Opposing Contributions of Oxytocin and Corticotropin-Release Factor to Alcohol Dependence

Overview

Alcohol use disorder is a global public health issue for which more effective treatments are urgently needed. alcohol dependence is characterized by exacerbated brain stress signaling that drives compulsive drinking. A major component of this signaling is the pro-stress neuropeptide corticotropin releasing factor (CRF). Oxytocin is a neuropeptide with an anti- stress, anti-CRF profile of action, which blocks compulsive drinking in alcohol-dependent rats. However, the neuronal circuitry through which oxytocin exerts its anti-compulsive drinking effect is not known. Therefore, the aim of the present Pathway to Independence Award proposal is to obtain the necessary training to identify, interrogate, and manipulate mechanisms underlying oxytocin’s ability to block compulsive alcohol drinking. Technical training will be conducted at the National Institute on drug abuse, Intramural Research Program and prepare the candidate to use these techniques independently in the proposed and future experiments. Training will be complimented with mentorship and career development activities tailored toward the candidate’s goal of securing a tenure-track academic position at an extramural research institute. Oxytocin fibers project from the hypothalamus to allow local release of oxytocin in sites throughout the brain, including the extended amygdala, a collection of brain nuclei in which CRF mediates dysregulated stress signaling in alcohol dependence. This proposal will first aim to map oxytocin projections throughout the whole brain, and identify CRF cells and their co- expression with the oxytocin receptor in terminal regions. The synaptic interaction between oxytocin fibers and CRF cells will be determined using immuno-electron microscopy. This will allow the identification of regions with high likelihood of oxytocin-CRF interaction. The second aim is to use fiber photometry to monitor the activity of CRF cells in awake-behaving CRF-Cre rats, in regions of likely oxytocin-CRF interaction. This will allow in vivo assessment of CRF cell function in alcohol dependence, as well as in response to alcohol drinking and oxytocin administration. The third aim is to use optogenetics to activate or inhibit the release of oxytocin from terminal fibers in regions of likely oxytocin-CRF interaction. This will allow determination of a causal role of local oxytocin action in alcohol drinking and other behaviors dysregulated in alcohol dependence (anxiety and pain). Completion of these studies will provide novel insights into the neurocircuitry and interaction of oxytocin and CRF, which have opposing roles in alcohol dependence. The present project is of high importance for public health, given the potentially high therapeutic value of oxytocin-based medications for alcoholism.