Chronic psychosocial adversity increases the risk of mental illnesses including schizophrenia and depression (van Os et al., 2010; Howes and Murray, 2014; Parker, 1983). These adverse factors include developmental psychological trauma (Bendall et al., 2008) and adult life events (situations or occurrences that bring about a negative change in personal circumstances and involve threat) (Beards et al., 2013; Brown and Birley, 1968). Several lines of evidence indicate a potential causative component to these relationships as these risk exposures demonstrate dose-response relationships (Janssen et al., 2004; Morgan and Fisher, 2007; Pedersen and Mortensen, 2001). Reverse causality in the form of recall bias does not appear to be driving these associations (Cutajar et al., 2010), and the cessation of stressor reduces the risk of illness (Kelleher et al., 2013). However, we lack a precise mechanistic understanding of how exposure to these risk factors induces vulnerability to mental illness, and why these exposures all increase risk. Understanding this is important to identify targets for prevention and novel treatment. One common component underlying these factors is exposure to psychosocial stress (Howes and Murray, 2014) via activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system as part of the normal biological stress response (Taylor, 2010).

The striatum is functionally connected to the threat detection system (Haber, 2014). Animal research has demonstrated that acute stressors including aversive stimuli induce a pronounced activation of the dopamine system in terms of dopamine neuron population activity (i.e. the numbers of neurons firing) and with regard to amphetamine-induced behaviours (Valenti et al., 2011). Long-lasting changes in dopamine function occur after single stress exposures, including altered responsivity to future stimulation (Holly and Miczek, 2016) in a manner similar to that induced by drugs of abuse (Saal et al., 2003) and such that stress plays a powerful role in the initiation, escalation, and relapse to drug abuse via dopaminergic mechanisms (Koob and Volkow, 2016).

In humans, childhood sexual abuse is associated with elevated urinary dopamine metabolites in childhood (De Bellis et al., 1994) and acute psychosocial stressors induce greater dopamine release in people with low self-reported maternal care (Pruessner et al., 2004). Stress-induced elevations in cortisol levels have been directly correlated with amphetamine-induced dopamine release (Wand et al., 2007) on the one hand, while corticotrophin-releasing hormone administration results in dopamine release on the other (Payer et al., 2017). In terms of long-term exposure, using fMRI in humans, there is evidence that institutional neglect is associated with reduced striatal reward function, which is mediated by the dopamine system (Mehta et al., 2010), and similar findings have been observed in prospective cohorts following childhood adversity (Dillon et al., 2009) suggestive of a possible causal relationship between childhood adversity and alterations of the dopamine system. Furthermore, maltreatment-associated reduced striatal function is associated with adverse outcomes including disrupted attachment (Takiguchi et al., 2015) and depression (Hanson et al., 2015). One study (Oswald et al., 2014) found positive associations between childhood trauma and amphetamine-induced dopamine release, which may be due to the phenomenon of cross-sensitization. Furthermore, within people who are at ultra-high clinical risk of psychosis raised dopamine synthesis capacity has been reported in those patients with high levels of childhood adversity (Egerton et al., 2016). In light of these findings, we wanted to examine the relationships between the autonomic, endocrine and subjective threat responses to an acute psychosocial stressor and dopaminergic function.

The relationships between neurobiological pathways and stress-induced physiological and subjective responses have yet to be fully elucidated in humans. Studies of psychosocial stressors and dopamine function have typically investigated risk factors in isolation, despite the fact that the risk factors cluster together and may share common underlying mechanisms (Hjern et al., 2004; Morgan and Fisher, 2007; Wicks et al., 2005). Since associations between one exposure and outcomes remain after controlling for the other exposures (Schäfer and Fisher, 2011), it is likely that additive effects and/or synergistic effects operate between risk factors (Morgan et al., 2014; Guloksuz et al., 2015; Lataster et al., 2012; Morgan et al., 2008; Schäfer and Fisher, 2011). Furthermore, there is evidence that childhood trauma increases risk of psychopathology in response to adult stressors (McLaughlin et al., 2010). It is also likely that ethnic minority status can increase the risk of psychopathology through social isolation, experiences of discrimination, victimisation and social defeat, which are all considered stressors (Morgan et al., 2010; Bécares et al., 2009; Cooper et al., 2008; Cooper et al., 2017; Selten and Cantor-Graae, 2005; Selten et al., 2012; Sharpley et al., 2001; Tidey and Miczek, 1996). Cognitive models propose that minority status is associated with greater levels of social threat (Combs et al., 2002; Morgan and Fisher, 2007). Indeed we have found evidence that black minority ethnic status is associated with greater amygdalar activation to out-group (i.e. white faces) than vice versa, neurobiological correlates of these theories/findings (McCutcheon et al., 2018) (McCutcheon et al., 2018). Taken with findings that experiences of racism are correlated with amygdala activation to white faces in black individuals (Greer et al., 2012), this suggests that ethnic minority status is associated with functional alterations in the brain circuits involved in threat processing. As minority ethnicity status has been found to be a chronic stressor and increase the risk of mental illness via chronic stress rather than a genetic component (Akdeniz et al., 2014), we included minority ethnic status as a stressor. The combined effect of the risk factors on dopamine function in humans is unknown. Furthermore, previous studies (Egerton et al., 2016; Oswald et al., 2014; Pruessner et al., 2004) in humans have investigated childhood factors alone. Given animal evidence that exposure to mild stressors potentiate dopaminergic activity whilst severe chronic stressors is associated with dopaminergic blunting (Holly and Miczek, 2016), a key outstanding question remains - what is the effect of chronic adversity, across both child and adult stages of life, on dopaminergic function? We therefore aimed to investigate the effects of exposures to multiple psychosocial risk factors for psychosis on dopaminergic function and the acute stress response. Given the findings of dopaminergic dysfunction associated with childhood maltreatment presented above, we hypothesised that healthy humans with a high cumulative exposure to psychosocial stressors would have altered striatal dopamine synthesis, compared to humans with a low exposure. We also sought examine the relationship between dopaminergic function and the subjective threat and physiological responses to acute psychosocial stress using the Montréal Imaging Stress Task (MIST), a validated stress task involving mental arithmetic under negative social appraisal (Dedovic et al., 2005; Lederbogen et al., 2011). We sought to measure salivary α-amylase, secreted from the parotid gland in response to adrenergic activity and a marker of stress-induced adrenergic activity (van Stegeren et al., 2006) which is associated with a faster increase during psychosocial stress than salivary cortisol (Maruyama et al., 2012), and mean arterial pressure (MAP), the product of cardiac output and total peripheral resistance, reflecting organ perfusion and providing a physiological measure of sympathetic activation.

Our main finding is that chronic exposure to psychosocial stressors is associated with significantly reduced striatal dopamine synthesis capacity, particularly in the limbic (ventral) striatum. In addition, we found evidence that striatal dopamine synthesis capacity correlated with both the physiological and subjective responses to an acute psychosocial stressor. Chronic stress exposure is associated with a dissociation between physiological and psychological acute stress responses in the form of an attenuated stress-induced increase in blood pressure alongside a potentiated stress-induced subjective response. These findings support our hypothesis that high cumulative exposure to psychosocial adversity would be associated with altered dopamine synthesis capacity.

This study was approved by the National Research Ethics Service (12/LO/1955) and the Administration of Radioactive Substances Advisory Committee (ARSAC). The study was conducted in accordance with the Helsinki Declaration. All participants provided informed written consent to participate after an oral and written explanation of the study.

Psychosocial stress paradigm

Request a detailed protocol

We induced psychosocial stress using the Montreal Imaging Stress Task (MIST) (Pruessner et al., 2004) 2 hr before PET scanning. The rationale for conducting the PET scan on the same day as the stress task was to reduce the variance in the time between the measures. Participants were aware that one of the measures would be inducing psychosocial stress; however, they were only told after the MIST was completed that this was the task to induce psychosocial stress, and they were then debriefed. They were told beforehand that they could stop the experimental procedures at any time. During the MIST, participants were asked to solve mental arithmetic problems first under a control condition during which no time constraint or feedback were present, and subsequently under the experimental condition where time and difficulty were automatically adjusted to result in a 30–40% error rate. During the experimental condition, we continuously made participants aware of their suboptimal performance via a visual performance bar and scripted verbal negative feedback delivered approximately every 1 min, where a confederate researcher reminded participants that they were performing much worse than average. The MIST was administered using pairs of researchers who were balanced for sex and ethnicity (i.e. male and female researchers, white British and minority ethnicities). There were 2 × 4 min blocks of control MIST control followed by a brief rest, and then 2 pairs of 2 × 4 min blocks of the experimental version including feedback and brief rest. We assessed subjective threat assessed before the task, at the end of control condition, after each 10 min paired block of MIST, and twice upon completion of the task at 30 min and 60 min after starting the experimental task (see Figure 4). We used visual analogue scales to measure subjective threat. Salivary cortisol and α-amylase (Engert et al., 2011) samples were taken at the same time points as the visual analogue scales. Heart rate and blood pressure recordings were taken at 3 min intervals during the control MIST and two experimental MIST conditions, with four readings in each of these three conditions.

