Is the Loudness Dependence of the Auditory Evoked Potential a Sensitive and Selective In Vivo Marker of Central Serotonergic Function?

Abstract

SirLang et al (2005) reported a negative association between serum brain-derived neurotrophic factor (BDNF) levels and central serotonergic neurotransmission as measured by the loudness dependence (LD) of the auditory-evoked potential (AEP). The authors suggest that low serum BDNF concentrations reflect low central serotonergic neurotransmission as indicated by the strong LD of the AEP. While these findings are interesting and may suggest a relationship between central serotonin neurotransmission and serum BDNF levels, they need to be viewed with caution for a number of reasons. First, the relationship between LD of the AEP (LDAEP) and serotonin function in humans is tenuous, with the most convincing evidence for a direct relationship coming from animal studies exploring the 5-HT 1A receptor system (Juckel et al, 1997), with no such studies conducted in humans. Second, the specificity of the LDAEP as a marker of serotonin neurotransmission is questionable. For example, dopamine metabolites in CSF and urine have been found to correlate with the intensity dependence of visual and auditory N1/P2 components (Von Knorring and Perris, 1981), and Juckel et al (1997) also found that the D 1 /D 2 agonist apomorphine decreased the intensity dependence in animals, and more recently, a study in patients with obsessive-compulsive disorder found a correlation between the LDAEP and striatal dopamine transporter (DAT) binding (Pogarell et al, 2004). Consequently, only a relative specificity can be expected with regard to the LDAEP and its relationship to functional aspects of the serotonergic system. It is apparent that further studies are required to clarify the direct role of serotonin and other neuromodulators on LDAEP before this measure could be considered an in vivo marker of central serotonergic system. Accordingly, we have recently demonstrated, for the first time, a direct relationship between enhanced serotonin neurotransmission and the LD of the AEP in humans (Simmons et al, 2003;Nathan et al, 2005). In these studies, we demonstrated that both acute and chronic serotonin enhancement (using the serotonin reuptake inhibitors, citalopram and sertraline) resulted in a reduction of the slope of the LD of the AEP.Finally, while there are interactions between BDNF and the serotonergic system, similar interactions have also been noted between BDNF and the dopaminergic system. For example, in vitro survival, differentiation and function of dopamine neurons have been shown to be promoted by BDNF (Beck et al, 1993;Spina et al, 1992;Hyman et al, 1994). Furthermore, dopamine and D 1 receptor agonists have been shown to increase BDNF mRNA and protein, indicating a potential role for dopamine in BDNF expression (Kuppers and Beyer, 2001).These findings, together with the demonstration of a relationship between the LDAEP and dopamine neurotransmission, suggest that the results of the study by Lang and colleagues may in part be influenced by the dopaminergic system.In summary, the relationship between the LDAEP and serotonergic neuro...

Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans

“…The issue of the specificity of the LDAEP for the serotonin system has largely been ignored in the literature, with several findings casting some doubt over its sensitivity to changes in serotonin function alone (Nathan et al 2005;Von Knorring and Perris 1981;Bruneau et al 1986;Juckel et al 1997;Pogarell et al 2004). For example, earlier studies on ERPs showed that a high-intensity dependence of auditory and visual evoked potentials was related to low levels of dopamine metabolites (i.e., homovanillic acid) in CSF and urine (Von Knorring andPerris 1981, Bruneau et al 1986).…”

High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans

“…Together these findings in humans cast doubt over the sensitivity of the LDAEP to changes in serotonergic neurotransmission and suggest that earlier findings showing abnormalities in patient groups have to be interpreted with caution with regard to their presumed link to serotonin dysfunction. Another critical component that has been largely neglected in the literature is the selectivity of the LDAEP to serotonin function (Nathan et al 2005). It has been postulated that the intensity dependence of the amplitude of AEPs to various stimulus intensities may be related to neuromodulatory systems located subcortically (Connolly 1987;Hegerl and Juckel 1993).…”

Functional Cortical Effects of Novel Allelic Variants of the Serotonin Transporter Gene-linked Polymorphic Region (5-HTTLPR) in Humans

“…The authors argued that this increase is mediated by a negative feedback via somatodendritic 5-HT1a-receptors. The question of specifi city of the association of LD and serotonin activity can be raised because in the SPECT investigation of Pogarell and colleagues, a correlation between LD and dopamine transporter availability was observed [41,44] . Additionally, animal investigations reported also some effects of the dopamine and choline system (but not noradrenaline) on the LD [26] .…”