Cannabidiol as a potential preventative treatment in a Neuregulin 1 mouse model of schizophrenia

Abstract

Cannabidiol (CBD) is a non-psychoactive cannabinoid that has antipsychotic-like and anti-inflammatory properties, however its potential as a preventative drug in schizophrenia has not yet been investigated. Brain maturation during adolescent development creates a window where CBD could potentially limit the development of schizophrenia. The Neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mouse shows face, predictive, and construct validity as a mouse model of schizophrenia. This project sought to determine if CBD given in adolescence could prevent the development of the schizophrenia-relevant phenotype in Nrg1 TM HET mice, as well as prevent susceptibility to the psychoactive cannabinoid ??-- tetrahydrocannabinol (THC), in these mice. In Experiment 1, the baseline behavioural and neuroinflammatory phenotype of Nrg1 TM HET mice was first re-established at the novel Western Sydney University behavioural laboratory. Nrg1 mutant mice exhibited hyperlocomotion, social interaction deficits, reduced startle response, and increased sensitivity to 3 mg/kg THC, with a trend for reduced sensorimotor gating. There were no changes in neuroinflammatory markers. In Experiment 2, Nrg1 mutant and wild type-like (WT) animals were treated daily with 30 mg/kg CBD for 3 weeks during adolescence, and then tested for hyperlocomotion, social behaviour, sensorimotor gating and fear-associated learning and memory (tests informed by Experiment 1) during the subsequent 3 weeks while treatment continued. A week after these, mice completed a behavioural test battery under acute THC treatment. Chronic CBD increased locomotion in both genotypes, and after an extended period increased social behaviours in all mice, as well as reducing levels of glutamate decarboxylase (GAD) in the hippocampus. Combined, prior CBD and acute THC impaired startle habituation in Nrg1 mutants, but not WT mice. THC alone increased social behaviours in Nrg1 mice. In Experiment 3, Nrg1 TM HET and WT mice were administered CBD during adolescence and then left in the home cage until adulthood (5-6 mo) before undergoing behavioural testing. CBD had converse effects, and reduced anxiety in mutants and overallsociability and hippocampal levels of cannabinoid 1 (CB1) receptors in both genotypes, though these were found to be increased in the hippocampus of mutant animals at this age. Combined, a prior chronic course of CBD then paired with later acute THC in adulthood decreased startle in Nrg1 mutants, but not WT mice. These data suggest chronic adolescent CBD has persistent effects on the brain and behaviour and may potentiate later effects of THC, particularly in Nrg1TM HET mice.

Date of Award	2021
Original language	English