Figure 4

Download asset Open asset

The raw data from this study are available on written request to the Chief Investigator. This restriction is due to sensitive data on human research participants. Processed data files for Figures 1 and 2, and table 2 are provided in Source data 1.

1. 1. Akdeniz C
   2. Tost H
   3. Streit F
   4. Haddad L
   5. Wüst S
   6. Schäfer A
   7. Schneider M
   8. Rietschel M
   9. Kirsch P
   10. Meyer-Lindenberg A

   (2014) Neuroimaging evidence for a role of neural social stress processing in ethnic minority-associated environmental risk

   JAMA Psychiatry 71:672–680.

   https://doi.org/10.1001/jamapsychiatry.2014.35

   • PubMed
   • Google Scholar
2. 1. Ali N
   2. Nitschke JP
   3. Cooperman C
   4. Pruessner JC

   (2017) Suppressing the endocrine and autonomic stress systems does not impact the emotional stress experience after psychosocial stress

   Psychoneuroendocrinology 78:125–130.

   https://doi.org/10.1016/j.psyneuen.2017.01.015

   • PubMed
   • Google Scholar
3. 1. Báez-Mendoza R
   2. Harris CJ
   3. Schultz W

   (2013) Activity of striatal neurons reflects social action and own reward

   PNAS 110:16634–16639.

   https://doi.org/10.1073/pnas.1211342110

   • PubMed
   • Google Scholar
4. 1. Beards S
   2. Gayer-Anderson C
   3. Borges S
   4. Dewey ME
   5. Fisher HL
   6. Morgan C

   (2013) Life events and psychosis: a review and meta-analysis

   Schizophrenia Bulletin 39:740–747.

   https://doi.org/10.1093/schbul/sbt065

   • PubMed
   • Google Scholar
5. 1. Bécares L
   2. Stafford M
   3. Nazroo J

   (2009) Fear of racism, employment and expected organizational racism: their association with health

   The European Journal of Public Health 19:504–510.

   https://doi.org/10.1093/eurpub/ckp071

   • PubMed
   • Google Scholar
6. 1. Beck AT
   2. Epstein N
   3. Brown G
   4. Steer RA

   (1988) An inventory for measuring clinical anxiety: psychometric properties

   Journal of Consulting and Clinical Psychology 56:893–897.

   https://doi.org/10.1037/0022-006X.56.6.893

   • PubMed
   • Google Scholar
7. Book

   1. Beck AT
   2. Steer RA
   3. Brown GK

   (1996)

   Manual for the Beck Depression Inventory-II

   San Antonio: Psychological Corporation.

   • Google Scholar
8. 1. Bendall S
   2. Jackson HJ
   3. Hulbert CA
   4. McGorry PD

   (2008) Childhood trauma and psychotic disorders: a systematic, critical review of the evidence

   Schizophrenia Bulletin 34:568–579.

   https://doi.org/10.1093/schbul/sbm121

   • PubMed
   • Google Scholar
9. Book

   1. Bernstein DP
   2. Fink L

   (1998)

   Childhood Trauma Questionnaire: A Retrospective Self-Report Manual

   San Antonio: The Psychological Corporation.

   • Google Scholar
10. 1. Bifulco A
    2. Bernazzani O
    3. Moran PM
    4. Jacobs C

    (2005) The childhood experience of care and abuse questionnaire (CECA.Q): validation in a community series

    British Journal of Clinical Psychology 44:563–581.

    https://doi.org/10.1348/014466505X35344

    • PubMed
    • Google Scholar
11. 1. Bloomfield MA
    2. Pepper F
    3. Egerton A
    4. Demjaha A
    5. Tomasi G
    6. Mouchlianitis E
    7. Maximen L
    8. Veronese M
    9. Turkheimer F
    10. Selvaraj S
    11. Howes OD

    (2014) Dopamine function in cigarette smokers: an [¹⁸F]-DOPA PET study

    Neuropsychopharmacology 39:2397–2404.

    https://doi.org/10.1038/npp.2014.87

    • PubMed
    • Google Scholar
12. 1. Brake WG
    2. Zhang TY
    3. Diorio J
    4. Meaney MJ
    5. Gratton A

    (2004) Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats

    European Journal of Neuroscience 19:1863–1874.

    https://doi.org/10.1111/j.1460-9568.2004.03286.x

    • PubMed
    • Google Scholar
13. 1. Brischoux F
    2. Chakraborty S
    3. Brierley DI
    4. Ungless MA

    (2009) Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli

    PNAS 106:4894–4899.

    https://doi.org/10.1073/pnas.0811507106

    • PubMed
    • Google Scholar
14. 1. Brown GW
    2. Birley JL

    (1968) Crises and life changes and the onset of schizophrenia

    Journal of Health and Social Behavior 9:203–214.

    https://doi.org/10.2307/2948405

    • PubMed
    • Google Scholar
15. 1. Brugha TS
    2. Cragg D

    (1990) The list of threatening experiences: the reliability and validity of a brief life events questionnaire

    Acta Psychiatrica Scandinavica 82:77–81.

    https://doi.org/10.1111/j.1600-0447.1990.tb01360.x

    • PubMed
    • Google Scholar
16. 1. Butterfield MI
    2. Panzer PG
    3. Forneris CA

    (1999) Victimization of women and its impact on assessment and treatment in the psychiatric emergency setting

    Psychiatric Clinics of North America 22:875–896.

    https://doi.org/10.1016/S0193-953X(05)70131-3

    • PubMed
    • Google Scholar
17. 1. Campbell J
    2. Ehlert U

    (2012) Acute psychosocial stress: does the emotional stress response correspond with physiological responses?

    Psychoneuroendocrinology 37:1111–1134.

    https://doi.org/10.1016/j.psyneuen.2011.12.010

    • PubMed
    • Google Scholar
18. 1. Castro SL
    2. Sved AF
    3. Zigmond MJ

    (1996) Increased neostriatal tyrosine hydroxylation during stress: role of extracellular dopamine and excitatory amino acids

    Journal of Neurochemistry 66:824–833.

    https://doi.org/10.1046/j.1471-4159.1996.66020824.x

    • PubMed
    • Google Scholar
19. 1. Chrapusta SJ
    2. Wyatt RJ
    3. Masserano JM

    (1997) Effects of single and repeated footshock on dopamine release and metabolism in the brains of fischer rats

    Journal of Neurochemistry 68:2024–2031.

    https://doi.org/10.1046/j.1471-4159.1997.68052024.x

    • PubMed
    • Google Scholar
20. 1. Cicero DC
    2. Kerns JG
    3. McCarthy DM

    (2010) The aberrant salience inventory: a new measure of psychosis proneness

    Psychological Assessment 22:688–701.

    https://doi.org/10.1037/a0019913

    • PubMed
    • Google Scholar
21. 1. Cohen JY
    2. Haesler S
    3. Vong L
    4. Lowell BB
    5. Uchida N

    (2012) Neuron-type-specific signals for reward and punishment in the ventral tegmental area

    Nature 482:85–88.

    https://doi.org/10.1038/nature10754

    • PubMed
    • Google Scholar
22. 1. Combs DR
    2. Penn DL
    3. Fenigstein A

    (2002) Ethnic differences in subclinical paranoia: an expansion of norms of the paranoia scale

    Cultural Diversity and Ethnic Minority Psychology 8:248–256.

    https://doi.org/10.1037/1099-9809.8.3.248

    • PubMed
    • Google Scholar
23. 1. Cooper MA
    2. McIntyre KE
    3. Huhman KL

    (2008) Activation of 5-HT1A autoreceptors in the dorsal raphe nucleus reduces the behavioral consequences of social defeat

    Psychoneuroendocrinology 33:1236–1247.

    https://doi.org/10.1016/j.psyneuen.2008.06.009

    • PubMed
    • Google Scholar
24. 1. Cooper SE
    2. Kechner M
    3. Caraballo-Pérez D
    4. Kaska S
    5. Robison AJ
    6. Mazei-Robison MS

    (2017) Comparison of chronic physical and emotional social defeat stress effects on mesocorticolimbic circuit activation and voluntary consumption of morphine

    Scientific Reports 7:8445.

    https://doi.org/10.1038/s41598-017-09106-3

    • PubMed
    • Google Scholar
25. 1. Cutajar MC
    2. Mullen PE
    3. Ogloff JR
    4. Thomas SD
    5. Wells DL
    6. Spataro J

    (2010) Schizophrenia and other psychotic disorders in a cohort of sexually abused children

    Archives of General Psychiatry 67:1114–1119.

    https://doi.org/10.1001/archgenpsychiatry.2010.147

    • PubMed
    • Google Scholar
26. 1. De Bellis MD
    2. Lefter L
    3. Trickett PK
    4. Putnam FW

    (1994) Urinary catecholamine excretion in sexually abused girls

    Journal of the American Academy of Child & Adolescent Psychiatry 33:320–327.

    https://doi.org/10.1097/00004583-199403000-00004

    • PubMed
    • Google Scholar
27. 1. Dedovic K
    2. Renwick R
    3. Mahani NK
    4. Engert V
    5. Lupien SJ
    6. Pruessner JC

    (2005)

    The Montreal imaging stress task: using functional imaging to investigate the effects of perceiving and processing psychosocial stress in the human brain

    Journal of Psychiatry & Neuroscience : JPN 30:319–325.

