Tuesday, May 13, 2025
5/13/2025
Stress-induced locus coeruleus dysfunction as a mediator of opioid abuse - Project Summary Opioid abuse and anxiety disorders are amongst the most prevalent psychiatric conditions in the United States, and diagnosis of one increases the risk of developing the other. Given their overlap and the current state of the opioid epidemic gripping the country, it is of critical importance to clarify the mechanisms that link these two conditions. The locus coeruleus (LC) is a brainstem nucleus involved in a wide array of central nervous system functions. Stress activates LC and promotes hypervigilant anxiety-like behavior. Although many studies in the past have investigated how stress affects the function of the LC at short intervals, less is known about how stressor exposure causes long term changes in the nucleus that are associated with a chronically altered behavioral state. Recent observations from our laboratory show that an acute traumatic stressor can produce long-lasting elevations in anxiety-like behavior and LC activity, and furthermore, these effects may be related to altered function of LC opioid receptors. This is of great importance due to the fact that endogenous opioid signaling in LC helps terminate the stress response, reduce LC activity, and promote a return to a non-anxious behavioral state. Thus, if stress blunts the function of opioid receptors in LC, endogenous opioids may not be sufficient to limit LC discharge to levels that do not promote anxiety. In this scenario, individuals with a history of chronic or traumatic stress might be predisposed to use abused opioids, because of their ability to potently inhibit LC. Furthermore, individuals who have recovered from opioid dependence might be likely to relapse when faced with a new stressor. Therefore, understanding the impact of stressor exposure on LC function and opioid signaling, and the role of endogenous opioid signaling in motivated behavior, may provide insights towards therapeutic approaches to counteract some of the abnormal behaviors seen in comorbid anxiety and opioid use disorders. The goals of this project are first to show that enhancing opioid signaling in LC is anxiolytic and reinforcing in animals that have experienced stress because of how it reduces LC hyperactivity, and therefore negative emotion. Second, we aim to show that traumatic stress also makes animals more likely to self- administer abused opioids because of stress-induced changes in LC. The hypothesis is that stress increases LC activity, which correlates with anxiety, and reduces the ability of LC to be inhibited by endogenous opioids. Therefore, animals will engage in behaviors that lead to artificially enhanced endogenous opioid signaling or delivery of intravenously abused opioids, because of their ability to reduce LC hyperactivity. The results of these experiments will demonstrate that a stress-induced neuroadaptation outside of the classical addiction circuitry has the ability make animals more likely to self-administer abused opioids. Such findings would have important implications for mechanisms of and treatments for both anxiety and opioid use disorders.
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