Is Cannabidiol During Neurodevelopment a Promising Therapy for Schizophrenia and Autism Spectrum Disorders?

Schizophrenia and autism spectrum disorders (ASD) are psychiatric neurodevelopmental disorders that cause high levels of functional disabilities. Also, the currently available therapies for these disorders are limited. Therefore, the search for treatments that could be beneficial for the altered course of the neurodevelopment associated with these disorders is paramount. Preclinical and clinical evidence points to cannabidiol (CBD) as a promising strategy. In this review, we discuss clinical and preclinical studies on schizophrenia and ASD investigating the behavioral, molecular, and functional effects of chronic treatment with CBD (and with cannabidivarin for ASD) during neurodevelopment. In summary, the results point to CBD's beneficial potential for the progression of these disorders supporting further investigations to strengthen its use.

Role of the endocannabinoid and endovanilloid systems in an animal model of schizophrenia-related emotional processing/cognitive deficit.

Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia. The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs. Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats - WRs). The following drugs were used: AM404 (anandamide uptake/metabolism inhibitor), WIN55-212,2 (non-selective CB1 agonist), capsaicin (TRPV1 agonist), and capsazepine (TRPV1 antagonist). SHRs displayed increased CB1 expression in prelimbic cortex and cingulate cortex area 1 and in CA3 region of the dorsal hippocampus. Conversely, SHRs exhibited decreases in TRPV1 expression in prelimbic and CA1 region of dorsal hippocampus and increases in the basolateral amygdala. AM404, WIN 55,212-2 and capsaicin attenuated SHRs CFC deficit, although WIN 55,212-2 worsened SHRs CFC deficit in higher doses. WRs and SHRs CFC were modulated by distinct doses, suggesting that these strains display different responsiveness to cannabinoid and vanilloid drugs. Treatment with capsazepine did not modify CFC in either strains. The effects of AM404 on SHRs CFC deficit was not blocked by pretreatment with rimonabant (CB1 antagonist) or capsazepine. These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.

Young spontaneously hypertensive rats (SHRs) display prodromal schizophrenia-like behavioral abnormalities.

The Spontaneously Hypertensive Rat (SHR) strain has been suggested as an animal model of schizophrenia, considering that adult SHRs display behavioral abnormalities that mimic the cognitive, psychotic and negative symptoms of the disease and are characteristic of its animal models. SHRs display: (I) deficits in fear conditioning and latent inhibition (modeling cognitive impairments), (II) deficit in prepulse inhibition of startle reflex (reflecting a deficit in sensorimotor gating, and associated with psychotic symptoms), (III) diminished social behavior (modeling negative symptoms) and (IV) hyperlocomotion (modeling the hyperactivity of the dopaminergic mesolimbic system/ psychotic symptoms). These behavioral abnormalities are reversed specifically by the administration of antipsychotic drugs. Here, we performed a behavioral characterization of young (27-50 days old) SHRs in order to investigate potential early behavioral abnormalities resembling the prodromal phase of schizophrenia. When compared to Wistar rats, young SHRs did not display hyperlocomotion or PPI deficit, but exhibited diminished social interaction and impaired fear conditioning and latent inhibition. These findings are in accordance with the clinical course of schizophrenia: manifestation of social and cognitive impairments and absence of full-blown psychotic symptoms in the prodromal phase. The present data reinforce the SHR strain as a model of schizophrenia, expanding its validity to the prodromal phase of the disorder.

A schizophrenia-like behavioral trait in the SHR model: Applying confirmatory factor analysis as a new statistical tool.

Questionnaires that assess symptoms of schizophrenia patients undergo strict statistical validation, often using confirmatory factor analysis (CFA). CFA allows testing the existence of a trait that both collectively explains the symptoms and gathers the information in a single general index. In rodents, some behaviors are used to model psychiatric symptoms, but no single test or paradigm adequately captures the disorder's phenotype in toto. This work investigated the existence of a behavioral trait in the SHR strain underlying five behavioral tasks used in schizophrenia animal studies and altered in this strain: locomotor activity, rearing behavior, social interaction, prepulse inhibition of startle and contextual fear conditioning. The analysis was conducted on a sample of Wistar (n = 290) and Spontaneously Hypertensive Rats (SHRs, n = 290). CFA showed the existence of a continuous trait in both strains, and higher values among SHRs. This work is the first to demonstrate the existence of a schizophrenia-like trait in an animal model. We suggest that using CFA to evaluate behavioral parameters in animals might facilitate the pre-clinical investigation of psychiatric disorders, diminishing the gap between animal and human studies.

Peripubertal exposure to environmental enrichment prevents schizophrenia-like behaviors in the SHR strain animal model.

Schizophrenia is a highly disabling mental disorder, in which genetics and environmental factors interact culminating in the disease. The treatment of negative symptoms and cognitive deficits with antipsychotics is currently inefficient and is an important field of research. Environmental enrichment (EE) has been suggested to improve some cognitive deficits in animal models of various psychiatric disorders. In this study, we aimed to evaluate a possible beneficial effect of early and long-term exposure to EE on an animal model of schizophrenia, the SHR strain. Young male Wistar rats (control strain) and SHRs (21 post-natal days) were housed for 6weeks in two different conditions: in large cages (10 animals per cage) containing objects of different textures, forms, colors and materials that were changed 3 times/week (EE condition) or in standard cages (5 animals per cage - Control condition). Behavioral evaluations - social interaction (SI), locomotion, prepulse inhibition of startle (PPI) and spontaneous alternation (SA) - were performed 6weeks after the end of EE. SHRs presented deficits in PPI (a sensorimotor impairment), SI (mimicking the negative symptoms) and SA (a working memory deficit), and also hyperlocomotion (modeling the positive symptoms). EE was able to reduce locomotion and increase PPI in both strains, and to prevent the working memory deficit in SHRs. EE also increased the number of neurons in the CA1 and CA3 of the hippocampus. In conclusion, EE can be a potential nonpharmacological strategy to prevent some behavioral deficits associated with schizophrenia.

Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test.

Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs present a hyperlocomotion that is reverted by typical and atypical antipsychotics, suggesting that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia as well as the effects of potential antipsychotics drugs. At the same time, an increase in social interaction in control animals similar to that induced by benzodiazepines is used to screen potential anxiolytic drugs. The aim of this study was to investigate the effects of CBD on social interaction presented by control animals (Wistar) and SHRs. The lowest dose of CBD (1mg/kg) increased passive and total social interaction of Wistar rats. However, the hyperlocomotion and the deficit in social interaction displayed by SHRs were not altered by any dose of CBD. Our results do not support an antipsychotic property of cannabidiol on symptoms-like behaviors in SHRs but reinforce the anxiolytic profile of this compound in control rats.

Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia.

OBJECTIVES: Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR). METHODS: Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2). RESULTS: In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant. DISCUSSION: Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.