Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis

Abstract

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [¹²³I]-IBZM (radiotracer for dopamine D_2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [¹²³I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.

Keywords

Acoustic startle response biomarkers dopamine dopamine receptor imaging pre-pulse inhibition psychosis schizophrenia sensorimotor gating high risk

Get full access to this article

View all access options for this article.

References

Abel

Waikar

Pedro

. (1998) Repeated testing of prepulse inhibition and habituation of the startle reflex: A study in healthy human controls. J Psychopharmacol 12: 330–337.

Abi-Dargham

Rodenhiser

Printz

. (2000) Increased baseline occupancy of D₂ receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97: 8104–8109.

Bitsios

Giakoumaki

Frangou

(2005) The effects of dopamine agonists on prepulse inhibition in healthy men depend on baseline PPI values. Psychopharmacology 182: 144–152.

Bloemen

De Koning

Boot

. (2008) Challenge and therapeutic studies using alpha-methyl-para-tyrosine (AMPT) in neuropsychiatric disorders: A review. CNS Agents Med Chem 8: 249–256.

Bloemen

De Koning

Gleich

. (2013) Striatal dopamine D_2/3 receptor binding following dopamine depletion in subjects at ultra high risk for psychosis. Eur Neuropsychopharmacol 23: 126–132.

Braff

Stone

Callaway

. (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15: 339–343.

Braff

Grillon

Geyer

(1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49: 206–215.

Cadenhead

(2011) Startle reactivity and prepulse inhibition in prodromal and early psychosis: Effects of age, antipsychotics, tobacco and Cannabis in a vulnerable population. Psychiatry Res 188: 208–216.

Cadenhead

Light

Geyer

. (2002) Neurobiological measures of schizotypal personality disorder: Defining an inhibitory endophenotype? Am J Psychiatry 159: 869–871.

10.

Cadenhead

Swerdlow

Shafer

. (2000) Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: Evidence of inhibitory deficits. Am J Psychiatry 157: 1660–1668.

11.

Canavan

Dunn

McMillan

(1986) Principal components of the WAIS-R. Brit J Clin Psychol 25: 81–85.

12.

De Koning

Boot

Bloemen

. (2012) Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val¹⁵⁸Met polymorphism in adults with 22q11 deletion syndrome. J Psychopharmacol 26: 1548–1560.

13.

Egerton

Chaddock

Winton-Brown

. (2013) Presynaptic striatal dopamine dysfunction in people at ultra-high risk for psychosis: Findings in a second cohort. Biol Psychiatry 74: 106–112.

14.

Giakoumaki

Roussos

Bitsios

(2008) Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val¹⁵⁸Met polymorphism. Neuropsychopharmacol 33: 3058–3068.

15.

Howes

Bose

Turkheimer

. (2011) Dopamine synthesis capacity before onset of psychosis: A prospective [¹⁸F]-DOPA PET imaging study. Am J Psychiatry 168: 1311–1317.

16.

Howes

Kambeitz

Kim

. (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69: 776–786.

17.

Howes

Montgomery

Asselin

. (2009) Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 66: 13–20.

18.

Kay

Fiszbein

Opler

(1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276.

19.

Klosterkotter

Hellmich

Steinmeyer

. (2001) Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry 58: 158–164.

20.

Kumari

Gray

(1999) Smoking withdrawal, nicotine dependence and prepulse inhibition of the acoustic startle reflex. Psychopharmacol 141: 11–15.

21.

McGowan

Lawrence

Sales

. (2004) Presynaptic dopaminergic dysfunction in schizophrenia: A positron emission tomographic [¹⁸F] fluorodopa study. Arch Gen Psychiatry 61: 134–142.

22.

Miller

McGlashan

Woods

. (1999) Symptom assessment in schizophrenic prodromal states. Psychiatr Q 70: 273–287.

23.

Quednow

Frommann

Berning

. (2008) Impaired sensorimotor gating of the acoustic startle response in the prodrome of schizophrenia. Biol Psychiatry 64: 766–773.

24.

Quednow

Wagner

Westheide

. (2006) Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated with amisulpride or olanzapine. Biol Psychiatry 59: 536–545.

25.

Roussos

Giakoumaki

Bitsios

(2009a) A risk PRODH haplotype affects sensorimotor gating, memory, schizotypy and anxiety in healthy male subjects. Biol Psychiatry 65: 1063–1070.

26.

Roussos

Giakoumaki

Bitsios

(2009b) Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818C/G polymorphism. Biol Psychiatry 66: 997–1004.

27.

Schellekens

Grootens

Neef

. (2010) Effect of apomorphine on cognitive performance and sensorimotor gating in humans. Psychopharmacol 207: 559–569.

28.

Schmand

Bakker

Saan

. (1991) [The Dutch Reading Test for Adults: A measure of premorbid intelligence level]. Tijdschr Gerontol Geriatr 22: 15–19.

29.

Shotbolt

Stokes

Owens

. (2011) Striatal dopamine synthesis capacity in twins discordant for schizophrenia. Psychol Med 41: 2331–2338.

30.

Suridjan

Rusjan

Addington

. (2013) Dopamine D₂ and D₃ binding in people at clinical high risk for schizophrenia, antipsychotic-naive patients and healthy controls, while performing a cognitive task. J Psychiatry Neurosci 38: 98–106.

31.

Swerdlow

Shoemaker

Bongiovanni

. (2007) Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration. Pharmacol Biochem Behav 87: 1–10.

32.

Swerdlow

Stephany

Shoemaker

. (2002) Effects of amantadine and bromocriptine on startle and sensorimotor gating: Parametric studies and cross-species comparisons. Psychopharmacol 164: 82–92.

33.

Swerdlow

Stephany

Wasserman

. (2003) Amphetamine effects on prepulse inhibition across-species: Replication and parametric extension. Neuropsychopharmacol 28: 640–650.

34.

Swerdlow

Weber

. (2008) Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacol 199: 331–388.

35.

Turetsky

Calkins

Light

. (2007) Neurophysiological endophenotypes of schizophrenia: The viability of selected candidate measures. Schizophr Bull 33: 69–94.

36.

Wechsler

(1987) Wechsler Adult Intelligence Scale Revised. New York: Psychological Corporation, Harcourt Brace.

37.

Yung

Phillips

Yuen

. (2003) Psychosis prediction: 12-Month follow up of a high-risk (‘prodromal’) group. Schizophr Res 60: 21–32.

38.

Yung

Yuen

McGorry

. (2005) Mapping the onset of psychosis: The Comprehensive Assessment of At-Risk Mental States. Aust NZ J Psychiatry 39: 964–971.

39.

Zavitsanou

Cranney

Richardson

(1999) Dopamine antagonists in the orbital prefrontal cortex reduce prepulse inhibition of the acoustic startle reflex in the rat. Pharmacol Biochem Behav 63: 55–61.

40.

Ziermans

Schothorst

Sprong

. (2012) Reduced prepulse inhibition as an early vulnerability marker of the psychosis prodrome in adolescence. Schizophr Res 134: 10–15.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.01 MB