    • PubMed
    • Google Scholar
28. 1. Del Giudice M
    2. Ellis BJ
    3. Shirtcliff EA

    (2011) The adaptive calibration model of stress responsivity

    Neuroscience & Biobehavioral Reviews 35:1562–1592.

    https://doi.org/10.1016/j.neubiorev.2010.11.007

    • PubMed
    • Google Scholar
29. 1. Demarest KT
    2. Moore KE
    3. Riegle GD

    (1985) Acute restraint stress decreases dopamine synthesis and turnover in the median eminence: a model for the study of the inhibitory neuronal influences on tuberoinfundibular dopaminergic neurons

    Neuroendocrinology 41:437–444.

    https://doi.org/10.1159/000124215

    • PubMed
    • Google Scholar
30. 1. Dillon DG
    2. Holmes AJ
    3. Birk JL
    4. Brooks N
    5. Lyons-Ruth K
    6. Pizzagalli DA

    (2009) Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood

    Biological Psychiatry 66:206–213.

    https://doi.org/10.1016/j.biopsych.2009.02.019

    • PubMed
    • Google Scholar
31. 1. Dong Y
    2. Saal D
    3. Thomas M
    4. Faust R
    5. Bonci A
    6. Robinson T
    7. Malenka RC

    (2004) Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA(-/-) mice

    PNAS 101:14282–14287.

    https://doi.org/10.1073/pnas.0401553101

    • PubMed
    • Google Scholar
32. 1. Egerton A
    2. Demjaha A
    3. McGuire P
    4. Mehta MA
    5. Howes OD

    (2010) The test-retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function

    NeuroImage 50:524–531.

    https://doi.org/10.1016/j.neuroimage.2009.12.058

    • PubMed
    • Google Scholar
33. 1. Egerton A
    2. Valmaggia LR
    3. Howes OD
    4. Day F
    5. Chaddock CA
    6. Allen P
    7. Winton-Brown TT
    8. Bloomfield MAP
    9. Bhattacharyya S
    10. Chilcott J
    11. Lappin JM
    12. Murray RM
    13. McGuire P

    (2016) Adversity in childhood linked to elevated striatal dopamine function in adulthood

    Schizophrenia Research 176:171–176.

    https://doi.org/10.1016/j.schres.2016.06.005

    • PubMed
    • Google Scholar
34. 1. Engert V
    2. Vogel S
    3. Efanov SI
    4. Duchesne A
    5. Corbo V
    6. Ali N
    7. Pruessner JC

    (2011) Investigation into the cross-correlation of salivary cortisol and alpha-amylase responses to psychological stress

    Psychoneuroendocrinology 36:1294–1302.

    https://doi.org/10.1016/j.psyneuen.2011.02.018

    • PubMed
    • Google Scholar
35. 1. Fergusson DM
    2. Horwood LJ
    3. Boden JM

    (2011) Structural equation modeling of repeated retrospective reports of childhood maltreatment

    International Journal of Methods in Psychiatric Research 20:93–104.

    https://doi.org/10.1002/mpr.337

    • PubMed
    • Google Scholar
36. 1. Finlay JM
    2. Zigmond MJ

    (1997) The effects of stress on central dopaminergic neurons: possible clinical implications

    Neurochemical Research 22:1387–1394.

    https://doi.org/10.1023/a:1022075324164

    • PubMed
    • Google Scholar
37. 1. Fisher HL
    2. Craig TK
    3. Fearon P
    4. Morgan K
    5. Dazzan P
    6. Lappin J
    7. Hutchinson G
    8. Doody GA
    9. Jones PB
    10. McGuffin P
    11. Murray RM
    12. Leff J
    13. Morgan C

    (2011) Reliability and comparability of psychosis patients' retrospective reports of childhood abuse

    Schizophrenia Bulletin 37:546–553.

    https://doi.org/10.1093/schbul/sbp103

    • PubMed
    • Google Scholar
38. 1. Freeman D

    (2007) Suspicious minds: the psychology of persecutory delusions

    Clinical Psychology Review 27:425–457.

    https://doi.org/10.1016/j.cpr.2006.10.004

    • PubMed
    • Google Scholar
39. 1. Fulford AJ
    2. Marsden CA

    (1998) Effect of isolation-rearing on conditioned dopamine release in vivo in the nucleus accumbens of the rat

    Journal of Neurochemistry 70:384–390.

    https://doi.org/10.1046/j.1471-4159.1998.70010384.x

    • PubMed
    • Google Scholar
40. 1. Gelernter J
    2. Goldman D
    3. Risch N

    (1993) The A1 allele at the D2 dopamine receptor gene and alcoholism. A reappraisal

    Jama 269:1673–1677.

    https://doi.org/10.1001/jama.1993.03500130087038

    • PubMed
    • Google Scholar
41. 1. Gilbert R
    2. Kemp A
    3. Thoburn J
    4. Sidebotham P
    5. Radford L
    6. Glaser D
    7. MacMillan HL

    (2009) Recognising and responding to child maltreatment

    The Lancet 373:167–180.

    https://doi.org/10.1016/S0140-6736(08)61707-9

    • Google Scholar
42. 1. Gooding HC
    2. Milliren CE
    3. Austin SB
    4. Sheridan MA
    5. McLaughlin KA

    (2016) Child abuse, resting blood pressure, and blood pressure reactivity to psychosocial stress

    Journal of Pediatric Psychology 41:5–14.

    https://doi.org/10.1093/jpepsy/jsv040

    • PubMed
    • Google Scholar
43. 1. Graziane NM
    2. Polter AM
    3. Briand LA
    4. Pierce RC
    5. Kauer JA

    (2013) Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity

    Neuron 77:942–954.

    https://doi.org/10.1016/j.neuron.2012.12.034

    • PubMed
    • Google Scholar
44. 1. Greer TM
    2. Vendemia JM
    3. Stancil M

    (2012) Neural correlates of race-related social evaluations for african americans and white americans

    Neuropsychology 26:704–712.

    https://doi.org/10.1037/a0030035

    • PubMed
    • Google Scholar
45. 1. Gresch PJ
    2. Sved AF
    3. Zigmond MJ
    4. Finlay JM

    (1994) Stress-induced sensitization of dopamine and norepinephrine efflux in medial prefrontal cortex of the rat

    Journal of Neurochemistry 63:575–583.

    https://doi.org/10.1046/j.1471-4159.1994.63020575.x

    • PubMed
    • Google Scholar
46. 1. Guloksuz S
    2. van Nierop M
    3. Lieb R
    4. van Winkel R
    5. Wittchen HU
    6. van Os J

    (2015) Evidence that the presence of psychosis in non-psychotic disorder is environment-dependent and mediated by severity of non-psychotic psychopathology

    Psychological Medicine 45:2389–2401.

    https://doi.org/10.1017/S0033291715000380

    • PubMed
    • Google Scholar
47. 1. Haber SN

    (2014) The place of dopamine in the cortico-basal ganglia circuit

    Neuroscience 282:248–257.

    https://doi.org/10.1016/j.neuroscience.2014.10.008

    • PubMed
    • Google Scholar
48. 1. Hall FS
    2. Wilkinson LS
    3. Humby T
    4. Robbins TW

    (1999) Maternal deprivation of neonatal rats produces enduring changes in dopamine function

    Synapse 32:37–43.

    https://doi.org/10.1002/(SICI)1098-2396(199904)32:1<37::AID-SYN5>3.0.CO;2-4

    • PubMed
    • Google Scholar
49. 1. Hanson JL
    2. Hariri AR
    3. Williamson DE

    (2015) Blunted ventral striatum development in adolescence reflects emotional neglect and predicts depressive symptoms

    Biological Psychiatry 78:598–605.

    https://doi.org/10.1016/j.biopsych.2015.05.010

    • PubMed
    • Google Scholar
50. 1. Hjern A
    2. Wicks S
    3. Dalman C

    (2004) Social adversity contributes to high morbidity in psychoses in immigrants--a national cohort study in two generations of swedish residents

