Hypothalamic Oxytocin Influence on Extended Amygdala CRF Neurons in Alcohol Dependence

Overview

Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive seeking and consumption of alcohol, the result of a transition from recreational use to abuse and dependence. Most AUD sufferers do not receive treatment, and current medications do not work for all patients, highlighting the need for new therapeutics. alcohol dependence induces heightened activity of brain stress systems, resulting in the negative affective state associated with withdrawal. The neuropeptide oxytocin (OT) is anti-stress, and systemic administration of OT decreases withdrawal symptom severity and drinking in AUD patients. The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are two brain regions considered to be hubs for stress processing, and the role of pro- and anti-stress neuropeptides in these brain regions are critical for the development of alcohol dependence. Synaptic activity in the CeA and BNST is sensitive to acute alcohol and plays a critical role in the behavioral effects of ethanol consumption. The CeA and BNST are rich in neuropeptides and their receptors, including corticotropin releasing factor (CRF) and OT, and ethanol’s effects on synaptic signaling in these regions may be modulated by neuropeptide activity. CRF is involved in the heightened stress and anxiety associated with alcohol dependence and withdrawal, and blocking CRF activity in the CeA and BNST can reduce alcohol drinking. Thus, the balance between anti- and pro-stress signaling is likely perturbed during the transition to alcohol dependence, characterized by an overactive CRF system. OT producing neurons in the paraventricular and supraoptic nuclei of the hypothalamus project to both the CeA and BNST, to specific subdivisions that contain CRF neurons. Thus, OT may act directly on CRF neurons of the CeA and BNST to decrease withdrawal severity and alcohol drinking. During the training phase of the Pathway to Independence award, under the mentorship of Drs. Marisa Roberto, Amanda Roberts, and Candice Contet, I obtained training in chemogenetics (in vivo and ex vivo), transgenic methodologies, molecular biology techniques, and behavioral pharmacology that will allow me to further characterize and manipulate hypothalamic OT neuronal input to CeA and BNST CRF neuron involvement in alcohol dependence. In the independent phase of this award, I will continue to characterize effects of OT, acute alcohol, and alcohol dependence on CRF neurons in the CeA and BNST, ensuring data obtained and protocols used during the training portion are replicable in my laboratory at UTHSC. I will then use chemogenetics in vivo to determine OT circuit involvement in alcohol dependence induced alcohol drinking, as well as interfere with the development of the alcohol dependence phenotype. These studies will allow determination of a causal role of dysregulated oxytocin action in alcohol dependence and related behavioral phenotypes (stress and anxiety). Completion of these studies will provide insight into the role of OT as a potential therapeutic in treating AUD and stress/anxiety disorders.