Neuropsychopharmacology (2008) 33, 1653–1666 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans 1 1,3 2 3 3 3 Collette Mann , Rodney J Croft , Kirsty E Scholes , Alan Dunne , Barry V O’Neill , Sumie Leung , 1 1,4 ,1,5,6 David Copolov , K Luan Phan and Pradeep J Nathan* 1 Behavioural Neuroscience Laboratory, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, VIC, Australia; 2 Centre for Clinical Research in Neuropsychiatry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia; 3 Biological Psychiatry Research Unit, Brain Sciences Institute, Faculty of Life and Social Sciences, Swinburne University of Technology, Melbourne, 4 VIC, Australia; Clinical Neuroscience and Psychopharmacology Research Unit (CNPRU), Department of Psychiatry, University of Chicago, Chicago, IL, USA; 5Department of Psychiatry, University of Cambridge, Cambridge, UK; 6Clinical Pharmacology and Experimental Medicine, GlaxoSimthKline, Cambridge, UK 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. Neuropsychopharmacology (2008) 33, 1653–1666; doi:10.1038/sj.npp.1301556; published online 26 September 2007 Keywords: sensory gating; PPI; P50 suppression; dopamine; serotonin; schizophrenia INTRODUCTION cognitive fragmentation (Braff and Geyer, 1990). Two psychophysiological measures of gating have been of A disturbance in information processing has long been particular interest to researchers in the study of schizophrenia, regarded as a significant feature of the deficits characteristic namely prepulse inhibition (PPI) of the acoustic startle of schizophrenia (Braff, 1993; McGhie and Chapman, 1961). response and P50 suppression of the auditory event-related In particular, the filtering or ‘gating’ of sensory information potential (ERP). is thought to be disrupted in schizophrenic patients, and The acoustic startle reflex is a defense response consisting this is hypothesized to lead to sensory flooding and of series of muscular contractions that can be elicited in response to a sudden loud stimulus with abrupt onsets *Correspondence: Professor PJ Nathan, Brain Mapping Unit, (Landis and Hunt, 1939; Prosser and Hunter, 1936). PPI of Department of Psychiatry, University of Cambridge, Addenbrooke’s the startle reflex refers to an attenuation of this startle Hospital, Hills Road, Cambridge CB2 2QQ, UK, Tel: + 61 3 99053952, reflex that occurs when the evoking stimulus is preceded Fax: + 61 3 99053948, E-mail: [email protected] by a non-startling ‘prepulse’ by approximately 30–500 ms Received 11 April 2007; revised 19 July 2007; accepted 31 July 2007 (Graham, 1975; Hoffman and Fleshler, 1963; Ison et al, Serotonin, dopamine and sensory gating C Mann et al 1654 1973). In humans, the startle reflex is typically measured via parameters used to measure gating (eg different prepulse the electrical activity of the orbicularis oculi muscle using intensities and prepulse to pulse intervals in PPI, lack of electromyography (EMG) (Graham, 1975), and the PPI is uniformity across laboratories in P50 peak detection, typically calculated as a percentage score of the reduction in EEG processing, and filtering and differences in findings magnitude of this measure of the startle reflex, with using different strains of animals) (Geyer et al, 2001). maximal inhibition generally observed with ‘lead intervals’ Pharmacological research on PPI and P50 suppression in of approximately 120 ms (Graham, 1975; Hoffman and humans is scarce, and discrepancies between animal and Fleshler, 1963; Ison et al, 1973). It has now been well human studies on sensorimotor and sensory gating have documented that patients with schizophrenia display a also been documented, particularly for the serotonergic deficit in PPI (for a review see Cadenhead and Braff, 1999; system (for a discussion see Hammer et al, 2007). Hence, it Braff et al, 2001, 2007), which is interpreted as reflecting a is critical that studies in humans are conducted to examine failure of ‘sensorimotor gating’ (Braff and Geyer, 1990), and the neurochemistry of both sensorimotor and sensory which may be normalized with the use of atypical gating. antipsychotic drugs (Weike et al, 2000; Hamm et al, 2001; Although it has been extensively hypothesized that Kumari and Sharma, 2002; Kumari et al, 2007). serotonin and dopamine play an important role in the P50 is a positive deflection in the auditory ERP that pathophysiology and treatment of Schizophrenia, their role occurs approximately 50 ms after the presentation of an in modulating PPI and P50 suppression in humans is yet to auditory stimulus. In a double-click (or double-tone) be fully clarified. Studies investigating the effects of paradigm, two clicks are presented 500 ms apart, and serotonergic modulation on PPI in healthy humans have normal individuals show a reduced response to the second been inconclusive. Enhancing serotonin neurotransmission click (Click 2 or S2) relative to the amplitude of the with MDMA (3,4-methylenedioxy-N-methylamphetamine first click (Click 1 or S1) (termed P50 suppression) with or ecstasy), a presynaptic serotonin releaser (Liechti et al, interstimulus intervals (ISIs) between 500 and 2000 ms. 2001), and the 5-HT2A/1A agonist, psilocybin (Gouzoulis- Analogous to PPI, the second stimulus is ‘gated’ or inhibited Mayfrank et al, 1998; Vollenweider et al, 1999), has been by the initial stimulus. The P50 is measured via electro- shown to increase PPI. However, the effects of psilocybin on encephalography (EEG), where it is maximal at the vertex, PPI may be dependant on the ISI, with another study and suppression is described as a ratio (ie Click 2 PS0 finding a decrease in PPI at ISIs of 30 ms, no effects at ISIs amplitude/Click 1 P50 amplitude) or difference score (ie of 60 ms, and an increase in PPI at 120–2000 ms (Vollen- Click 2 P50 amplitudeÀClick 1 P50 amplitude). Normal weider et al, 2007). On the other hand, reducing serotoner- control participants normally exhibit suppression in the gic neurotransmission with ketanserin (a non-selective range of 50–70% (Adler et al, 1999), while it has been 5-HT2 receptor antagonist) (Graham et al, 2002) or buspirone demonstrated that patients with schizophrenia display (a 5-HT1A partial agonist acting presynaptically) (Gogos significantly lower P50 suppression (Adler et al, 1982; et al, 2006) has been found to reduce PPI. Nevertheless, Boutros et al, 1991; Light et al, 2000; Ward et al, 1996; Yee other studies have found no effects on PPI following and White, 2001; Braff et al, 2007), which is interpreted as enhancement of central serotonin levels with the adminis- reflecting a deficit in ‘sensory gating’ (Adler et al, 1982). tration of serotonin reuptake inhibitors, fenfluramine (Abel Analogous to the PPI findings, there is also some evidence et al, 2007), fluvoxamine (Phillips et al, 2000b), citalopram that P50 suppression deficits in schizophrenia may be (Liechti et al, 2001), and escitalopram (Jensen et al, 2007). normalized with the use of atypical antipsychotic drugs To our knowledge, the effects of serotonergic modulation (Light et al, 2000; Nagamoto et al, 1996, 1999; Adler et al, on P50 suppression in healthy humans has only been 2004; Becker et al, 2004). investigated once, with findings showing a decrease in P50 Although PPI and P50 suppression are