Benzodiazepines alter cochleo-cochlear loop in humansN. Moranda, E. Veuilleta;*, M.C. Gagnieub, P. Lemoinec, L. ColletaaLaboratoire `Neurosciences et Systeémes Sensoriels', 3 place d'Arsonval, Pavillon U, Hoêpital Edouard Herriot, 69003 Lyon, FrancebLaboratoire de Pharmacologie, Hoêpital Edouard Herriot, Lyon, FrancecUniteèClinique de Psychiatrie Biologique, Le Vinatier, Bron, FranceReceived 26 November 1997; revised 26 March 1998; accepted 7 April 1998AbstractBy using otoacoustic emission, we looked for change in outer hair cell (OHC) motile activity and medial olivocochlear (MOC)system inhibition due to benzodiazepine administration, a drug that is known to produce a pharmacological effect by interactingwith GABAergic inhibitory neurotransmission. No effect was observed on OHC motile activity, in contrast benzodiazepinesdecreased MOC system effectiveness suggesting the existence of GABAergic fibers projecting onto the MOC system. z 1998Elsevier Science B.V. All rights reserved.Key words: Gamma-aminobutyric acid; Outer hair cell; Olivocochlear e¡erent system; Otoacoustic emission1. IntroductionThe organ of Corti is innervated by the olivocochleare¡erent system (Rasmussen, 1946), in which two sub-components have been clearly distinguished (Warr,1992; Warr and Guinan, 1979). The lateral olivo-cochlear (LOC) system originates from lateral superiorolivary neurons making synaptic contact with the a¡er-ent inner radial ¢bers of the inner hair cell system. Themedial e¡erent system originates from the medialsuperior olivary complex (SOC) or trapezoid body,synapsing with the basal pole of outer hair cells(OHCs).Various neurotransmitters seem to be involved be-tween the medial olivocochlear (MOC) system and theOHCs, principally acetylcholine (Ach) and the inhibi-tory neurotransmitter Q-aminobutyric acid (GABA) (forreview see Eybalin, 1993). Concerning GABA, severalstudies seem to prove the presence of GABAergic syn-apses in the cochlea. The presence of GABA and glu-tamic acid decarboxylase in ¢bers and e¡erent endingssynapsing onto OHC bodies has been revealed by im-munocytochemistry data (Fex and Altschuler, 1984;Fex et al., 1986; Thompson et al., 1986; Eybalin etal., 1990). Furthermore, the presence of GABAArecep-tors in the outer cell membrane of isolated OHCs hasbeen demonstrated using monoclonal antibodies againstthe K- and L-subunits of GABAAreceptors (Plinkert etal., 1989). GABAAreceptors are at the basal pole ofOHCs. GABA uptake by e¡erent endings has also beendemonstrated (Schwartz and Ryan, 1983; Ryan et al.,1992).The action of GABA or agonists of GABA on OHCmechanisms has been studied, leading to contradictoryconclusions. In vitro, OHC hyperpolarization was ob-served after GABA application; this hyperpolarizationwas increased by an application of benzodiazepines(Plinkert et al., 1993). GABA also decreased the electro-motile response (Sziklai et al., 1996). In contrast, Evanset al. (1996) observed no OHC response during whole-0378-5955 / 98 / $19.00 ß 1998 Elsevier Science B.V. All rights reserved.PII: S0378-5955(98)00068-9HEARES 3034 29-6-98* Corresponding author. Tel.: +33 04 72 11 05 02;Fax: +33 04 72 11 05 04 ; E-mail: [email protected]: Ach, acetylcholine; CAP, compound action potential;DP, distortion product; EOAE, evoked otoacoustic emission; GABA,Q-aminobutyric acid; IC, inferior colliculus; LOC, lateral olivococh-zlear; MOC, medial olivocochlear; OAE, otoacoustic emission; SL,sensation level; SPL, sound pressure level; SOAE, spontaneousotoacoustic emission; SOC, superior olivary complexHearing Research 121 (1998) 71^76cell recording after GABA application. In vivo, OHCfunction can be explored by otoacoustic emission(OAE) recordings. OAEs are sounds recorded in theexternal ear canal in the presence of acoustic stimula-tion (evoked OAEs (EOAEs) and distortion products(DP)) or without acoustic stimulation (spontaneousemissions (SOAEs)). OAEs are generated in the coch-lea, probably by OHC motile activity. The in£uence ofbenzodiazepines on EOAE amplitude has been studiedin humans: Hauser et al. (1992) found no signi¢cantdi¡erence in EOAE amplitude under premedicationwith midazolam; likewise diazepam and £unitrazepamhad no e¡ect on EOAE amplitude (Delb et al., 1994). Ithas been shown that contralateral acoustic stimulationdecreases the EOAE amplitude in humans (Collet et al.,1990) and acoustic DPs in guinea pig (Puel and Rebil-lard, 1990). The medial e¡erent system is involved inthis contralateral suppression e¡ect, which is greatlyreduced in humans after sectioning of the vestibularnerve, which severs olivocochlear e¡erents (Giraud etal., 1995). Thus this suppression e¡ect observed onEOAEs in the presence of contralateral acoustic stim-ulation is a good means of investigating the MOC sys-tem in vivo. In guinea pigs, the perfusion of the cochleawith bicuculline (GABA antagonist) abolished the f23f1DP reduction normally observed after contralateralstimulation in guinea pigs (Kirk and Johnstone, 1993),thus con¢rming a role for GABA in the OHC mecha-nism. So the terminal elements involved in the contra-lateral acoustical suppression of f23f1can be identi¢edas being part of a GABAergic innervation, whetherLOC or MOC system, of the apical OHCs.Thus a majority of studies con¢rm the presence ofGABAergic e¡erents on OHCs and presence ofGABAAreceptors on the basal pole of OHC, but thereis no evidence of a real action of GABA on outer haircell mechanisms. Furthermore the presence of GA-BAergic synapses in human cochlea has not beenstudied.On the other hand, the olivocochlear e¡erent systemcould be under the control of central auditory path-ways. The inferior colliculus (IC) receives descendinginput from the auditory cortex, and sends ipsilateraland contralateral projections onto the medial olivo-cochlear system (Hu¡man and Henson, 1990). So it isanatomically possible that the IC plays a role in theactivity of the olivocochlear e¡erent system. Further-more, physiological studies show an IC contributionto the olivocochlear e¡erent system. Stimulating theIC induces a decrease in compound action potential(CAP) (Dolan and Nuttal, 1988a) that is similar tothe change seen after electrical stimulation of thecrossed olivocochlear bundle (Dolan and Nuttal,1988b). Furthermore, stimulating the IC protects thecochlea from noise, as does stimulation of the crossedolivocochlear bundle (Rajan, 1990).GABA is an inhibitory transmitter which is