Currently, there are no effective pharmacological
therapies for chronic
tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel
anxiolytic with
potassium channel activity in suppressing
salicylate induced
tinnitus in animals. Kv7
potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity.
Maxipost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2-Kv7.5 channels, was administered to rats with behavioral evidence of
salicylate induced
tinnitus.
Tinnitus was measured using our previously established animal model, Schedule Induced
Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound.
Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of
tinnitus.
Maxipost at 10 mg/kg suppressed behavioral evidence of
tinnitus as it completely reversed
salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of
Maxipost, R-
Maxipost, which has no
anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of
tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in
tinnitus generation and that
Maxipost but not R-
Maxipost would suppress
tinnitus; however, it appears that a shared mechanism between
Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of
BK channels or some novel mechanism common to both compounds, underlies
salicylate induced
tinnitus as both compounds completely abolished behavioral evidence of
tinnitus in a dose-dependent manner. Further studies with specific
BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of
tinnitus or determine novel targets that could be related to
tinnitus.