{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T08:58:08Z","timestamp":1769158688662,"version":"3.49.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T00:00:00Z","timestamp":1684972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Tinnitus impacts between 10\u201320% 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 (<jats:xref>Brozoski et al., 2019<\/jats:xref>). <jats:italic>In vitro<\/jats:italic> 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\u2019s 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.<\/jats:p>","DOI":"10.3389\/fnins.2023.1197909","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T04:26:25Z","timestamp":1684988785000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Desensitizing nicotinic agents normalize tinnitus-related inhibitory dysfunction in the auditory cortex and ameliorate behavioral evidence of tinnitus"],"prefix":"10.3389","volume":"17","author":[{"given":"Madan","family":"Ghimire","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynne","family":"Ling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin A.","family":"Brownell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt W.","family":"Wisner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon C.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Troy A.","family":"Hackett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas J.","family":"Brozoski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald M.","family":"Caspary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1124\/jpet.112.194506","article-title":"The Antinociceptive effects of nicotinic partial agonists Varenicline and Sazetidine-a in murine acute and tonic pain models","volume":"342","author":"AlSharari","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref2","first-page":"273","article-title":"Long-term effects of the \u201cHeidelberg model of music therapy\u201d in patients with chronic tinnitus","volume":"5","author":"Argstatter","year":"2012","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e22116","DOI":"10.1002\/syn.22116","article-title":"Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex","volume":"73","author":"Askew","year":"2019","journal-title":"Synapse"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3389\/fneur.2014.00206","article-title":"Central gain control in tinnitus and Hyperacusis","volume":"5","author":"Auerbach","year":"2014","journal-title":"Front. Neurol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/s101620010030","article-title":"Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model","volume":"2","author":"Bauer","year":"2001","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/S0194-5998(99)70237-8","article-title":"Behavioral model of chronic tinnitus in rats","volume":"121","author":"Bauer","year":"1999","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1038\/s41467-017-01755-2","article-title":"Progress and challenges for understanding the function of cortical microcircuits in auditory processing","volume":"8","author":"Blackwell","year":"2017","journal-title":"Nat. Commun."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e51890","DOI":"10.7554\/eLife.51890","article-title":"Auditory cortex shapes sound responses in the inferior colliculus","volume":"9","author":"Blackwell","year":"2020","journal-title":"elife"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e77674","DOI":"10.1371\/journal.pone.0077674","article-title":"Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model","volume":"8","author":"Brozoski","year":"2013","journal-title":"PLoS One"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.neuroscience.2018.10.013","article-title":"Chronic sound-induced tinnitus and auditory attention in animals","volume":"407","author":"Brozoski","year":"2019","journal-title":"Neuroscience"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1471-2202-13-3","article-title":"Altered networks in bothersome tinnitus: a functional connectivity study","volume":"13","author":"Burton","year":"2012","journal-title":"BMC Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1038\/nn.4595","article-title":"Activation of cortical somatostatin interneurons prevents the development of neuropathic pain","volume":"20","author":"Cichon","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"3474","DOI":"10.1021\/jm050069n","article-title":"Varenicline: an \u03b14\u03b22 nicotinic receptor partial agonist for smoking cessation","volume":"48","author":"Coe","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"24","DOI":"10.3389\/fncir.2019.00024","article-title":"Cellular, synaptic and network effects of acetylcholine in the neocortex","volume":"13","author":"Colangelo","year":"2019","journal-title":"Front. Neural Circuits"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1097\/ALN.0b013e3181834490","article-title":"Analgesic effects of Sazetidine-a, a new nicotinic cholinergic drug","volume":"109","author":"Cucchiaro","year":"2008","journal-title":"Anesthesiology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-68652-5","article-title":"Increasing endogenous activity of NMDARs on GABAergic neurons increases inhibition, alters sensory processing and prevents noise-induced tinnitus","volume":"10","author":"Deng","year":"2020","journal-title":"Sci. Rep."