    Psychological Medicine 34:1025–1033.

    https://doi.org/10.1017/S003329170300148X

    • PubMed
    • Google Scholar
51. 1. Holly EN
    2. Miczek KA

    (2016) Ventral tegmental area dopamine revisited: effects of acute and repeated stress

    Psychopharmacology 233:163–186.

    https://doi.org/10.1007/s00213-015-4151-3

    • PubMed
    • Google Scholar
52. 1. Holmes TH
    2. Rahe RH

    (1967) The social readjustment rating scale

    Journal of Psychosomatic Research 11:213–218.

    https://doi.org/10.1016/0022-3999(67)90010-4

    • PubMed
    • Google Scholar
53. 1. Howes OD
    2. Montgomery AJ
    3. Asselin MC
    4. Murray RM
    5. Valli I
    6. Tabraham P
    7. Bramon-Bosch E
    8. Valmaggia L
    9. Johns L
    10. Broome M
    11. McGuire PK
    12. Grasby PM

    (2009) Elevated striatal dopamine function linked to prodromal signs of schizophrenia

    Archives of General Psychiatry 66:13–20.

    https://doi.org/10.1001/archgenpsychiatry.2008.514

    • PubMed
    • Google Scholar
54. 1. Howes OD
    2. Shotbolt P
    3. Bloomfield M
    4. Daalman K
    5. Demjaha A
    6. Diederen KM
    7. Ibrahim K
    8. Kim E
    9. McGuire P
    10. Kahn RS
    11. Sommer IE

    (2013) Dopaminergic function in the psychosis spectrum: an [18F]-DOPA imaging study in healthy individuals with auditory hallucinations

    Schizophrenia Bulletin 39:807–814.

    https://doi.org/10.1093/schbul/sbr195

    • PubMed
    • Google Scholar
55. 1. Howes OD
    2. Murray RM

    (2014) Schizophrenia: an integrated sociodevelopmental-cognitive model

    The Lancet 383:1677–1687.

    https://doi.org/10.1016/S0140-6736(13)62036-X

    • Google Scholar
56. 1. Imperato A
    2. Puglisi-Allegra S
    3. Casolini P
    4. Zocchi A
    5. Angelucci L

    (1989) Stress-induced enhancement of dopamine and acetylcholine release in limbic structures: role of corticosterone

    European Journal of Pharmacology 165:337–338.

    https://doi.org/10.1016/0014-2999(89)90735-8

    • PubMed
    • Google Scholar
57. 1. Janssen I
    2. Krabbendam L
    3. Bak M
    4. Hanssen M
    5. Vollebergh W
    6. de Graaf R
    7. van Os J

    (2004) Childhood abuse as a risk factor for psychotic experiences

    Acta Psychiatrica Scandinavica 109:38–45.

    https://doi.org/10.1046/j.0001-690X.2003.00217.x

    • PubMed
    • Google Scholar
58. 1. Karssen AM
    2. Meijer OC
    3. Berry A
    4. Sanjuan Piñol R
    5. de Kloet ER

    (2005) Low doses of dexamethasone can produce a hypocorticosteroid state in the brain

    Endocrinology 146:5587–5595.

    https://doi.org/10.1210/en.2005-0501

    • PubMed
    • Google Scholar
59. 1. Kelleher I
    2. Keeley H
    3. Corcoran P
    4. Ramsay H
    5. Wasserman C
    6. Carli V
    7. Sarchiapone M
    8. Hoven C
    9. Wasserman D
    10. Cannon M

    (2013) Childhood trauma and psychosis in a prospective cohort study: cause, effect, and directionality

    American Journal of Psychiatry 170:734–741.

    https://doi.org/10.1176/appi.ajp.2012.12091169

    • PubMed
    • Google Scholar
60. 1. Kirschbaum C
    2. Kudielka BM
    3. Gaab J
    4. Schommer NC
    5. Hellhammer DH

    (1999) Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal Axis

    Psychosomatic Medicine 61:154–162.

    https://doi.org/10.1097/00006842-199903000-00006

    • PubMed
    • Google Scholar
61. 1. Koob GF
    2. Caine SB
    3. Parsons L
    4. Markou A
    5. Weiss F

    (1997) Opponent process model and psychostimulant addiction

    Pharmacology Biochemistry and Behavior 57:513–521.

    https://doi.org/10.1016/S0091-3057(96)00438-8

    • PubMed
    • Google Scholar
62. 1. Koob GF
    2. Volkow ND

    (2016) Neurobiology of addiction: a neurocircuitry analysis

    The Lancet Psychiatry 3:760–773.

    https://doi.org/10.1016/S2215-0366(16)00104-8

    • PubMed
    • Google Scholar
63. 1. Kosten TA
    2. Zhang XY
    3. Kehoe P

    (2003) Chronic neonatal isolation stress enhances cocaine-induced increases in ventral striatal dopamine levels in rat pups

    Developmental Brain Research 141:109–116.

    https://doi.org/10.1016/S0165-3806(03)00003-8

    • PubMed
    • Google Scholar
64. 1. Kumakura Y
    2. Cumming P

    (2009) PET studies of cerebral levodopa metabolism: a review of clinical findings and modeling approaches

    The Neuroscientist 15:635–650.

    https://doi.org/10.1177/1073858409338217

    • PubMed
    • Google Scholar
65. 1. Lataster J
    2. Myin-Germeys I
    3. Lieb R
    4. Wittchen HU
    5. van Os J

    (2012) Adversity and psychosis: a 10-year prospective study investigating synergism between early and recent adversity in psychosis

    Acta Psychiatrica Scandinavica 125:388–399.

    https://doi.org/10.1111/j.1600-0447.2011.01805.x

    • PubMed
    • Google Scholar
66. 1. Lederbogen F
    2. Kirsch P
    3. Haddad L
    4. Streit F
    5. Tost H
    6. Schuch P
    7. Wüst S
    8. Pruessner JC
    9. Rietschel M
    10. Deuschle M
    11. Meyer-Lindenberg A

    (2011) City living and urban upbringing affect neural social stress processing in humans

    Nature 474:498–501.

    https://doi.org/10.1038/nature10190

    • PubMed
    • Google Scholar
67. 1. Lewinsohn PM
    2. Rosenbaum M

    (1987) Recall of parental behavior by acute depressives, remitted depressives, and nondepressives

    Journal of Personality and Social Psychology 52:611–619.

    https://doi.org/10.1037/0022-3514.52.3.611

    • PubMed
    • Google Scholar
68. 1. Lindley SE
    2. Bengoechea TG
    3. Schatzberg AF
    4. Wong DL

    (1999) Glucocorticoid effects on mesotelencephalic dopamine neurotransmission

    Neuropsychopharmacology 21:399–407.

    https://doi.org/10.1016/S0893-133X(98)00103-1

    • PubMed
    • Google Scholar
69. 1. Love TM

    (2014) Oxytocin, motivation and the role of dopamine

    Pharmacology Biochemistry and Behavior 119:49–60.

    https://doi.org/10.1016/j.pbb.2013.06.011

    • PubMed
    • Google Scholar
70. 1. Mangiavacchi S
    2. Masi F
    3. Scheggi S
    4. Leggio B
    5. De Montis MG
    6. Gambarana C

    (2001) Long-term behavioral and neurochemical effects of chronic stress exposure in rats

    Journal of Neurochemistry 79:1113–1121.

    https://doi.org/10.1046/j.1471-4159.2001.00665.x

    • PubMed
    • Google Scholar
71. 1. Martinez D
    2. Slifstein M
    3. Broft A
    4. Mawlawi O
    5. Hwang DR
    6. Huang Y
    7. Cooper T
    8. Kegeles L
    9. Zarahn E
    10. Abi-Dargham A
    11. Haber SN
    12. Laruelle M

    (2003) Imaging human mesolimbic dopamine transmission with positron emission tomography. part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum

    Journal of Cerebral Blood Flow & Metabolism 23:285–300.

    https://doi.org/10.1097/01.WCB.0000048520.34839.1A

    • PubMed
    • Google Scholar
72. 1. Maruyama Y
    2. Kawano A
    3. Okamoto S
    4. Ando T
    5. Ishitobi Y
    6. Tanaka Y
    7. Inoue A
    8. Imanaga J
    9. Kanehisa M
    10. Higuma H
    11. Ninomiya T
    12. Tsuru J
    13. Hanada H
    14. Akiyoshi J

    (2012) Differences in salivary alpha-amylase and cortisol responsiveness following exposure to electrical stimulation versus the trier social stress tests

    PLOS ONE 7:e39375.

    https://doi.org/10.1371/journal.pone.0039375

    • PubMed
    • Google Scholar
73. 1. Matthews K
    2. Hall FS
    3. Wilkinson LS
    4. Robbins TW

