Interaction of the Opioid and Oxytocin Systems in the Context of Anxiety-Like Behavior

Anxiety and mood disorders affect approximately 20% of the United States population and increase the national economic burden. These disorders are also major contributors to the global burden of diseases as they are a leading cause of disability worldwide and increase the risk of developing other physical and mental ailments. Additionally, despite the availability of numerous pharmacotherapies for anxiety and mood disorders, these approved medications have low remission rates and often have negative side effects. Neuropeptides, such as oxytocin and endogenous opioids, are important for emotion regulation. Previous studies demonstrated that activation of oxytocin or -opioid receptors can attenuate the stress and fear response and increase social interaction in male and female mice, suggesting that they have similar functions and work together. Additionally, previous studies demonstrated that the oxytocin system can be influenced by opioids and opioid blockers in the context of parturition and lactation. However, it remains to be determined whether these systems interact to facilitate emotion-like behavior. I hypothesized that oxytocin would reduce anxiety- and depression-like behavior in male and female mice. Using the elevated zero maze and the tail suspension test, I demonstrated that centrally administered oxytocin increased open zone occupancy and entries and reduced immobility duration in the tail suspension test. I also hypothesized that the opioid and oxytocin systems could interact, such that -opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin, and that -opioid receptor blockade would not have an effect. To test this hypothesis, I blocked -opioid receptors using naloxone or CTAP and blocked -opioid receptors using norbinaltorphimine, then infused oxytocin directly to the brain of male and female mice. Contrary to my hypothesis, I found that blocking -opioid receptors enhanced the anxiolytic-like effect of oxytocin, whereas blocking -opioid receptors inhibited the anxiolytic-like effect of oxytocin. Given the observed interaction and reports of oxytocin, -opioid receptor, or -opioid receptor expression in brain regions important to emotion regulation (i.e., the central amygdala), I hypothesized that oxytocin (oxtr), -opioid (oprm1), and -opioid (oprk1) receptors were expressed in the same cell in the central amygdala. I used RNAScope technology to label and enumerate cells containing oxytocin, -opioid, and -opioid receptor mRNA. This study demonstrated that 38% of oxtr-expressing cells colocalized only oprm1 and 56% of oxtr-expressing cells colocalized both oprm1 and oprk1. These findings suggest that opioid and oxytocin receptors can interact at the cellular level. Future work will examine the physiological basis for the interaction between opioid and oxytocin receptors using transgenic behavior and electrophysiological assays. The present thesis highlights the interaction between endogenous opioids and the oxytocin system in emotion regulation and has implications for the development of novel clinical treatments for anxiety disorders.