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/S0030-6665(02)00168-8","article-title":"Depression and tinnitus","volume":"36","author":"Dobie","year":"2003","journal-title":"Otolaryngol. Clin. N. Am."},{"key":"ref18","first-page":"1","article-title":"Overview: Suffering from tinnitus","volume-title":"Tinnitus: theory and management","author":"Dobie","year":"2004"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.heares.2018.01.008","article-title":"Subcortical pathways: towards a better understanding of auditory disorders","volume":"362","author":"Felix","year":"2018","journal-title":"Hear. Res."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1152\/jn.00184.2019","article-title":"Muscarinic acetylcholine receptor-dependent persistent activity of layer 5 intrinsic-bursting and regular-spiking neurons in primary auditory cortex","volume":"122","author":"Fu","year":"2019","journal-title":"J. Neurophysiol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"921873","DOI":"10.3389\/fnins.2022.921873","article-title":"Functional changes in the auditory cortex and associated regions caused by different acoustic stimuli in patients with presbycusis and tinnitus","volume":"16","author":"Fuksa","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1113\/jp284675","article-title":"Increased Pyramidal and VIP Neuronal Excitability in Primary Auditory Cortex Directly Correlates with Tinnitus Behavior","author":"Ghimire","year":"2023","journal-title":"The Journal of physiology"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"5724","DOI":"10.1523\/JNEUROSCI.0093-20.2020","article-title":"Nicotinic receptor subunit distribution in auditory cortex: impact of aging on receptor number and function","volume":"40","author":"Ghimire","year":"2020","journal-title":"J. Neurosci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.heares.2017.05.002","article-title":"Amino acid and acetylcholine chemistry in the central auditory system of young, middle-aged and old rats","volume":"350","author":"Godfrey","year":"2017","journal-title":"Hear. Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1080\/14992020400050030","article-title":"Tinnitus impairs cognitive efficiency","volume":"43","author":"Hallam","year":"2004","journal-title":"Int. J. Audiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1038\/nn.4619","article-title":"Functions and dysfunctions of neocortical inhibitory neuron subtypes","volume":"20","author":"Hattori","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e2001392","DOI":"10.1371\/journal.pbio.2001392","article-title":"Chrna 2-Martinotti cells synchronize layer 5 type a pyramidal cells via rebound excitation","volume":"15","author":"Hilscher","year":"2017","journal-title":"PLoS Biol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"597401","DOI":"10.3389\/fncir.2021.597401","article-title":"Nicotine enhances amplitude and consistency of timing of responses to acoustic trains in A1","volume":"15","author":"Intskirveli","year":"2021","journal-title":"Front. Neural Circuits"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1037\/0735-7044.102.6.811","article-title":"Phantom auditory sensation in rats: an animal model for tinnitus","volume":"102","author":"Jastreboff","year":"1988","journal-title":"Behav. Neurosci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.2165\/00003495-200969100-00003","article-title":"Varenicline","volume":"69","author":"Jim\u00e9nez-Ruiz","year":"2009","journal-title":"Drugs"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"5465","DOI":"10.1113\/JP282321","article-title":"Corticothalamic projections deliver enhanced responses to medial geniculate body as a function of the temporal reliability of the stimulus","volume":"599","author":"Kommajosyula","year":"2021","journal-title":"J. Physiol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1517\/14656566.2012.739608","article-title":"Current pharmacological treatments for tinnitus","volume":"13","author":"Langguth","year":"2012","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1146\/annurev-pharmtox-010818-021556","article-title":"Therapeutic approaches to the treatment of tinnitus","volume":"59","author":"Langguth","year":"2019","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"489","DOI":"10.3109\/15622975.2011.575178","article-title":"Tinnitus and depression","volume":"12","author":"Langguth","year":"2011","journal-title":"World J. Biol. Psychiatry"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.3390\/brainsci12091192","article-title":"A combined image-and coordinate-based Meta-analysis of whole-brain voxel-based morphometry studies investigating subjective tinnitus","volume":"12","author":"Makani","year":"2022","journal-title":"Brain Sci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3389\/fneur.2014.00196","article-title":"A scientific cognitive-behavioral model of tinnitus: novel conceptualizations of tinnitus distress","volume":"5","author":"McKenna","year":"2014","journal-title":"Front. Neurol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2058","DOI":"10.1016\/j.neubiorev.2010.11.010","article-title":"Functional connectivity and cholinergic modulation in auditory cortex","volume":"35","author":"Metherate","year":"2011","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/syn.890140206","article-title":"Nucleus basalis stimulation facilitates thalamocortical synaptic transmission in the rat auditory