_ Approximately 51% of people over the age of 12 are drinkers (120 million), and of these current users, 13.9% have met the criteria for alcohol use disorder (AUD). Severe AUD is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative emotional states (e.g., dysphoria, anxiety, pain) and the development of negative motivational symptoms (e.g., escalation of drug intake and compulsive drug seeking). This transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Accordingly, alcohol may be sought after and taken in excessive amounts to alleviate the negative, withdrawal-related symptoms. Our rodent model of alcohol dependence reliably demonstrates escalated alcohol drinking and alcohol seeking during withdrawal. Importantly, we have also identified the emergence of significant pain hypersensitivity (or hyperalgesia) in dependent animals, which may serve as a key negative reinforcement mechanism. During alcohol withdrawal, the robust escalation of drinking and hyperalgesia in dependent animals is associated with an increase in central brain glucocorticoid receptor (GR) signaling, a key mediator of stress responsiveness. Importantly, systemic GR antagonism via mifepristone reduces alcohol-mediated hyperalgesia as well as escalated drinking in both preclinical animal models as well as early clinical trials. The main research objective of the current proposal is to investigate the convergence of central nociceptive and alcohol-seeking biobehavioral mechanisms in promoting and/or maintaining the alcohol-dependent state. Our preliminary work has identified an increase in GR phosphorylation within the cingulate cortex of alcohol-dependent rats, and we hypothesize a specific role for increased cingulate glucocorticoid activity in the promotion of both excessive drinking and hyperalgesia. This proposal will provide a promising PhD student with vital research training through studies that use an integrative approach to test the predictions that: 1) alcohol dependence-related escalation of drinking and hyperalgesia is mediated by GR signaling within the cingulate, and 2) alcohol dependence-related potentiation of in GR activity in the cingulate cortex is localized to ?pro-nociceptive? excitatory pyramidal neurons and can be attenuated with mifepristone-mediated GR antagonism. These experiments will train a future independent scientist in the functional analysis of candidate mechanisms underlying alcohol dependence and chronic pain. The results of these studies will provide a greater understanding of the neurobiology of alcohol use disorder and an emerging therapeutic, and will additionally contribute to the development of effective treatment strategies for comorbid AUD and pain, leading to improvements in health and decreased morbidity of affected individuals.
This application for an individual research fellowship will provide an immensely valuable training opportunity for an aspiring future independent scientist in the alcohol research field. The project proposed as part of a comprehensive training plan will examine the role of glucocorticoid signaling in the cingulate cortex in the development and maintenance of alcohol dependence and associated pain conditions.
