Brain substrates of behavioural endophenotypes predictive of compulsive drug-seeking

Abstract

Addiction, also known as severe substance use disorder, is characterised by compulsive drug-seeking and intake in the face of mounting adverse and negative consequences. Despite the prevalence of illicit drug use within society only a small subset of individuals lose control over their intake after protracted drug use. Several antecedent behavioural endophenotypes and perturbations in underlying reward-related circuitry have been linked with increased vulnerability of the development of addiction. To what extent these behavioural and neural markers pre-exist or are induced by drug exposure is still yet to be fully addressed. In this thesis, behavioural testing for risk endophenotypes was combined with a self-administration model of compulsive cocaine seeking and translationally relevant magnetic resonance imaging to investigate the behavioural and neurobiological underpinnings of vulnerability to compulsive cocaine seeking in rats. A behavioural screening procedure was employed and the underlying relationships between several risk endophenotypes was assessed. Attribution of incentive salience was unrelated to impulsivity yet was positively associated with novelty place preference and locomotor reactivity. ‘Stickiness’ – the tendency to repeat the same choice regardless of reward outcome – on a reversal learning procedure was positively associated with motor impulsivity. A concurrent punishment- drug-seeking procedure was next implemented to assess vulnerability to compulsive cocaine seeking. Of the behavioural risk endophenotytpes assessed, impulsivity along with stickiness significantly predicted compulsive cocaine seeking. In the final chapter, impulsivity and compulsivity were shown to predict lower grey matter volume in the infralimbic cortex and ventral striatum. Functionally, compulsivity and stickiness were predicted by decreased connectivity between the prelimbic cortex and the anterior cingulate cortex with the posterior dorsomedial striatum. In summary, this thesis supports previous work implicating impulsivity as a vulnerability marker for substance dependence in humans, and as a marker for compulsive cocaine use in rodents. These findings extend earlier reports to show that impulsivity, alongside stickiness, predicts future compulsive cocaine seeking. Furthermore, this thesis shows overlapping abnormalities in cortico-striatal networks in future compulsive animals and convergent structural deficits in the infralimbic cortex and ventral striatum of high compulsive and impulsive rats. These findings expand our understanding of vulnerability to drug-seeking by showing that pre-existing deficits in circuits contributing to impulse control and flexible, goal-directed behaviour may be precursors for the emergence of compulsive cocaine seeking.