Examining the pharmacology of mismatch negativity: an electrophysiological investigation in healthy subjects

Schizophrenia is associated with impairments in pre-attentive change detection, as represented by reduced mismatch negativity (MMN) amplitudes. While most researchers believe that this reduced MMN is primarily due to the impaired glutamate (GLU) system, mediated by N-methyl-D-aspartate (NMDA) receptors, it is yet to clarify whether imbalances in other neurotransmitter systems contribute to this diminished MMN. Among the various neurotransmitter systems, whether dopamine (DA) imbalance in schizophrenia contributes to the attenuated MMN is of particular interest, because the two main neurochemical hypotheses of this disorder are the GLU and the DA hypotheses. In addition, given that the serotonin (5HT) system is also involved in the disorder, and glycine (an NMDA receptor co-agonist) has been trialled as an adjunct therapy in schizophrenia, the role of the 5HT system and the effect of glycine in MMN generation also warrant investigation. However, it is difficult to examine these issues from the clinical MMN studies due to a range of substances [drugs] misused by patients. Thus, the current thesis examined the roles of these systems in MMN generation by manipulating them in healthy volunteers, with the primary aim to determine whether acute DA manipulation modulates MMN, and the secondary aim to determine the role of the 5HT system and the effect of an NMDA agonist on MMN generation. The first experiment examined the effects from acute DA receptor stimulation on MMN, where each of 15 subjects was tested under 3 treatment conditions; placebo, 2.5mg bromocriptine (D2 receptor stimulation) and 0.1mg pergolide (D1/D2 receptor stimulation). The results showed that neither bromocriptine nor pergolide had an overall effect on MMN, suggesting that acute stimulation of D2, or D1 and D2 receptors, does not modulate MMN. The second experiment examined the effects from acutely depleting DA precursors, 5HT precursor, and all DA and 5HT precursors simultaneously on MMN, where each of 16 subjects was tested under 4 treatment conditions; balanced (no depletion), tyrosine/phenylalanine depletion (reduced DA function), tryptophan depletion (reduced 5HT function) and tyrosine/phenylalanine/tryptophan depletion (reduced both DA+5HT functions). The results showed that none of the depletion conditions had an overall effect on MMN, suggesting that acutely depleting the precursors of DA, 5HT, or both DA and 5HT systems simultaneously, do not modulate MMN. The third experiment examined the effects from an acute high-dose of glycine on MMN, where each of 16 subjects was tested under 2 treatment conditions; placebo and 0.8g/kg glycine. The results showed that high-dose glycine significantly attenuated the duration MMN amplitude measured at frontal electrodes in healthy subjects. In conclusion, while the DA agonist and monoamine depletion findings suggest that the DA and 5HT systems do not acutely play a significant role in MMN generation, acute high dose glycine resulted in MMN attenuation. This may have important ramifications for the use of chronic adjunct glycine therapy in schizophrenia, as it indicates that high dose glycine may worsen the pre-attentive change detection system of patients with relatively normal plasma glycine levels or NMDA receptor expression