Is the loudness dependence of the auditory evoked potential a valid marker of serotonin function?

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans. However, while animal studies suggest that LDAEP is sensitive to changes in central serotonin neurotransmission, evidence in humans has been indirect and inconsistent. The main aim of this thesis was to examine the effect of acute serotonin modulation on LDAEP in healthy humans. We also compared two analysis methods, dipole source analysis (DSA) and scalp topography analysis (ASF), to assess the outcome of serotonin function modulation on LDAEP. The first study examined the effect of acutely enhancing synaptic serotonin availability with three selective serotonin reuptake inhibitors (SSRIs), citalopram, escitalopram or sertraline. The results failed to replicate previous research in that we did not show shallower LDAEP slopes with any of the drugs. In addition, no differences were found between the effects of SSRIs using ASF- or DSA-derived LDAEP methods. The second study examined the effect of decreasing central serotonin function using the acute tryptophan depletion (ATD) paradigm. The results support previous research on the effect of ATD on LDAEP in that they did not show steeper LDAEP slopes. Similar to the first study, no differences were found between ASF- and DSA-derived LDAEP methods. The aim of the third study was to investigate the relationship between the serotonin-1A (5-HT1A) receptor and LDAEP using acute administration of the 5-HT1A receptor partial agonist, buspirone. In line with previous animal research, DSA revealed that acute activation of 5-HT1A receptors resulted in a steeper LDAEP slope of the tangential dipole. However, there were no effects observed using ASF. Thus, contrary to the two previous studies, this experiment found a difference in the outcome between the two LDAEP analysis methods, DSA and ASF. In conclusion, the present work does not support LDAEP as a marker for 5-HT function in healthy humans, based upon the lack of effect of acute treatment with SSRIs or after ATD. On the other hand, based upon the observed effect of buspirone, it is suggested that the LDAEP may not reflect central serotonergic function per se but may be related to specific receptor function, namely the 5-HT1A receptor.