    (1996) Retarded acquisition and reduced expression of conditioned locomotor activity in adult rats following repeated early maternal separation: effects of Prefeeding, d-amphetamine, dopamine antagonists and clonidine

    Psychopharmacology 126:75–84.

    https://doi.org/10.1007/BF02246414

    • PubMed
    • Google Scholar
74. 1. Mauss IB
    2. Levenson RW
    3. McCarter L
    4. Wilhelm FH
    5. Gross JJ

    (2005) The tie that binds? coherence among emotion experience, behavior, and physiology

    Emotion 5:175–190.

    https://doi.org/10.1037/1528-3542.5.2.175

    • PubMed
    • Google Scholar
75. 1. McCutcheon R
    2. Bloomfield MAP
    3. Dahoun T
    4. Quinlan M
    5. Terbeck S
    6. Mehta M
    7. Howes O

    (2018) Amygdala reactivity in ethnic minorities and its relationship to the social environment: an fMRI study

    Psychological Medicine 48:1985–1992.

    https://doi.org/10.1017/S0033291717003506

    • PubMed
    • Google Scholar
76. 1. McEwen BS

    (1998) Stress, adaptation, and disease. allostasis and allostatic load

    Annals of the New York Academy of Sciences 840:33–44.

    https://doi.org/10.1111/j.1749-6632.1998.tb09546.x

    • PubMed
    • Google Scholar
77. 1. McGowan S
    2. Lawrence AD
    3. Sales T
    4. Quested D
    5. Grasby P

    (2004) Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study

    Archives of General Psychiatry 61:134–142.

    https://doi.org/10.1001/archpsyc.61.2.134

    • PubMed
    • Google Scholar
78. 1. McLaughlin KA
    2. Kubzansky LD
    3. Dunn EC
    4. Waldinger R
    5. Vaillant G
    6. Koenen KC

    (2010) Childhood social environment, emotional reactivity to stress, and mood and anxiety disorders across the life course

    Depression and Anxiety 27:1087–1094.

    https://doi.org/10.1002/da.20762

    • PubMed
    • Google Scholar
79. 1. Meaney MJ
    2. Brake W
    3. Gratton A

    (2002) Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse?

    Psychoneuroendocrinology 27:127–138.

    https://doi.org/10.1016/S0306-4530(01)00040-3

    • PubMed
    • Google Scholar
80. 1. Mehta MA
    2. Gore-Langton E
    3. Golembo N
    4. Colvert E
    5. Williams SC
    6. Sonuga-Barke E

    (2010) Hyporesponsive reward anticipation in the basal ganglia following severe institutional deprivation early in life

    Journal of Cognitive Neuroscience 22:2316–2325.

    https://doi.org/10.1162/jocn.2009.21394

    • PubMed
    • Google Scholar
81. 1. Meyer JS

    (1985) Biochemical effects of corticosteroids on neural tissues

    Physiological Reviews 65:946–1020.

    https://doi.org/10.1152/physrev.1985.65.4.946

    • PubMed
    • Google Scholar
82. 1. Meyer-Lindenberg A
    2. Miletich RS
    3. Kohn PD
    4. Esposito G
    5. Carson RE
    6. Quarantelli M
    7. Weinberger DR
    8. Berman KF

    (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia

    Nature Neuroscience 5:267–271.

    https://doi.org/10.1038/nn804

    • PubMed
    • Google Scholar
83. 1. Miczek KA
    2. Nikulina EM
    3. Shimamoto A
    4. Covington HE

    (2011) Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats

    Journal of Neuroscience 31:9848–9857.

    https://doi.org/10.1523/JNEUROSCI.0637-11.2011

    • PubMed
    • Google Scholar
84. 1. Miller GA
    2. Chapman JP

    (2001) Misunderstanding analysis of covariance

    Journal of Abnormal Psychology 110:40–48.

    https://doi.org/10.1037/0021-843X.110.1.40

    • PubMed
    • Google Scholar
85. 1. Moreines JL
    2. Owrutsky ZL
    3. Grace AA

    (2017) Involvement of infralimbic prefrontal cortex but not lateral habenula in dopamine attenuation after chronic mild stress

    Neuropsychopharmacology 42:904–913.

    https://doi.org/10.1038/npp.2016.249

    • PubMed
    • Google Scholar
86. 1. Morgan C
    2. Kirkbride J
    3. Hutchinson G
    4. Craig T
    5. Morgan K
    6. Dazzan P
    7. Boydell J
    8. Doody GA
    9. Jones PB
    10. Murray RM
    11. Leff J
    12. Fearon P

    (2008) Cumulative social disadvantage, ethnicity and first-episode psychosis: a case-control study

    Psychological Medicine 38:1701–1715.

    https://doi.org/10.1017/S0033291708004534

    • PubMed
    • Google Scholar
87. 1. Morgan C
    2. Charalambides M
    3. Hutchinson G
    4. Murray RM

    (2010) Migration, ethnicity, and psychosis: toward a sociodevelopmental model

    Schizophrenia Bulletin 36:655–664.

    https://doi.org/10.1093/schbul/sbq051

    • PubMed
    • Google Scholar
88. 1. Morgan C
    2. Reininghaus U
    3. Fearon P
    4. Hutchinson G
    5. Morgan K
    6. Dazzan P
    7. Boydell J
    8. Kirkbride JB
    9. Doody GA
    10. Jones PB
    11. Murray RM
    12. Craig T

    (2014) Modelling the interplay between childhood and adult adversity in pathways to psychosis: initial evidence from the AESOP study

    Psychological Medicine 44:407–419.

    https://doi.org/10.1017/S0033291713000767

    • PubMed
    • Google Scholar
89. 1. Morgan C
    2. Fisher H

    (2007) Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma--a critical review

    Schizophrenia Bulletin 33:3–10.

    https://doi.org/10.1093/schbul/sbl053

    • PubMed
    • Google Scholar
90. 1. Niehaus JL
    2. Murali M
    3. Kauer JA

    (2010) Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area

    European Journal of Neuroscience 32:108–117.

    https://doi.org/10.1111/j.1460-9568.2010.07256.x

    • PubMed
    • Google Scholar
91. 1. Nutt DJ

    (2006)

    The role of dopamine and norepinephrine in depression and antidepressant treatment

    The Journal of Clinical Psychiatry 67 Suppl 6:3–8.

    • PubMed
    • Google Scholar
92. Book

    1. Olweus DA

    (1996) The Revised Olweus Bully/Victim Questionnaire

    Bergen: University of Bergen.

    https://doi.org/10.1037/t09634-000

    • Google Scholar
93. 1. Osborn DP
    2. Levy G
    3. Nazareth I
    4. Petersen I
    5. Islam A
    6. King MB

    (2007) Relative risk of cardiovascular and Cancer mortality in people with severe mental illness from the united kingdom's General Practice Rsearch Database

    Archives of General Psychiatry 64:242–249.

    https://doi.org/10.1001/archpsyc.64.2.242

    • PubMed
    • Google Scholar
94. 1. Oswald LM
    2. Wand GS
    3. Kuwabara H
    4. Wong DF
    5. Zhu S
    6. Brasic JR

    (2014) History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine

    Psychopharmacology 231:2417–2433.

    https://doi.org/10.1007/s00213-013-3407-z

    • PubMed
    • Google Scholar
95. 1. Paivio SC

    (2001) Stability of retrospective self-reports of child abuse and neglect before and after therapy for child abuse issues

    Child Abuse & Neglect 25:1053–1068.

    https://doi.org/10.1016/S0145-2134(01)00256-3

    • PubMed
    • Google Scholar
96. 1. Parker G

    (1983) Parental 'affectionless control' as an antecedent to adult depression. A risk factor delineated

    Archives of General Psychiatry 40:956–960.

    https://doi.org/10.1001/archpsyc.1983.01790080038005

    • PubMed
    • Google Scholar
97. 1. Payer D
    2. Williams B
    3. Mansouri E
    4. Stevanovski S
    5. Nakajima S
    6. Le Foll B
    7. Kish S
    8. Houle S
    9. Mizrahi R
    10. George SR
    11. George TP
    12. Boileau I

    (2017) Corticotropin-releasing hormone and dopamine release in healthy individuals

    Psychoneuroendocrinology 76:192–196.

    https://doi.org/10.1016/j.psyneuen.2016.11.034

    • Google Scholar
98. 1. Pedersen CB
    2. Mortensen PB

    (2001) Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk

    Archives of General Psychiatry 58:1039–1046.

    https://doi.org/10.1001/archpsyc.58.11.1039

    • PubMed
    • Google Scholar
99. 1. Penninx BW

    (2017) Depression and cardiovascular disease: epidemiological evidence on their linking mechanisms

