- Title
- Exploration of the molecular determinants of comorbid addiction in Schizophrenia
- Creator
- Greco, Laura Ashley
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2023
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Complex polygenic brain disorders including psychiatric, and substance use disorders (SUDs) pose a significant burden on individuals, families, and the global economy. These disorders are highly heritable and are thought to have both genetic and environmental aetiology. Schizophrenia, a common psychiatric disorder affecting approximately 1% of the global population, is characterised by a range of symptoms such as hallucinations, delusion, social withdrawal, and flat effect. Schizophrenia frequently co-occurs with SUDs, affecting nearly half of individuals (37-41.7%). This comorbidity is associated with poorer clinical outcomes, treatment resistance, contraindications, and non-compliance. Currently, 30% of patients with schizophrenia do not respond to first or second-generation anti-psychotics, with only 50-60% of the treatment resistance cohort responding to clozapine, one of the only alternative treatment options available. Non-compliance with schizophrenia treatment is likely due to side effects such as emotional blunting, metabolic syndrome, sexual dysfunction, nausea, vomiting, dizziness, and fatigue. Current treatment options for schizophrenia can even exacerbate substance-seeking behaviour. Treatment options for SUDs mainly focus on alleviating withdrawal symptoms, but they can be highly addictive themselves and do not address the underlying biological factors that contribute to dependence. The high heritability of schizophrenia and SUDs has paved the way for using genomic tools to unravel the molecular intricacies of these conditions. Genome-wide association studies (GWAS) have played a crucial role in advancing our understanding of schizophrenia and SUDs by examining genetic variations throughout the entire genome in large groups of individuals. Through GWAS, researchers have identified multiple genetic loci that are associated with these disorders, providing insights into the underlying molecular mechanisms and pathways involved in their development. Schizophrenia has seen remarkable progress in genomic research, with the identification of over 280 genome-wide associated loci. These findings have unveiled new genes, pathways, and potential therapeutic targets related to the disorder. In contrast to schizophrenia, the identification of therapeutic loci associated with SUDs has been more challenging. Several factors contribute to this difficulty, including the underpowered nature of studies focusing on specific substances like cocaine and methamphetamines. Additionally, the lack of differentiation between different patterns of substance use, the limited replication and validation of GWAS findings, and the heterogeneity in diagnostic criteria, inclusion, and exclusion criteria all contribute to the complexity of studying SUDs at the genetic level. To attempt to gain further insights into the genetic basis of SUDs and their overlap with schizophrenia, a meta-analysis was conducted. The analysis revealed a significant enrichment of genes and gene pathways associated with inflammatory and metabolic processes, along with an enrichment in microRNA target genes. This finding suggests that these biological processes may play a role in the development and manifestation of both SUDs and schizophrenia. Recent research has underscored the importance of small non-coding microRNAs (miRNAs) in modulating gene expression, influencing neuronal development, regulating synapse formation, and contributing to long-term plasticity. Notably, the MIR137 host gene located on human chromosome 1p22 has emerged as one of the most significant schizophrenia genome-wide associations. Additionally, abnormalities in synaptic plasticity within the central nervous system, particularly in orbito-striatal circuits, have been implicated in the development of addictive behaviours. Studies have shown dysregulation of miR-137 expression in the dorsal striatum of addiction-prone rats, with its expression being highly dependent on the stage of the addiction cycle. These findings highlight the potential involvement of miR-137 and synaptic plasticity in the underlying mechanisms of both schizophrenia and SUDs. To further explore the functional role of miR-137 in SUDs and schizophrenia, we over-expressed miR-137 in the dorsomedial striatum (DMS) of rats trained to reliably self-administer cocaine. We found that over-expression of miR-137 (miR-137OE) in the DMS promoted a compulsive-like phenotype that was significantly more likely to engage in drug-seeking behaviours despite negative consequences (foot-shock) compared to controls. Our findings also revealed that miR-137OE animals showed significantly reduced lever-presses during the time-out period when cocaine reinforcement was unavailable. Lever pressing during the time-out period is commonly associated with an inability to resist drug taking. Therefore, miR-137OE animals exhibiting a decrease in impulsive-like behaviour is suggestive that the downstream effects of miR-137 over expression manifest as a more concerning phenotype, with impulsive behaviour known to transition into compulsive behaviour in the later stages of the addiction cycle. This work highlights the complex but important contribution of dorsal striatal circuits to learning that might influence the development of addictive drug taking and seeking and the influence of synaptic plasticity associated microRNAs in the development of neuropsychiatric conditions. In addition to population-level approaches such as analysing GWAS summary statistics and conducting animal studies, it is crucial to consider individual patient characteristics when treating complex, polygenic disorders. This is because these disorders often require tailored approaches instead of a one-size-fits-all approach. To address this, we employed the pharmagenic enrichment score (PES) method, which considers the combined effects of common variants in clinically actionable pathways, alongside our population-level analyses of Cannabis use disorder (CUD). A significant number of individuals diagnosed with schizophrenia report using cannabis, with cannabis use associated with an earlier onset of schizophrenia and is a predictive risk factor for psychosis, particularly in individuals with a genetic predisposition to schizophrenia. Currently, there are no approved medications specifically for the treatment of CUD, making cannabis use and dependence a significant obstacle in the treatment and prognosis of schizophrenia. By utilising population and individual-level analyses to investigate CUD, we aimed to gain insights into potential pharmacogenomic targets and interventions that could address this challenging aspect of schizophrenia treatment. This uncovered intriguing findings regarding the association between liability to CUD and certain components of the extracellular matrix, particularly dysregulated expression of the hyaluronidase enzyme and inflammatory processes. One example of this association is the genetic correlation observed with inflammatory biomarkers such as C-reactive protein (CRP), which has been previously established to have a causal relationship with schizophrenia. Furthermore, the application of precision gene-set based drug repurposing techniques revealed potential candidates for repurposing existing drugs with immune-related properties. By combining in vivo biological investigations with bioinformatic and statistical analyses, our research strengthens the evidence supporting the existence of shared underlying biological mechanisms that contribute to the overlap between SUDs and schizophrenia.
- Subject
- addiction; Schizophrenia; microRNAs; SUDs; substances; bioinformatics
- Identifier
- http://hdl.handle.net/1959.13/1479638
- Identifier
- uon:50345
- Rights
- Copyright 2023 Laura Ashley Greco
- Language
- eng
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