Probing the role of dopamine at the intersection of addiction, decision making, and sex

Addiction is an escalating, compulsive, and relapsing psychiatric disease that affects millions worldwide and exacts immense socioeconomic cost. As for potential pharmacotherapeutic targets, the dopamine system is of most interest, but it is unclear as to whether increasing or decreasing dopamine is the best approach. There is consensus that the cues associated with cocaine use and gambling (e.g., a crack pipe or flashing casino lights) are critical in driving disordered behaviour. It is also clear that the responsivity to drug and gambling cues is governed by dopamine and that there is considerable comorbidity between cocaine use and gambling disorder. Biological sex also plays a critical role in addiction but is confounded by the socioeconomic construct of gender in human studies, necessitating animal models. In the following thesis, we preclinically modeled the complex intersection of cocaine use and gambling-like behaviour by combining operant cocaine self-administration with the cued rat gambling task. While female and male rats gambled and took cocaine, we used chemogenetics to bidirectionally modulate the dopaminergic neurons projecting from the ventral tegmental area. We showed that chemogenetic inhibition of dopamine neurons decreased numerous addiction-like behaviours (e.g., risk-taking, impulsivity) in males, but surprisingly increased risk-taking in females. In both sexes, stimulation of the dopamine system had generally deleterious effects. Both inhibition and stimulation caused females and males to take more cocaine, but paradoxically prevented the increased risk-taking that results from cocaine self-administration. Drawing on the reward deficiency and incentive sensitization theories of addiction, this thesis furthermore proposes a biobehavioural framework through which the present findings may be understood.Medicine, Faculty ofGraduat