    Neuroscience & Biobehavioral Reviews 74:277–286.

    https://doi.org/10.1016/j.neubiorev.2016.07.003

    • PubMed
    • Google Scholar
100. 1. Pruessner JC
     2. Champagne F
     3. Meaney MJ
     4. Dagher A

     (2004) Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride

     Journal of Neuroscience 24:2825–2831.

     https://doi.org/10.1523/JNEUROSCI.3422-03.2004

     • PubMed
     • Google Scholar
101. 1. Reininghaus U
     2. Gayer-Anderson C
     3. Valmaggia L
     4. Kempton MJ
     5. Calem M
     6. Onyejiaka A
     7. Hubbard K
     8. Dazzan P
     9. Beards S
     10. Fisher HL
     11. Mills JG
     12. McGuire P
     13. Craig TK
     14. Garety P
     15. van Os J
     16. Murray RM
     17. Wykes T
     18. Myin-Germeys I
     19. Morgan C

     (2016) Psychological processes underlying the association between childhood trauma and psychosis in daily life: an experience sampling study

     Psychological Medicine 46:2799–2813.

     https://doi.org/10.1017/S003329171600146X

     • PubMed
     • Google Scholar
102. 1. Saal D
     2. Dong Y
     3. Bonci A
     4. Malenka RC

     (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons

     Neuron 37:577–582.

     https://doi.org/10.1016/S0896-6273(03)00021-7

     • PubMed
     • Google Scholar
103. 1. Salokangas RK
     2. Vilkman H
     3. Ilonen T
     4. Taiminen T
     5. Bergman J
     6. Haaparanta M
     7. Solin O
     8. Alanen A
     9. Syvälahti E
     10. Hietala J

     (2000) High levels of dopamine activity in the basal ganglia of cigarette smokers

     American Journal of Psychiatry 157:632–634.

     https://doi.org/10.1176/appi.ajp.157.4.632

     • PubMed
     • Google Scholar
104. 1. Schäfer I
     2. Fisher HL

     (2011)

     Childhood trauma and psychosis - what is the evidence?

     Dialogues in Clinical Neuroscience 13:360–365.

     • PubMed
     • Google Scholar
105. 1. Schultz W

     (2016) Dopamine reward prediction-error signalling: a two-component response

     Nature Reviews Neuroscience 17:183–195.

     https://doi.org/10.1038/nrn.2015.26

     • PubMed
     • Google Scholar
106. 1. Scott KM
     2. McLaughlin KA
     3. Smith DA
     4. Ellis PM

     (2012) Childhood maltreatment and DSM-IV adult mental disorders: comparison of prospective and retrospective findings

     British Journal of Psychiatry 200:469–475.

     https://doi.org/10.1192/bjp.bp.111.103267

     • PubMed
     • Google Scholar
107. 1. Seeman MV
     2. Seeman P

     (2014) Is schizophrenia a dopamine supersensitivity psychotic reaction?

     Progress in Neuro-Psychopharmacology and Biological Psychiatry 48:155–160.

     https://doi.org/10.1016/j.pnpbp.2013.10.003

     • PubMed
     • Google Scholar
108. 1. Selten JP
     2. Laan W
     3. Kupka R
     4. Smeets HM
     5. van Os J

     (2012) Risk of psychiatric treatment for mood disorders and psychotic disorders among migrants and Dutch nationals in Utrecht, The Netherlands

     Social Psychiatry and Psychiatric Epidemiology 47:271–278.

     https://doi.org/10.1007/s00127-010-0335-7

     • Google Scholar
109. 1. Selten JP
     2. Cantor-Graae E

     (2005) Social defeat: risk factor for schizophrenia?

     British Journal of Psychiatry 187:101–102.

     https://doi.org/10.1192/bjp.187.2.101

     • PubMed
     • Google Scholar
110. 1. Shaham Y
     2. Erb S
     3. Stewart J

     (2000) Stress-induced relapse to heroin and cocaine seeking in rats: a review

     Brain Research Reviews 33:13–33.

     https://doi.org/10.1016/S0165-0173(00)00024-2

     • PubMed
     • Google Scholar
111. 1. Sharpley M
     2. Hutchinson G
     3. McKenzie K
     4. Murray RM

     (2001)

     Understanding the excess of psychosis among the African-Caribbean population in England. review of current hypotheses

     The British Journal of Psychiatry. Supplement 40:s60–s68.

     • PubMed
     • Google Scholar
112. 1. Shimamoto A
     2. Debold JF
     3. Holly EN
     4. Miczek KA

     (2011) Blunted accumbal dopamine response to cocaine following chronic social stress in female rats: exploring a link between depression and drug abuse

     Psychopharmacology 218:271–279.

     https://doi.org/10.1007/s00213-011-2364-7

     • PubMed
     • Google Scholar
113. 1. Sinha R

     (2007) The role of stress in addiction relapse

     Current Psychiatry Reports 9:388–395.

     https://doi.org/10.1007/s11920-007-0050-6

     • PubMed
     • Google Scholar
114. 1. Sinha R

     (2009) Modeling stress and drug craving in the laboratory: implications for addiction treatment development

     Addiction Biology 14:84–98.

     https://doi.org/10.1111/j.1369-1600.2008.00134.x

     • PubMed
     • Google Scholar
115. 1. Stokes PR
     2. Shotbolt P
     3. Mehta MA
     4. Turkheimer E
     5. Benecke A
     6. Copeland C
     7. Turkheimer FE
     8. Lingford-Hughes AR
     9. Howes OD

     (2013) Nature or nurture? determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study

     Neuropsychopharmacology 38:485–491.

     https://doi.org/10.1038/npp.2012.207

     • PubMed
     • Google Scholar
116. 1. Studholme C
     2. Hill DL
     3. Hawkes DJ

     (1996) Automated 3-D registration of MR and CT images of the head

     Medical Image Analysis 1:163–175.

     https://doi.org/10.1016/S1361-8415(96)80011-9

     • PubMed
     • Google Scholar
117. 1. Takiguchi S
     2. Fujisawa TX
     3. Mizushima S
     4. Saito DN
     5. Okamoto Y
     6. Shimada K
     7. Koizumi M
     8. Kumazaki H
     9. Jung M
     10. Kosaka H
     11. Hiratani M
     12. Ohshima Y
     13. Teicher MH
     14. Tomoda A

     (2015) Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study

     BJPsych Open 1:121–128.

     https://doi.org/10.1192/bjpo.bp.115.001586

     • PubMed
     • Google Scholar
118. 1. Taylor SE

     (2010) Mechanisms linking early life stress to adult health outcomes

     PNAS 107:8507–8512.

     https://doi.org/10.1073/pnas.1003890107

     • PubMed
     • Google Scholar
119. 1. Teicher MH
     2. Samson JA
     3. Anderson CM
     4. Ohashi K

     (2016) The effects of childhood maltreatment on brain structure, function and connectivity

     Nature Reviews Neuroscience 17:652–666.

     https://doi.org/10.1038/nrn.2016.111

     • PubMed
     • Google Scholar
120. 1. Thompson JL
     2. Urban N
     3. Slifstein M
     4. Xu X
     5. Kegeles LS
     6. Girgis RR
     7. Beckerman Y
     8. Harkavy-Friedman JM
     9. Gil R
     10. Abi-Dargham A

     (2013) Striatal dopamine release in schizophrenia comorbid with substance dependence

     Molecular Psychiatry 18:909–915.

     https://doi.org/10.1038/mp.2012.109

     • PubMed
     • Google Scholar
121. 1. Thoresen S
     2. Tambs K
     3. Hussain A
     4. Heir T
     5. Johansen VA
     6. Bisson JI

     (2010) Brief measure of posttraumatic stress reactions: impact of event Scale-6

     Social Psychiatry and Psychiatric Epidemiology 45:405–412.

     https://doi.org/10.1007/s00127-009-0073-x

     • PubMed
     • Google Scholar
122. 1. Tidey JW
     2. Miczek KA

     (1996) Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study

     Brain Research 721:140–149.

     https://doi.org/10.1016/0006-8993(96)00159-X

     • PubMed
     • Google Scholar
123. 1. Turkheimer FE
     2. Brett M
     3. Visvikis D
     4. Cunningham VJ

     (1999) Multiresolution analysis of emission tomography images in the wavelet domain

     Journal of Cerebral Blood Flow & Metabolism 19:1189–1208.

     https://doi.org/10.1097/00004647-199911000-00003

     • PubMed
     • Google Scholar
124. 1. Valenti O
     2. Cifelli P
     3. Gill KM
     4. Grace AA

     (2011) Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia

     Journal of Neuroscience 31:12330–12338.

     https://doi.org/10.1523/JNEUROSCI.2808-11.2011

     • PubMed
     • Google Scholar
125. 1. van Os J
     2. Kenis G
     3. Rutten BP

