The pharmacology of the loudness dependence of the auditory evoked potential (LDAEP)

The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a valid means of assessing brain serotonin (5-hydroxytryptamine, 5-HT) function. This electrophysiological biomarker may prove useful for diagnosis of psychiatric conditions and possible pharmacological intervention. While there is some evidence that supports the validity of this measure, there is also evidence suggesting that it may not be solely specific to the 5-HT system. The present thesis utilised a series of acute pharmacological challenges in healthy volunteers, in order to assess its sensitivity to other neurotransmitter systems and to clarify the relative specificity of the LDAEP for 5-HT. Initially, the acute tryptophan depletion paradigm was used to assess the serotonergic sensitivity of the LDAEP. In addition, the acute tyrosine/phenylalanine depletion paradigm was employed to investigate whether depletion of central dopamine levels may affect the LDAEP. In an effort to elucidate possible synergistic interactions between the monoaminergic systems as regards the modulation of the LDAEP a recent novel approach, the combined tryptophan/tyrosine/phenylalanine depletion paradigm, was utilised. The selective and combined 5-HT and dopamine depletions had no effect on the LDAEP, suggesting the LDAEP may be insensitive to acute changes in serotonergic neurotransmission and possibly monoaminergic activity in general. In the second study of this thesis, the dopaminergic sensitivity of the LDAEP was investigated further by augmenting dopamine neurotransmission utilising the dopamine agonists pergolide and bromocriptine. Despite previous evidence present in the literature, dopaminergic receptor stimulation resulted in no change in the LDAEP. In addition to alterations induced by neuromodulators such as the monoamines, evoked potentials may be influenced by both inhibitory (i.e. γ-aminobutyric acid- GABA) and excitatory (i.e. glutamate) neurotransmitters. Hence the final experiment in this thesis examined the effects of acute administration of highdose oral glycine (an excitatory NMDA receptor co-agonist/inhibitory glycine receptor agonist) on the LDAEP. Glycine administration attenuated the LDAEP though the mechanism by which this was achieved is yet to be ascertained. Nevertheless this result demonstrates modulation of the LDAEP by neurochemical systems other than the serotonergic system. In summary, acute dopaminergic stimulation, selective and combined monoaminergic depletion had no effect, while possible NMDA receptor stimulation resulted in a significant attenuation of the LDAEP in healthy humans. The implications of the findings of this thesis, when taken together with previous observations from pre-clinical and clinical literature, seem to indicate that the LDAEP may be insensitive to acute changes in monoaminergic neurotransmission as well as exhibiting a sensitivity to neurotransmitter systems other than 5-HT. However, before disregarding the LDAEP as a specific indicator of serotonergic function altogether, the chronic sensitivity and selectivity of this electrophysiological biomarker needs to be elucidated.