Tinnitus impacts between 10-20% of the population. Individuals most troubled by their
tinnitus have their attention bound to and are distracted by, their
tinnitus percept. While numerous treatments to ameliorate
tinnitus have been tried, no therapeutic approach has been clinically accepted. The present study used an established condition-suppression noise-exposure rat model of
tinnitus to: (1) examine
tinnitus-related changes in nAChR function of layer 5 pyramidal (PNs) and of
vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1) and (2) examine how the partial desensitizing nAChR agonists,
sazetidine-A and
varenicline, can act as potential therapeutic agents in the treatment of
tinnitus. We posited that
tinnitus-related changes in layer 5 nAChR responses may underpin the decline in attentional resources previously observed in this animal model (Brozoski et al., 2019). In vitro whole-cell patch-clamp studies previously revealed a significant
tinnitus-related loss in nAChR-evoked excitatory postsynaptic currents from A1 layer 5 PNs. In contrast, VIP neurons from animals with behavioral evidence of
tinnitus showed significantly increased nAChR-evoked excitability. Here we hypothesize that
sazetidine-A and
varenicline have therapeutic benefits for subjects who cannot divert their attention away from the phantom sound in their heads. We found that
sazetidine-A or
varenicline normalized
tinnitus-related reductions in GABAergic input currents onto A1 layer 5 PNs. We then tested
sazetidine-A and
varenicline for the management of
tinnitus using our
tinnitus animal model.
Subcutaneous injection of
sazetidine-A or
varenicline, 1 h prior to
tinnitus testing, significantly decreased the rat's behavioral evidence of
tinnitus in a dose-dependent manner. Collectively, these results support the need for additional clinical investigations of partial desensitizing nAChR agonists
sazetidine-A and
varenicline for the treatment of
tinnitus.