Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Steven Laviolette

2nd Supervisor

Walter Rushlow

Co-Supervisor

Abstract

Opiate addiction is a chronic disorder with high rates of relapse. The failure to maintain sobriety after prolonged abstinence is believed to be due in part to the persistence of potent memories associated with the drug-taking experience. Activation of these memories by re-exposure to drug-related cues can trigger craving in many individuals. Thus, understanding the neurobiological processes underlying the formation of these memories may provide insight into the persistence of addiction. The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. There is some evidence that chronic opiate exposure results in alterations to the function of dopamine (DA) D1 and D2 receptors and their intracellular targets within the BLA, but critical questions remain in regards to these effects within the BLA-mPFC circuit. For instance, opiate-induced alterations to intra-mPFC DA signaling in the context of associative opiate memories has not yet been explored. Furthermore, the role of the DA D3 receptor has not yet been investigated. Finally, there is little understanding of the temporal dynamics underlying these changes in DAergic signaling. Using behavioural models of associative memory formation (conditioned place preference and conditioned place aversion) paired with analyses of protein expression, we further characterized how chronic opiate exposure results in neuroplastic changes to DA receptor expression and signaling in the BLA-mPFC pathway. Here, we report that chronic opiate exposure results in a series of alterations to D1, D2 and D3 signaling within the BLA-mPFC circuit in the context of both opiate reward and withdrawal aversion memories. Specifically, we highlighted the importance of D2 and CaMKIIα signaling within the mPFC, identified the role of intra-BLA D3-Cdk5-calcineurin signaling in reward and aversion memory formation, and temporally mapped opiate-induced alterations to intra-BLA memory molecules. Together, these results provide a more complete understanding of how opiate exposure profoundly alters DA signaling between the dependent and non-dependent states. Interestingly, we found that many of the changes induced by chronic opiate exposure are not only transient, but may be functionally reversible, thus providing an avenue for future development of pharmacological interventions for opiate addiction.

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