Understanding the impact of addictive drugs on stress circuits

Drugs of abuse cause significant economic and societal harm. Currently, existing treatments for addiction are limited in their effectiveness and are easily undermined by the high propensity to relapse. Notably, a primary obstacle to the development of better treatments for addiction and relapse is the significant knowledge gaps in our understanding of the aberrant neurobiology that promotes addiction, relapse vulnerability, and the differences in neurobiological substrates engaged at distinct phases of the addiction. Stress has been widely associated with addiction and relapse propensity, with decades of research investigating the role of the HPA axis in modulating addiction. Most of this work has neuroendocrine changes to infer the functional status of the apex of the HPA axis, the corticotrophin-releasing-hormone (CRH) neurons of the hypothalamic paraventricular nucleus PVN following drug-taking or drug exposure. First, this thesis assessed the addiction-stress literature and synthesised the findings- and established the current gaps within the field. Secondly, we used utilised modern neuroscience techniques including photometry-based Ca2+ imaging and RNA scope to examine how CRH neurons respond to stress during exposure and early withdrawal from cocaine. Several mouse lines were utilised including, including CRH-cre, CRH::GCaMP, and wild type C57BL/6J, of both sexes. These studies were able to uncover variability in individual animals in bulk CRH neuron responses following cocaine exposure, along with aberrant corticosterone levels following stress and some evidence of altered coping behaviours. Notably, a significant reduction in CRHR2, and NPY1R but not CRHR1 expression was identified on CRH neurons after cocaine. Together, these findings suggest that altered functioning of PVN CRH neurons during early withdrawal from cocaine treatment alters stress coping. Unfortunately, due to the impacts of COVID-19, several follow-up studies to were unable to be performed. Regardless, this study has advanced our knowledge of how cocaine can interact with stress-response processes that influence behavioural and endocrine outputs, that are associated with an increase in the likelihood of relapse.