Can GABAkines quiet the noise? The GABAA receptor neurobiology and pharmacology of tinnitus

Tinnitus is a highly prevalent and disabling disorder in which sound is perceived in the absence of an external auditory energy source. The disorder is complex and can arise from multiple etiologies. Co-morbid symptoms of anxiety, depression, and sleep loss are prevalent. There are no approved medications and the treatments that have been studied produce marginal improvements in symptoms. A major hypothesis of the etiology and maintenance of tinnitus is that inhibitory input mechanisms become compromised where impaired γ-aminobutyric acid (GABA) synaptic transmission has been implicated. This general idea lends support to the potential for enhanced inhibition by drugs that enhance GABA function (GABAkines) to dampen symptoms of tinnitus. Convergent evidence from neurochemical, anatomical, physiological, and pharmacological studies support the GABAA hypothesis. Although there is surprising a relatively sparse data set, examples of therapeutic efficacy have been reported with GABAkines. These studies have relied primarily on classical benzodiazepine anxiolytics like alprazolam and clonazepam. However, the possibility that novel GABAkines with unique activities might be effective have yet to be intensively explored. For example, data implicating extrasynaptic GABAAreceptors in the control of tinnitus suggests the potential for extrasynaptic GABAA receptor modulators. The large medical need, a basis for further testing of the GABAA hypothesis, and the recent reinvigoration of the drug development pipeline of new GABAkines, combine to give impetus and promise for further inquiry.