LOSS OF CONTROL OVER SUBSTANCE USE: Preclinical studies into the behavioural and neural mechanisms of addiction

Substance addiction is a major medical and societal problem affecting millions of people. Loss of control over substance use is a hallmark of addiction. This is reflected, for example, in persistent substance use despite knowledge of substance-related problems. This thesis focusses on loss of control over substance use and other behavioural characteristics of addiction. The overarching aim of this thesis was to gain insight into changes in brain and behaviour that characterise substance addiction. To this aim, we used behavioural models that capture important aspects of addictive behaviour in combination with neuropharmacological interventions in rats. We developed a new behavioural task to assess control over reward seeking, which can be further used in future preclinical research. We also investigated how different behavioural aspects that are associated with alcohol addiction were related. For this analysis, we considered alcohol intake, habit formation, motivation for alcohol and the degree to which alcohol consumption is sensitive to negative stimuli. These behavioural components were found to contribute in different degrees to the addiction phenotype across individual animals. Moreover, we investigated the role of the neurotransmitter dopamine in weighing costs and benefits, and we studied the involvement of other neurotransmitters, namely GABA, opioids, and glutamate, in individual differences in alcohol consumption. Altogether, the findings in this thesis contribute to a better understanding of the underlying behavioural and neurobiological processes of addiction. Ultimately, the accumulating knowledge on addiction will help the development of more effective treatments for this brain disorder.