Dr Chesworth and her team investigated the therapeutic potential of the non-toxic cannabis plant compound, cannabidiol (CBD) for the treatment of substance use problems in mouse models for schizophrenia. CBD’s therapeutic potential was first examined in healthy animals (i.e. with no genetic mutation; Project 1) and then in mice which carry a genetic risk (i.e. mutation) to develop schizophrenia, the Neuregulin 1 transmembrane domain heterozygous (Nrg1) mouse (Project 2).
Project 1: Dr Chesworth examined if CBD could limit cocaine-induced behaviours and cocaine memories in control mice with no genetic mutations (Chesworth & Karl 2020 Pharmacology, Biochemistry & Behavior). It was demonstrated that CBD could limit how well cocaine-associated events and environments are remembered, for up to three weeks after stopping CBD treatment. A similar experiment was conducted using a self-administration apparatus, where animals could freely administer cocaine by pressing a lever in a chamber. It was found that CBD could reduce cocaine self-administration in healthy mice. In addition, Dr Chesworth examined the potential of CBD to prevent relapse-like behaviour when CBD is given during abstinence, as well as the molecular mechanisms that CBD acts by. It was found that CBD can prevent how cocaine-associated memories are formed via a process called consolidation, and this effect is associated with increased expression of the main cannabinoid receptor in the brain, cannabinoid receptor 1, in a brain region strongly associated with learning and memory, the hippocampus.
In collaboration with Prof Emad El-Omar, Dr Chesworth’s team have also recently started to investigate how CBD can affect the gut microbiome. They found that, in alignment with behavioural data showing CBD reduces how well cocaine-associated environments are remembered, CBD also ameliorates cocaine-induced gut microbiome changes. This suggests CBD may be acting on the gut, as well as the brain, to change drug addiction-related behaviours.
Project 2: In Dr Chesworth’s mouse model of genetic schizophrenia risk, she examined if CBD is effective in reducing how well cocaine-associated environments are remembered. Surprisingly, it was found that while CBD reduced cocaine memory in control animals, it had no effect on Nrg1 mice, suggesting CBD may not be effective in reducing the strength of cocaine memory in individuals with mutations in the Neuregulin 1 gene. This finding is being further investigated by examining if CBD can reduce cocaine self-administration in Nrg1 mice. Deficits in the ability of Nrg1 mice to stop cocaine use have been found and Dr Chesworth’s team is evaluating if CBD can change this deficit.
Finally, as an extension to the funded proposal, Dr Chesworth’s team found that adolescent CBD treatment actually increased susceptibility to suppressant effects of THC (Visini et al 2022 Frontiers in Cellular Neuroscience), again suggesting that CBD may not be protective in individuals with a Neuregulin 1 mutation. Together, this highlights the importance of testing novel therapeutics such as CBD in models of schizophrenia risk, to determine the efficacy of these therapeutics in individuals with schizophrenia who carry these genetic mutations.
