs display diminished social interaction (that mimics the negative symptoms of schizophrenia – File and Seth, 2003), increased locomotor activity (a model for the positive symptoms – Lipska and Weinberger, 2000), deficit in contextual fear conditioning (that reflects alterations in emotional processing – Maren et al., 2013), and impaired prepulse inhibition of startle (PPI, associated with deficits in the processing of pre-attentional information commonly seen in schizophrenia – Braff et al., 2001). In addition, we have recently performed a behavioral characterization of young (30– 50 days old) SHRs. Contrary to what seen in adulthood, 30- days old SHRs do not display hyperlocomotion or PPI deficit; on the other hand, 30- and 45-days old SHRs already display decreased social interaction and impaired fear conditioning, respectively (Niigaki et al., unpublished). This early emergence of negative-like symptoms and late emergence of positive-like symptoms is in accordance with schizophrenia’s clinical course (Piskulic et al., 2012; Fusar-Poli et al., 2013). Taken as a whole, these data reinforce the SHR strain as a model to investigate the development of the disorder and not only therapeutic interventions (Levin et al., 2012, 2014; Almeida et al., 2013, 2014), but also preventive strategies (Santos et al., 2016; Diana et al., 2018).
Cannabidiol (CBD) is a non-psychotomimetic compound of Cannabis sativa that presents antipsychotic profile in rodents and humans (Rohleder et al., 2016). In animals, treatment with CBD attenuates several schizophrenia-like behavioral abnormalities. Acute administration of CBD restores SHRs’ impairments in both PPI and fear conditioning tasks (Levin et al., 2012, 2014). More recently, Osborne et al. (2017) described beneficial effects of prolonged treatment with CBD during late adolescence /adulthood on social interaction and memory impairments in a neurodevelopmental animal model of schizophrenia – the maternal immune activation by poly I:C (Meyer and Feldon, 2012). Accordingly, clinical studies show that prolonged treatment with CBD is able to treat the symptoms of schizophrenia patients (Rohleder et al., 2016), and the psychotic symptoms induced by L-DOPA in patients with Parkinson’s disease (Zuardi et al., 2009). Moreover, CBD does not promote motor effects, such as catalepsy and oral dyskinesia (Zuardi et al., 1991; Dos-Santos-Pereira et al., 2016), extrapyramidal side effects commonly induced by antipsychotic drugs (Briles et al., 2012). However, despite the growing evidence of CBD’s neuroprotective effects (Campos et al., 2017) and therapeutic applications in schizophrenia, so far only one previous study investigated peripubertal administration of CBD as a preventive strategy (Peres et al., 2016a): CBD prevents the emergence of hyperlocomotion in adulthood in the poly I:C model.
The aim of the present study was to evaluate whether CBD would prevent the emergence of schizophrenia-like behavioral abnormalities in the SHR model. For that, animals were treated during peri-adolescence and their behaviors were evaluated at adulthood. Throughout treatment, we assessed motor and metabolic side effects commonly associated with antipsychotic drugs. With respect to possible mechanisms of action, several molecular targets have been associated to CBD’s beneficial effects
(Ibeas Bih et al., 2015). Considering its antipsychotic profile and the neurodevelopmental course of schizophrenia, we quantified the levels of dopamine, serotonin and their metabolites as well as of brain derived neurotrophic factor (BDNF) in striatum and prefrontal cortex, two regions associated to the pathophysiology of the disorder. These evaluations were performed after the end of CBD treatment and in adulthood.