Allelic variation in serotonin transporter function associated with the intensity dependence of the auditory evoked potential

Abstract

The intensity dependence of the auditory evoked potential (AEP) has been suggested as an indicator of central serotonergic function, a strong intensity dependence presumably reflecting low serotonergic activity. As individual differences in serotonergic neurotransmission can be accounted for in part by genetic variation in genes of the serotonergic pathway, we investigated whether a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with the AEP intensity dependence. Because dopaminergic influences on the intensity dependence have also been reported, we furthermore explored the role of a functional polymorphism in the dopamine D4 receptor gene (DRD4 exon III) in the modulation of the AEP intensity dependence. AEPs to tones of six intensity levels were recorded from 60 healthy young individuals, and N1/P2 linear as well as median slopes at central electrode sites were computed as measures of the AEP intensity dependence. Analyses of variance showed that there was a significant effect of the 5-HTTLPR on the AEP intensity dependence. Individuals with the ll genotype exhibited a stronger intensity dependence compared to individuals with the ls genotype. This effect was even more pronounced when DRD4 exon III was considered in the analyses. In conclusion, these findings provide further evidence for a role of serotonergic neurotransmission in the modulation of the AEP intensity dependence. The results also point to possible dopaminergic influences on the AEP intensity dependence.

Serotonin transporter gene variation impacts innate fear processing: acoustic startle response and emotional startle

“…Taking into account earlier findings on the impact of 5-HTTLPR on brain function, it can be subsumed that 5-HTTLPR differentially modulates multiple stages of information processing, ranging from (1) fast reflexes as demonstrated here and (2) early sensory processing as shown in recent event-related potential (ERP) studies [41][42][43] over (3) short-and middle-latency stages of more conscious emotional processing as observed in the imaging studies mentioned above, to (4) later processes of cognitive response control and error processing as evidenced in the ERP studies of Fallgatter et al, 44,45 who were the first to report an association between 5-HTTLPR and prefrontal cortex-limbic excitability in a Go-NoGo task and an error-processing task. As different kinds of the startle paradigm afford to examine information processing at several stages, the startle paradigm can be seen as an integrative tool to further our understanding of the serotonergic influences on complex behavior.…”

Effects of Serotonin Transporter Promoter Polymorphisms on Serotonin Function

“…Decreased serotonin function has been associated with the s allele compared to the l allele based upon: (1) a blunted neuroendocrine response to fenfluramine (the serotonin reuptake inhibitor and releasing agent) and clomipramine (a tricyclic antidepressant); (2) lower platelet serotonin uptake and (3) lower concentrations of serotonin metabolites (5-hydroxyindoleacetic acid, 5-HIAA) in cerebrospinal fluid (Whale et al, 2000;Reist et al, 2001;Strickland et al, 2003;Greenberg et al, 1999;Williams et al, 2003). Consistent with these observations, neurophysiologic indices of information processing in motor and auditory cortices have demonstrated an increased responsiveness associated with the ll genotype, following acute pharmacologic increase of serotonin concentrations (citalopram administration, Strobel et al, 2003;Eichhammer et al, 2003). These data suggest that in normal function, the 5-HTTLPR may be associated with differential serotonin sensitivity and behavioral responses mediated by serotonin.…”

Intensity dependence of auditory P2 in monozygotic twins discordant for Vietnam combat: Associations with posttraumatic stress disorder

“…Furthermore, as discussed in the "Introduction," the biological underpinning of these hypothetical subtypes may be specific alterations in the 5-HT system (e.g., hyper-or hypofunction of 5-HT neurotransmission). Although other neurochemical systems (e.g., dopamine, acetylcholine) have been implicated in the modulation of intensity dependence response patterns (e.g., Strobel et al [31]), the most consistent evidence supports central 5-HT as the key neuromodulator [12], with low 5-HT neurotransmission associated with increased intensity dependence and high 5-HT neurotransmission with decreased intensity dependence. Within this framework, decreased intensity dependence (reflecting high 5-HT tone) may characterize a subtype of PTSD dominated by anxiety and avoidance symptoms, behaviors associated with the overstimulation of postsynaptic 5-HT2 receptors [47].…”

“…Two studies found that individuals with long (l) forms of the 5-HTTLPR genotype (or l/l genotype) demonstrated increased intensity dependence [30][31], whereas the third study found that individuals with the l/l genotype demonstrated decreased intensity dependence [32]. The short (s) form of the 5-HTTLPR allele (or s allele) impairs gene transcription and reduces 5-HTTLPR levels and reuptake compared with the l/l genotype [33], purportedly resulting in higher 5-HT availability.…”