     (2010) The environment and schizophrenia

     Nature 468:203–212.

     https://doi.org/10.1038/nature09563

     • PubMed
     • Google Scholar
126. 1. van Stegeren A
     2. Rohleder N
     3. Everaerd W
     4. Wolf OT

     (2006) Salivary alpha amylase as marker for adrenergic activity during stress: effect of betablockade

     Psychoneuroendocrinology 31:137–141.

     https://doi.org/10.1016/j.psyneuen.2005.05.012

     • PubMed
     • Google Scholar
127. 1. Wand GS
     2. Oswald LM
     3. McCaul ME
     4. Wong DF
     5. Johnson E
     6. Zhou Y
     7. Kuwabara H
     8. Kumar A

     (2007) Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress

     Neuropsychopharmacology 32:2310–2320.

     https://doi.org/10.1038/sj.npp.1301373

     • PubMed
     • Google Scholar
128. 1. Watson S
     2. Gallagher P
     3. Dougall D
     4. Porter R
     5. Moncrieff J
     6. Ferrier IN
     7. Young AH

     (2014) Childhood trauma in bipolar disorder

     Australian & New Zealand Journal of Psychiatry 48:564–570.

     https://doi.org/10.1177/0004867413516681

     • PubMed
     • Google Scholar
129. 1. Wenzel JM
     2. Rauscher NA
     3. Cheer JF
     4. Oleson EB

     (2015) A role for phasic dopamine release within the nucleus accumbens in encoding aversion: a review of the neurochemical literature

     ACS Chemical Neuroscience 6:16–26.

     https://doi.org/10.1021/cn500255p

     • PubMed
     • Google Scholar
130. 1. Wicks S
     2. Hjern A
     3. Gunnell D
     4. Lewis G
     5. Dalman C

     (2005) Social adversity in childhood and the risk of developing psychosis: a national cohort study

     American Journal of Psychiatry 162:1652–1657.

     https://doi.org/10.1176/appi.ajp.162.9.1652

     • PubMed
     • Google Scholar
131. 1. Wiers CE
     2. Towb PC
     3. Hodgkinson CA
     4. Shen P-H
     5. Freeman C
     6. Miller G
     7. Lindgren E
     8. Shokri-Kojori E
     9. Demiral Ş B
     10. Kim SW
     11. Tomasi D
     12. Sun H
     13. Wang G-J
     14. Goldman D
     15. Volkow ND

     (2018) Association of genetic ancestry with striatal dopamine D2/D3 receptor availability

     Molecular Psychiatry 23:1711–1716.

     https://doi.org/10.1038/mp.2017.208

     • Google Scholar
132. 1. Yung AR
     2. Yuen HP
     3. McGorry PD
     4. Phillips LJ
     5. Kelly D
     6. Dell'Olio M
     7. Francey SM
     8. Cosgrave EM
     9. Killackey E
     10. Stanford C
     11. Godfrey K
     12. Buckby J

     (2005) Mapping the onset of psychosis: the comprehensive assessment of At-Risk mental states

     Australian & New Zealand Journal of Psychiatry 39:964–971.

     https://doi.org/10.1080/j.1440-1614.2005.01714.x

     • PubMed
     • Google Scholar
133. 1. Zweifel LS
     2. Fadok JP
     3. Argilli E
     4. Garelick MG
     5. Jones GL
     6. Dickerson TM
     7. Allen JM
     8. Mizumori SJ
     9. Bonci A
     10. Palmiter RD

     (2011) Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety

     Nature Neuroscience 14:620–626.

     https://doi.org/10.1038/nn.2808

     • PubMed
     • Google Scholar

Thank you for submitting your article "The effects of chronic psychosocial stress on dopaminergic function and psychiatric imaging group" for consideration by eLife. Your article has been reviewed by three peer reviewers, and the evaluation has been overseen by Christian Büchel as the Senior and Reviewing Editor. The reviewers have opted to remain anonymous.

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

Summary:

This paper is on chronic psychosocial adversity and vulnerability to mental illness. The authors follow the lead that dopamine might be an important link here and used [¹⁸ F]-DOPA PET to compare dopamine synthesis capacity of participants with high cumulative exposure to psychosocial adversity and controls (both groups n=17). The results show (i) that DA synthesis was correlated with subjective threat and physiological response to acute psychosocial stress, (ii) psychosocial stress dampened striatal dopaminergic and (iii) psychosocial adversity blunted physiological subjective responses to acute psychosocial stress.

Essential revisions:

Apart from addressing all points raised by the reviewers (see below), the authors should put particular emphasis on the following topics:

1) Explain and justify why the stress task (MIST) was performed two hours prior to the PET scanning.

2) How can acute control and experimental effects be disentangled and how is the interaction with chronic adversity resolved?

3) The sections regarding basic science and dopamine population activity needs clarifications.

Reviewer #1:

In this manuscript, the authors examine the impact of prior exposure to psychosocial stress on indices of DA function in humans. The paper is quite interesting and potentially important; however, there are some issues that need to be addressed:

1) The link with animal literature as written is confusing with regard to DA release and stress vs. synthesis capacity in humans. One potential caveat is that overall release in animals in response to stressors may not be the critical variable; since the authors are studying synthesis capacity (i.e., number of terminals that are active), a better comparison would be with DA neuron population activity (i.e., number of neurons firing) which was shown in studies of repeated stress by Valenti and Grace. These data would be more consistent and less confusing than the literature cited, which confounds release, metabolites, and activation.

2) Which regions of the DA system are activated vs. blunted with acute vs. chronic stress is an important variable. Acute and repeated stress activate the entire DA system projecting to much of the striatum (Valenti and Grace), in particular the associative striatum where object salience is important, whereas in chronic stress-induced depression (Holly and Miczek), the blunting occurs primarily in the neurons projecting to the ventromedial striatum (Moreines and Grace), where reward-related variables are processed. Therefore these are different systems mediating the DA stress response that varies with duration of stress exposure, and with the induction of anxiety (acute or repeated stress) vs. depression (chronic stress). This is consistent with Koob's opponent process model, where acute stress activates the DA system, which upon chronic exposure leads to a compensatory down-regulation.

3) Stress in Juvenile/adolescence has very different effects than chronic stress in adults. Therefore it is not valid to compare repeated adult stress with juvenile stress factors.

4) Discussion interpretation of findings – Holly and Miczek did not record from DA neurons.

5). The section on maternal deprivation occurs during very early juvenile period (i.e., postnatal day 7-8), which is far earlier than the juvenile/adolescent stress referred to in the paper.

Reviewer #2:

The authors present findings on dopamine synthesis capacity (using PET) in individuals with high exposure to adversity as compared to matched controls with low adversity (each group with N=17). PET scans are performed two hours after an acute psychosocial stress task (MIST), were participants with high exposure to adversity show enhanced threat experience, but lower arterial blood-pressure and trend-wise lower cortisol responses.

I am intrigued by these findings, since the author link a basal neurotransmitter function to cumulative adversity across different experiences in a non-clinical population. My excitement is however damped due to the order of the MIST and the PET scans: If the authors expect an effect of stressful events (chronically) on dopamine function, the PET scans would also be influenced (acutely) by the preceding stress-experience.

The authors need to clarify this effect. Since the design cannot be changed, the least would be a clear statement in the Abstract and main text.

The authors need to provide a power analyses. This study has a low number of subjects (I know that this might be common for PET studies), hence the authors need to show convincingly that the effects are well powered.

An additional factor, which needs to be considered (e.g., by covariation) is the amount of smoking in both groups. Even though the numbers of smokers is equal in both groups, the amount of smoking differs and has been shown to influence dopamine neurotransmission.

In the mediation analysis, the limbic subdivision of the striatum was chosen (subsection “The relationships between physiological and subjective measures”). The motivation for this subregion in the text ("connectivity to the threat system") and in the Materials and methods ("Exploratory analyses were performed in the functional subdivisions of the striatum.") is not very strong. I would suggest to perform regression analyses to identify which subregion is actually the best predictor for the physiological measures.

Reviewer #3:

In the study described by Bloomfield and colleagues, authors wanted to investigate whether exposure to chronic psychosocial stress, as assessed through a combination of childhood and adult stressors, would be associated with dopamine synthesis capacity. Authors exposed 34 subjects (17 with high and 17 with low cumulative stress exposure) to the Montreal Imaging stress task (MIST) and measured subjective, physiological and endocrine stress responses; two hours later, subjects were scanned for their dopamine synthesis capacity using 18F-Dopa in a Positron Emission Tomography experiment. Authors report that dopamine synthesis correlated with subjective threat and physiological response to acute psychosocial stress, and that high cumulative stress dampened striatal dopaminergic function.

