Tinnitus is the perception of sound in the absence of an external environmental stimulus. This phantom sound in the head, sometimes referred to as “ringing in the ears,” is a Fiscal Year 2018 Peer Reviewed Medical Research Program topic area. It is most commonly caused by noise exposure, resulting in damage to the inner ear containing the hair cells and nerve fibers that carry sound to the brain. The military working environment presents many high noise situations with noise levels often so intense that standard hearing protection is not adequate. A recent study found that Soldiers deployed to battle zones were ~52 times more likely to suffer auditory damage than non-deployed Soldiers. The American Tinnitus Association reports that within the Veteran population seeking Department of Veterans Affairs (VA) care, 16%-27% suffer from serious hearing loss and tinnitus. The VA awarded disability compensation for serious hearing loss tinnitus to approximately 972,000 Veterans with an annual aggregate cost of nearly $1.5 billion. The U.S. Centers for Disease Control and Prevention estimates that more than 50 million Americans – nearly 15% of the population – experience some form of tinnitus, with 10%-15% of this total suffering extreme and debilitating tinnitus. Conversely, the majority of chronic tinnitus sufferers are able to ignore their tinnitus, tuning out the din while going about their daily lives. Unfortunately, those most affected are bound to the sounds in their heads; they have great difficulty concentrating, suffer from depression, cannot do regular work and may even contemplate suicide. Studies proposed here are focused on developing a treatment for those individuals most impacted by tinnitus. Our hypothesis postulates that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus, allowing patients to return to a more normal life. We propose that drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention could ameliorate tinnitus. Our preliminary studies have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. All proposed studies will be carried out in our well-established rat tinnitus model, and our laboratories have significant experience in all proposed methods. Proposed studies will test the ability of Chantix to ameliorate tinnitus. Similar to what is seen in human tinnitus patients, our recent studies in a rat tinnitus model finds tinnitus-related deficits in selective attention. We will test if both these drugs related to nicotine can normalize selective attention in our animal model. Proposed basic science studies will test if these agents can normalize aberrant brain cell response properties recorded in structures located at the highest level of the central auditory system, the auditory cortex. Preliminary receptor binding studies suggest that nicotinic acetylcholine receptors are altered in animals with evidence of tinnitus. Proposed studies will map the markers for the different receptor subtypes that make up these acetylcholine receptors in animals with and without tinnitus. Using brain slices from auditory cortex of animals with and without tinnitus, proposed studies will examine the function and the pharmacology of these receptors and the impact of Chantix and similar nicotinic drugs on the response properties of these brain cells. Collectively, these studies will provide new pharmacologic information on possible novel treatments for tinnitus while improving our understanding of the relationship between attention and tinnitus suffering and the cellular mechanisms that underpin this hypothesis.