Impact of individual variability in rat models of alcohol use disorder

Alcohol use disorder (AUD) has been defined as a chronically relapsing disorder associated with compulsion in alcohol seeking and taking, loss of control over alcohol intake, and the emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when alcohol is no longer available. Just a small proportion of people consuming alcohol develops AUD. AUD aetiology lies in the complex interaction between genetic and environmental factors which makes some individuals more vulnerable to escalate alcohol use and develop AUD than others who show a resilient phenotype. Moreover, AUD patients also differ in their pattern of alcohol consumption and symptoms, and AUD treatments and medications are not effective in all of them. Several phenotyping and genotyping criteria have been proposed to group alcoholic patients into more homogeneous subpopulations. Similarly, different rat models appear to differ in their phenotypes and genetic background. Therefore, as a heterogeneous and multifactorial disorder, AUD investigation benefits from the use of animal models since each rat model may well resemble a specific subpopulation of AUD patients. Focusing on three main objectives, the present thesis aims to investigate the impact of individual variability in different rat models of AUD to clarify how specific rat models can be suitable for the investigation of specific AUD populations and hence can contribute to the development of target therapies. After providing an overview of the research background in Chapter 1, the first study exposed in Chapter 2 aimed to develop a multisymptomatic animal model of AUD that would well mimic the high heterogeneity in alcohol phenotypes and treatment responses observed in patients. For this purpose, we selected as rat model the outbred NIH heterogeneous stock rats, a line that well resembles the genetically and phenotypically variability existing in the human population. Data collected from the screening of alcohol-related behaviors, allows me to group the HS population into three different clusters having different profiles of AUD-like behaviors. Responder and non-responder animals were individuated to naltrexone treatment, while memantine failed as alcohol-specific treatment, results that are both consistent with clinical outcomes. Moreover, I also detected a relationship between the anxiety trait and naltrexone efficacy. In Chapter 3, I focused on the role of the environment in inducing alcohol consumption. Specifically, I explored the short and long-term effects of adolescent sleep restriction on alcohol consumption and related behaviors in two different rat lines: the heterogeneous Wistar line and the genetically selected Marchigian Sardinian alcohol-preferring (msP) line. MsP rats mimic a specific AUD population in which ethanol abuse is associated with high comorbid anxiety and depression and their response to sleep restriction was homogenous and seemed to be driven by stress. In the outbred Wistar rats, instead, we observed interindividual variability in response to sleep restriction with a subgroup of animals showing a life-long lasting increase in alcohol consumption. Finally, since recent evidence from our laboratory has highlighted the existence of interindividual variability also in the highly homogenous msP rat line, in Chapter 4, I investigated this aspect in relation to the effect of the neuropeptide S, recently proposed as a potential target to develop new treatments for AUD. To contribute to filling the gap in gender-related studies in the AUD field, female msP rats were used for the present study. Thanks to their phenotypical characteristics, msP rats may represent a good animal model to study the relationship between anxiety and alcohol consumption in females. From this study, two clusters of animals were identified showing different responses to the treatment with NPS and pointing out the possibility of differences in the NPS/NPSR system in female msP rats. In conclusion, these studies together demonstrate how different rat lines may catch some aspects of the human disorder, making it possible to deeply explore the heterogeneity characterizing AUD and maximize the translational power of preclinical research in AUD.