Alcoholism 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 alcoholics do not receive treatment, and current medications do not work for all sufferers, 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 alcoholics. 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. CeA and BNST synaptic activity are sensitive to acute alcohol and play a critical role in the behavioral effects of ethanol consumption. The CeA and oval BNST are rich in corticotropin releasing factor (CRF) neurons, as well as OT receptors, and acute OT modulates synaptic signaling in these regions in sex-specific ways. 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, but it is not yet known if OT exerts its effects through action on CRF neurons. Thus, OT may act directly on CRF neurons of the CeA and BNST to decrease withdrawal severity and alcohol drinking. The purpose of this project is to characterize hypothalamic OT neuronal input to CRF neurons of the CeA and BNST, whether these circuits are disrupted by alcohol dependence, and involvement of these circuits in alcohol dependence induced drinking. OT effects on GABAergic transmission in the CeA of nave and alcohol dependent animals has been elucidated, finding sexually dimorphic effects of OT and alcohol. Additionally, oxytocin receptor co-expression with CRF was high in the lateral CeA and independent of sex or alcohol history, but alcohol dependence decreased OT expressing neurons in the paraventricular nucleus of the hypothalamus (PVN), one major source of OT in the brain. The research progress of this project, as well as the timely transition of the principal investigator (PI) to a position as head of an independent laboratory at a new institution, has been directly negatively impacted by the COVID-19 pandemic and resulting hiring freezes and shut down of research activities. The requested supplement and extension would allow the completion of experiments investigating OT effects on CRF+ specific neurons of the CeA and BNST, as well as completion of experiments characterizing the PVN(OT) -> CeA(CRF) and PVN(OT) -> BNST(CRF) pathways via viral vector mediated expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). The supplement and extension will also allow for the principal investigator (PI) to transition to a position as a PI of an independent laboratory at a new institution, in line with the career goals of the PI and the intention of the Pathway to Independence award.
Oxytocin (OT) is a promising therapeutic for the treatment of alchohol dependence and withdrawal, and its sex-specific effects may be through direct actions on corticotropin (CRF) neurons of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), that are involved in stress/anxiety induced alcohol drinking. Further research into the basal functioning of the OT/CRF systems of the brain and how they are disrupted in alcohol dependence in a sex specific manner will lead towards a more targeted therapeutic use of OT in the treatment and prevention of alcohol dependence. This supplement will allow completion of preliminary experiments that were ended prematurely due to the COVID-19 pandemic and resulting shut down of research activities.
