Desensitizing nicotinic agents normalize tinnitus-related inhibitory dysfunction in the auditory cortex and ameliorate behavioral evidence of tinnitus

Madan Ghimire; Rui Cai; Lynne Ling; Kevin A Brownell; Kurt W Wisner; Brandon C Cox; Troy A Hackett; Thomas J Brozoski; Donald M Caspary

doi:10.3389/fnins.2023.1197909

Desensitizing nicotinic agents normalize tinnitus-related inhibitory dysfunction in the auditory cortex and ameliorate behavioral evidence of tinnitus

Front Neurosci. 2023 May 25:17:1197909. doi: 10.3389/fnins.2023.1197909. eCollection 2023.

Authors

Madan Ghimire¹, Rui Cai¹, Lynne Ling¹, Kevin A Brownell¹, Kurt W Wisner², Brandon C Cox^{1

2}, Troy A Hackett³, Thomas J Brozoski², Donald M Caspary^{1

2}

Affiliations

¹ Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, United States.
² Department of Otolaryngology, Head and Neck Surgery, Southern Illinois University School of Medicine, Springfield, IL, United States.
³ Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, United States.

Abstract

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.

Keywords: VIP neuron; nicotinic cholinergic receptor; primary auditory cortex; pyramidal neuron; sazetidine-A; tinnitus; varenicline.

Abstract

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