Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia

Abstract

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Timemated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for postmortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:Cinduced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect Nmethyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid, anandamide. Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model.

The Alternations of Endocannabinoid System and its Therapeutic Potential in Autism Spectrum Disorder

“…As the main molecular target of eCBs, CB1R is found high densities on presynaptic termini of glutamatergic and GABAergic neuron, thereby, the activation of CB1R is implicated in regulation of excitatory-inhibitory balance, synaptic strength and neurotransmitter release, ultimately mediating social functioning, learning and memory [35,36]. In conjunction, genetic variants in CNR1 (encoding CB1R) gene were correlated to not only verbal but non-verbal social communication as well in ASD researches [37,38].…”

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

“…In males, chronic CBD treatment in early adulthood rescued deficits in short term working memory in the novel object recognition test and rewarded t-maze, as well as social interaction deficits in Poly I:C rats, with no effects of CBD in non-Poly I:C treated rats [174]. Chronic CBD treatment in early adulthood attenuated Poly I:C-induced deficits in CB 1 receptor binding in the PFC as well as GAD67 binding in the hippocampus [175]. CBD also increased protein levels of the interneuron marker parvalbumin in the hippocampus, irrespective of maternal infection, but did not affect NMDA or GABA-A receptor binding or protein levels of fatty acid amide hydrolase (FAAH), the enzyme which degrades anandamide, in the PFC or hippocampus.…”

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

“…Four of the studies used a peripubertal/adolescence CBD treatment without continuing it throughout adulthood ( Peres et al, 2016a ; Peres et al, 2018a ; Stark et al, 2019 ; Stark et al, 2020 ). In the other six, CBD administration started at late adolescence and extended throughout adulthood ( Gomes et al, 2014 ; Gomes et al, 2015 ; Osborne et al, 2017 ; Osborne et al, 2019a ; Osborne et al, 2019b ; Jimenez Naranjo et al, 2019 ). Considering the long-term effects of CBD as a preventive strategy, it should be noted that, in four studies ( Osborne et al, 2017 ; Osborne et al, 2019a ; Osborne et al, 2019b ; Jimenez Naranjo et al, 2019 ), the chronic preventive effect of CBD could be confounded with a subacute effect (or even an acute effect).…”

“…In the other six, CBD administration started at late adolescence and extended throughout adulthood ( Gomes et al, 2014 ; Gomes et al, 2015 ; Osborne et al, 2017 ; Osborne et al, 2019a ; Osborne et al, 2019b ; Jimenez Naranjo et al, 2019 ). Considering the long-term effects of CBD as a preventive strategy, it should be noted that, in four studies ( Osborne et al, 2017 ; Osborne et al, 2019a ; Osborne et al, 2019b ; Jimenez Naranjo et al, 2019 ), the chronic preventive effect of CBD could be confounded with a subacute effect (or even an acute effect). In the other two studies, CBD administration occurred concomitantly with the pharmacological induction of the schizophrenic-like phenotype ( Gomes et al, 2014 ; Gomes et al, 2015 ).…”

“…This section will discuss CBD treatment's impact during later periods of development (end of adolescence/early adulthood) on the schizophrenia-like phenotype in adulthood. Two different schizophrenia animal models were used: the already mentioned MIA through poly I:C administration during the gestational period ( Osborne et al, 2017 ; Osborne et al, 2019a ; Osborne et al, 2019b ; Jimenez Naranjo et al, 2019 ) and a late adolescence/early adulthood transient NMDA receptor antagonism model ( Li et al, 2011 ; Uttl et al, 2018 ; Ma et al, 2020 ) through daily MK-801 administration during 28 days ( Gomes et al, 2014 ; Gomes et al, 2015 ). Similar to the above-discussed data, prolonged administration of CBD during late adolescence/early adulthood also presented several benefits regarding the manifestation of a schizophrenia-like phenotype in all the studies.…”