1. ¹Behavioural Neuroscience Laboratory, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, VIC, Australia
2. ²Centre for Clinical Research in Neuropsychiatry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia
3. ³Biological Psychiatry Research Unit, Brain Sciences Institute, Faculty of Life and Social Sciences, Swinburne University of Technology, Melbourne, VIC, Australia
4. ⁴Clinical Neuroscience and Psychopharmacology Research Unit (CNPRU), Department of Psychiatry, University of Chicago, Chicago, IL, USA
5. ⁵Department of Psychiatry, University of Cambridge, Cambridge, UK
6. ⁶Clinical Pharmacology and Experimental Medicine, GlaxoSimthKline, Cambridge, UK

Correspondence: Professor PJ Nathan, Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. Tel: +61 3 99053952; Fax: +61 3 99053948; E-mail: pradeep.nathan@med.monash.edu.au

Received 11 April 2007; Revised 19 July 2007; Accepted 31 July 2007; Published online 26 September 2007.

Abstract

Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal 'gating' function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.