Evidence for sex differences in the loudness dependence of the auditory evoked potential in humans Jessica L. Oliva 1 , Sumie Leung 2 , Rodney J. Croft 4 , Barry V. O’Neill 3,5 , Julie C. Stout 1 and Pradeep J. Nathan 1,3,5 * 1 School of Psychology and Psychiatry, Monash University, Melbourne, VIC, Australia 2 Brain Sciences Institute, Swinburne University of Technology, Melbourne, VIC, Australia 3 Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK 4 Department of Psychology, University of Wollongong, Wollongong, NSW, Australia 5 Clinical Unit Cambridge, GlaxoSmithKline Pharmaceuticals, Cambridge, UK Objective The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP. Methods Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified. Results Mean N1/P2 slopes for female participants were higher than those for male participants ( p < 0.0001). Conclusion These findings suggest that the LDAEP is modulated by sex potentially because of differences in serotonergic neurotransmission, and these differences may account for some of the inconsistent findings linking serotonin function and LDAEP. Copyright © 2011 John Wiley & Sons, Ltd. key words —sex; gender; loudness dependence; auditory evoked potential; LDAEP; serotonin INTRODUCTION The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as an electro- physiological marker of serotonin function (Hegerl and Juckel, 1993). It is a measure of auditory cortex activity reflected by a change in the amplitude of the N1/P2 component of the auditory evoked potential with increasing auditory tone loudness (Hegerl and Juckel, 1993). It is believed that the serotonergic neurons that innervate the auditory cortex, particularly the primary auditory cortex, modulate this relation- ship, whereby greater increases in amplitude represent diminished serotonin function and smaller increases in amplitude represent higher serotonin function (Hegerl and Juckel, 1993). Most of the supporting evidence for this inverse relationship has derived from studies in human populations with a presumed serotonin dysfunction (Hegerl et al., 1995; Juckel et al., 1995; Wang et al., 1999; Brocke et al., 2000; Croft et al., 2001; Norra et al., 2003; Senkowski et al., 2003), with supporting evidence from pharmacological studies in animals (Juckel et al., 1997; Juckel et al., 1999; Manjarrez et al., 2005). However, human studies that have examined changes in synaptic serotonin with selective serotonin reuptake inhibitors (SSRIs) or serotonin precursor depletion (i.e. tryptophan depletion) have been inconsistent and largely negative (for a review, see O’Neill et al., 2008a). For example, we initially showed that increasing serotonin with the SSRI citalopram reduced the LDAEP (Nathan et al., 2006) consistent with the animal studies; however, subse- quent studies with citalopram (Uhl et al., 2006; Oliva et al., 2010) and the SSRIs citalopram, sertraline and escitalopram (Guille et al., 2008) failed to show any relationship. Similarly, tryptophan depletion studies have failed to demonstrate the relationship between the decreased levels of serotonin and the LDAEP (Dierks et al., 1999; Massey et al., 2004; Norra et al., 2008; O’Neill et al., 2008b), except one study which * Correspondence to: P. J. Nathan, Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK. Tel: +44 (0) 1223 296000; Fax: +44 (0) 1223 296002. E‐mail: pn254@cam.ac.uk SHORT COMMUNICATIONS Received 13 August 2010 Accepted 28 January 2011 Copyright © 2011 John Wiley & Sons, Ltd. human psychopharmacology Hum. Psychopharmacol Clin Exp 2011; 26: 172 –176. Published online 31 March 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.1187