Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model

Ashleigh L. Osborne, Nadia Solowij, Ilijana Babic, Xu-Feng Huang and Katrina Weston-Green

Neuropsychopharmacology, 2017, 42, 1447–1457
0893-133X/17
www.neuropsychopharmacology.org

doi:10.1038/npp.2017.40

Neuropsychiatric disorders such as schizophrenia are associated with cognitive impairment, including learning, memory and attention deficits. Antipsychotic drugs are limited in their efficacy to improve cognition; therefore, new therapeutic agents are required. Cannabidiol (CBD), the non-intoxicating component of cannabis, has anti-inflammatory, neuroprotective and antipsychotic-like properties; however, its ability to improve the cognitive deficits of schizophrenia remains unclear. Using a prenatal infection model, we examined the effect of chronic CBD treatment on cognition and social interaction. Time-mated pregnant Sprague-Dawley rats (n=16) were administered polyinosinic-polycytidilic acid (poly I:C) (POLY; 4 mg/kg) or saline (CONT) at gestation day 15. Male offspring (PN56) were injected twice daily with 10 mg/kg CBD (CONT+CBD, POLY+CBD; n=12 per group) or vehicle (VEH; CONT+VEH, POLY+VEH; n =12 per group) for 3 weeks. Body weight, food and water intake was measured weekly. The Novel Object Recognition and rewarded T-maze alternation tests assessed recognition and working memory, respectively, and the social interaction test assessed sociability. POLY+VEH offspring exhibited impaired recognition and working memory, and reduced social interaction compared to CONT+VEH offspring (po0.01). CBD treatment significantly improved recognition, working memory and social interaction deficits in the poly I:C model (po0.01 vs POLY +VEH), did not affect total body weight gain, food or water intake, and had no effect in control animals (all p40.05). In conclusion, chronic CBD administration can attenuate the social interaction and cognitive deficits induced by prenatal poly I:C infection. These novel findings present interesting implications for potential use of CBD in treating the cognitive deficits and social withdrawal of schizophrenia.

INTRODUCTION

Evidence suggests that exposure to a prenatal infection during the first or second trimester of pregnancy can disrupt neurodevelopment, increasing the risk of developing neuropsychiatric disorders such as schizophrenia (Meyer, 2013). Prenatal infection with polyinosinic-polycytidilic acid (poly I:C), a synthetic double-stranded RNA virus, is a welldocumented rodent model of schizophrenia-like phenotypes (Meyer, 2014; Meyer and Feldon, 2012). Following administration to the pregnant dam, poly I:C binds to the Toll-like receptor 3 and initiates a maternal immune response that raises pro-inflammatory cytokines in the placenta, amniotic fluid, and fetal brain (Meyer, 2013; Meyer et al, 2009). Neuro-inflammation in the foetal brain activates microglia, causing white matter injury and neuronal apoptosis (Meyer, 2013). Consequently, behavioral (eg deficits in cognition, social interaction and sensorimotor gating), neurochemical (eg striatal dopaminergic hyperfunction) and structural (eg reduced hippocampal and prefrontal cortical volumes) brain changes are observed in poly I:C offspring, which reflect observations in schizophrenia patients (as reviewed in Meyer, (2014)). These alterations emerge in the offspring during early adulthood, reflecting the delayed onset of schizophrenia symptoms observed in the clinic (Meyer, 2013). Moreover, some of the behavioral and structural changes induced by poly I:C can be reversed with clozapine and risperidone administration (Piontkewitz et al, 2009, 2011). Therefore, the poly I:C model shows construct, face and predictive validity, making it a useful tool to investigate pharmacological interventions for the treatment of schizophrenia (Meyer, 2014).

Cognitive dysfunction, including impairments to memory, attention, and executive functioning, is experienced by 75–85% of people with schizophrenia (Barch and Ceaser, 2012). Cognitive deficits often precede the onset of other symptoms and are associated with poor medication compliance and a higher tendency for relapse in first episode psychosis (Meyer et al, 2011b). In fact, cognitive deficits are thought to be a better prognostic indicator in patients than other symptom domains, as earlier disease onset correlates with the severity of cognitive dysfunction (Gray and Roth, 2007) and cognitive dysfunction predicts clinical course and future functional outcomes (Green, 2006). The negative symptoms, which include alogia (lack of speech), avolition (lack of motivation), anhedonia (inability to feel pleasure), and social withdrawal, are frequently associated with disturbances to psychosocial functioning, relationships, employment and overall quality of life (Lindenmayer et al, 2013). While the positive symptoms of schizophrenia (hallucinations and delusions) are usually controlled by antipsychotic drug (APD) treatment, the drugs have minimal efficacy to improve the cognitive symptoms (Gray and Roth, 2007) and one-third of patients who experience negative symptoms are APD-resistant (Lindenmayer et al, 2013). Furthermore, APDs can cause side effects, particularly motor and metabolic (obesity and type 2 diabetes mellitus) disturbances (Weston-Green et al, 2013). Therefore, there is a requirement to improve the pharmacological treatment of schizophrenia.

A growing body of evidence demonstrates that cannabidiol (CBD), a component of Cannabis sativa, prevents hallucinations and cognitive impairment induced by cannabis and delta-9-tetrahydro-cannabinol (Δ9-THC) administration (reviewed in Schubart et al (2014)). Studies reported that CBD limited the positive and negative schizophrenia-like phenotypes in the MK-801 model, suggesting that CBD has antipsychotic potential (reviewed in Schubart et al (2014)). These findings translate to the clinic, where CBD treatment improved positive and negative symptoms in schizophrenia patients, performing comparably to a current APD, amisulpride, with fewer side effects (Leweke et al, 2012). A number of preclinical models of cognitive impairment suggest that CBD improves learning and memory (as reviewed in Osborne et al (2017)); however, the effect of CBD on the cognitive deficits of schizophrenia is unclear. For example, acute CBD did not improve selective attention in schizophrenia outpatients (Hallak et al, 2010), or MK-801-induced social recognition memory deficits in rats (Deiana et al, 2015). CBD was protective against MK-801-induced object recognition memory impairment at high doses (Gomes et al, 2015a,b); its effect on other cognitive domains impaired in schizophrenia (ie working memory) is unknown. A disadvantage of pharmacological models is that they do not incorporate neurodevelopmental or genetic approaches, which underlie the aetiology of schizophrenia in humans (Mouri et al, 2013). Therefore, the aim of this study was to determine whether chronic CBD treatment could improve recognition and working memory impairment, and social withdrawal in a neurodevelopmental model of schizophrenia- like phenotypes. Body weight, food and water intake was also measured to determine whether CBD induces weight gain or hyperphagia.

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