cortex","volume":"14","author":"Metherate","year":"1993","journal-title":"Synapse"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-1-60761-145-5_14","article-title":"Similarities between tinnitus and pain","volume-title":"Textbook of tinnitus","author":"M\u00f8ller","year":"2011"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.neuron.2016.03.031","article-title":"The basal forebrain and motor cortex provide convergent yet distinct movement-related inputs to the auditory cortex","volume":"90","author":"Nelson","year":"2016","journal-title":"Neuron"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1016\/j.neubiorev.2010.11.003","article-title":"An integrative model of tinnitus based on a central gain controlling neural sensitivity","volume":"35","author":"Norena","year":"2011","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1124\/jpet.109.164566","article-title":"Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes","volume":"333","author":"Papke","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.celrep.2017.07.001","article-title":"Cortical interneurons differentially regulate the effects of acoustic context","volume":"20","author":"Phillips","year":"2017","journal-title":"Cell Rep."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.neuron.2010.04.032","article-title":"Tuning out the noise: limbic-auditory interactions in tinnitus","volume":"66","author":"Rauschecker","year":"2010","journal-title":"Neuron"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s00213-012-2895-6","article-title":"Effects of chronic sazetidine-a, a selective \u03b14\u03b22 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats","volume":"226","author":"Rezvani","year":"2013","journal-title":"Psychopharmacology"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1523\/JNEUROSCI.3277-12.2013","article-title":"Reduced GABA<sub>a<\/sub> receptor-mediated tonic inhibition in aged rat auditory thalamus","volume":"33","author":"Richardson","year":"2013","journal-title":"J. Neurosci."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1016\/j.neubiorev.2013.07.007","article-title":"Role of attention in the generation and modulation of tinnitus","volume":"37","author":"Roberts","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/j.bcp.2009.05.033","article-title":"Preclinical pharmacology of the \u03b14\u03b22 nAChR partial agonist varenicline related to effects on reward, mood and cognition","volume":"78","author":"Rollema","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1044\/1092-4388(2006\/012)","article-title":"Tinnitus and its effect on working memory and attention","volume":"49","author":"Rossiter","year":"2006","journal-title":"J. Speech Lang. Hear. Res."},{"key":"ref50","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-3-319-71798-2_9","article-title":"Circuits for modulation of auditory function","volume-title":"The mammalian auditory pathways: synaptic organization and microcircuits","author":"Schofield","year":"2018"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/nrneurol.2016.12","article-title":"Maladaptive plasticity in tinnitus \u2014 triggers, mechanisms and treatment","volume":"12","author":"Shore","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1080\/14992020601102329","article-title":"Severe tinnitus and its effect on selective and divided attention","volume":"46","author":"Stevens","year":"2007","journal-title":"Int. J. Audiol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"13804","DOI":"10.1038\/ncomms13804","article-title":"Layer-specificity in the effects of attention and working memory on activity in primary visual cortex","volume":"8","author":"van Kerkoerle","year":"2017","journal-title":"Nat. Commun."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.pnpbp.2018.08.015","article-title":"Tinnitus and neuropathic pain share a common neural substrate in the form of specific brain connectivity and microstate profiles","volume":"88","author":"Vanneste","year":"2019","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"e42974","DOI":"10.7554\/eLife.42974","article-title":"Parallel pathways for sound processing and functional connectivity among layer 5 and 6 auditory corticofugal neurons","volume":"8","author":"Williamson","year":"2019","journal-title":"Eife"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.tips.2016.03.005","article-title":"Heteromeric \u03b17\u03b22 nicotinic acetylcholine receptors in the brain","volume":"37","author":"Wu","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1124\/mol.106.027318","article-title":"Sazetidine-a, a novel ligand that desensitizes \u03b14\u03b22 nicotinic acetylcholine receptors without activating them","volume":"70","author":"Xiao","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.neuron.2012.11.004","article-title":"Neocortical somatostatin-expressing GABAergic interneurons disinhibit the Thalamorecipient layer 4","volume":"77","author":"Xu","year":"2013","journal-title":"Neuron"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1197909\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T04:26:31Z","timestamp":1684988791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1197909\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,25]]},"references-count":58,"alternative-id":["10.3389\/fnins.2023.1197909"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2023.1197909","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,25]]},"article-number":"1197909"}}