Any PET study is a serious investment in time and resources and therefore authors should be commended to have undertaken this endeavor. The research question is not completely new as previous studies have investigated the possible role of stress in dopamine function, also using PET (and the authors make reference to this). What is unusual is the combination of early life and adult stressors to create a high cumulative lifetime adversity group; I have not come across this before. One can certainly argue whether this represents a useful approach as it confounds the early life (likely programming) effects with the later in life acute stressors which occur past the critical development periods. In fact, some authors (e.g., Ellis and colleagues with their work on life history theory) argue that early life adversity changes the stress systems to better prepare you for the adult life that is likely to be similar. In that sense, early life stress that is followed by adult stress might thus represent the expected outcome for the organism, that it is now better prepared for.

Be that as it may, I would simply have wished for a stronger justification for the particular chosen experimental approach as I was unclear on what exactly made the authors select these criteria. Also, why minority ethnic status was considered an adult stressor per se which was considered to be on par with bereavement or unemployment was not immediately clear to me and I would like to see more references justifying this approach.

What might be a potentially bigger concern had to do with the methodological approach chosen by the authors – if I understood the Materials and methods section correctly, authors did the stress task (the MIST) two hours prior to the PET scanning. Is the assumption that the stress would have the effect on the dopamine synthesis two hours after stress cessation? If that was the case, this should be made very explicit to the reader, and then I would like to see a section in the manuscript where this is systematically explained; right now, the reader is left in the dark about the choice of this exact rationale. Further, there was no stress – control comparison; subjects performed the first block of control followed by directly the experimental condition of the MIST; how can the authors be sure that what they then observe in the PET is specific to the stress part of the experimental manipulation? This is completely unclear to me, and I (and I am assuming the average reader as well) would benefit from a more thorough explanation of this part of the study.

[Editors' note: further revisions were requested prior to acceptance, as described below.]

Thank you for resubmitting your work entitled "The Effects of Chronic Psychosocial Stress on Dopaminergic Function and the Acute Stress Response" for further consideration at eLife. Your revised article has been favorably evaluated by Christian Büchel as the Senior and Reviewing Editor, and three reviewers.

The manuscript has been improved but there is one remaining issue that needs to be addressed before acceptance:

The data does not allow to say that DA synthesis is driven by early adversity alone, because it could be the interaction of childhood adversity and acute stress manipulation. The reviewers and the editor think that this does not lower the importance of this paper, but that it needs to be made clear in the paper, including the title (see below).

Reviewer #2:

The author responded to my comments and made an effort to clarify critical points in the manuscript.

The authors agree that the current study cannot disentangle chronic and acute stress, which is why I will consult with the other reviewers if the term "chronic" should be removed/changed from the title.

Reviewer #3:

The manuscript has benefited from the revision and now appears substantially improved. The authors have addressed all major points raised previously.

For the major points, the first point that was raised by this reviewer, i.e. the question of why a high cumulative lifetime adversity group was created, was answered thoroughly and convincingly, resulting in helpful revision in both the Introduction and the Discussion.

The second point previously raised, i.e. why a stress task preceded the PET scan by two hours, was answered by stating that the rationale was to reduce the variance in time. Here I am less enthusiastic that this is a sufficient response. Why would it be important to reduce the variation in time? On the other hand, by putting these two tests so close to each other, my fear would be that potential after effects from the stressor might have influenced what was observed during the PET scan. Authors do clarify that they are not aware of any evidence indicating that an acute stressor can have an effect on the parameters looked at in the PET, but then again, a controlled study comparing stress and no stress prior to PET to investigate the effects probably does not exist at this point, so obviously it is not known. Any number of things can occur two hours after an acute stressor – e.g., immune system changes, genomic effects of glucocorticoids, refractory period of hpa axis responsivity, which might or might not have an effect on the subsequent PET scan.

Thus, the decision to induce acute stress so close before the PET scan is in my opinion problematic, in the absence of a good rationale. Just to avoid the impression that it isn't, and to prevent other researchers from copying this design, it might be worth adding that having more time pass after an acute stressor might have been the superior choice.

Essential revisions:

Apart from addressing all points raised by the reviewers (see below), the authors should put particular emphasis on the following topics:

1) Explain and justify why the stress task (MIST) was performed two hours prior to the PET scanning.

Please see our response to reviewer 2 (below).

2) How can acute control and experimental effects be disentangled and how is the interaction with chronic adversity resolved?

We have addressed the reviewers comments relating to this below. We have commented on this in the Discussion:

“However, a potential limitation of our combination of early developmental and adult stressors is that if may confound the early life (i.e. likely programming) effects with the later in life acute stressors which occur after developmental sensitive periods. […] Future work is therefore needed to disentangle the effects of acute vs. chronic stressors on the dopamine system.”

3) The sections regarding basic science and dopamine population activity needs clarifications.

We have clarified these sections as requested by the reviewers.

Reviewer #1:

In this manuscript, the authors examine the impact of prior exposure to psychosocial stress on indices of DA function in humans. The paper is quite interesting and potentially important; however, there are some issues that need to be addressed:

1) The link with animal literature as written is confusing with regard to DA release and stress vs. synthesis capacity in humans. One potential caveat is that overall release in animals in response to stressors may not be the critical variable; since the authors are studying synthesis capacity (i.e., number of terminals that are active), a better comparison would be with DA neuron population activity (i.e., number of neurons firing) which was shown in studies of repeated stress by Valenti and Grace. These data would be more consistent and less confusing than the literature cited, which confounds release, metabolites, and activation.

Thank you for this suggestion. We have separated the animal from the human work. We have removed studies investigating stress-induced dopamine release from the animal work and added the following text to the paragraph on animal work:

“Animal research has demonstrated that acute stressors including aversive stimuli induce a pronounced activation of the dopamine system in terms of dopamine neuron population activity (i.e. the numbers of neurons firing) and with regards to amphetamine-induced behaviours (Valenti et at.).”

2) Which regions of the DA system are activated vs. blunted with acute vs. chronic stress is an important variable. Acute and repeated stress activate the entire DA system projecting to much of the striatum (Valenti and Grace), in particular the associative striatum where object salience is important, whereas in chronic stress-induced depression (Holly and Miczek), the blunting occurs primarily in the neurons projecting to the ventromedial striatum (Moreines and Grace), where reward-related variables are processed. Therefore these are different systems mediating the DA stress response that varies with duration of stress exposure, and with the induction of anxiety (acute or repeated stress) vs. depression (chronic stress). This is consistent with Koob's opponent process model, where acute stress activates the DA system, which upon chronic exposure leads to a compensatory down-regulation.

Thank you very much indeed for raising these important points. We have added the following text to the Discussion:

“There is evidence of regional specificity in the direction of effects of acute vs. chronic stress exposure. […] Our findings are consistent with Koob's opponent process model, where acute stress activates the dopamine system, which upon chronic exposure leads to a compensatory down-regulation (Koob et al., 1997)”.

3) Stress in Juvenile/adolescence has very different effects than chronic stress in adults. Therefore it is not valid to compare repeated adult stress with juvenile stress factors.

We have edited the relevant section of the Discussion to make it clearer when we are referring to developmental vs. adult stress exposure. We have revised the text as follows:

"Our results extend these findings and are consistent with evidence from anima/ models whereby subcortical dopamine transmission is blunted in response to multiple stressors in adulthood (Chrapusta, Wyatt and Masserano, 1997; Gresch et al., 1994)... Whilst stress exposure in animals during the juvenile period and adolescence has a very different effect from to chronic stress in adulthood, our findings are also broadly consistent with developmental stress models (Brake et al., 2004). "

4) Discussion interpretation of findings – Holly and Miczek did not record from DA neurons.

Reference to the review by Holly and Miczek has been replaced with reference to the study by Saal et al., 2003.

5). The section on maternal deprivation occurs during very early juvenile period (i.e., postnatal day 7-8), which is far earlier than the juvenile/adolescent stress referred to in the paper.

We have made the timing of maternal deprivation studies clear in the text:

"Likewise, early maternal deprivation models in the very early juvenile period (from post-natal day 5) have been associated with hypodopaminergic behaviours…”

Reviewer #2:

The authors present findings on dopamine synthesis capacity (using PET) in individuals with high exposure to adversity as compared to matched controls with low adversity (each group with N=17). PET scans are performed two hours after an acute psychosocial stress task (MIST), were participants with high exposure to adversity show enhanced threat experience, but lower arterial blood-pressure and trend-wise lower cortisol responses.

I am intrigued by these findings, since the author link a basal neurotransmitter function to cumulative adversity across different experiences in a non-clinical population.

My excitement is however damped due to the order of the MIST and the PET scans: If the authors expect an effect of stressful events (chronically) on dopamine function, the PET scans would also be influenced (acutely) by the preceding stress-experience. The authors need to clarify this effect. Since the design cannot be changed, the least would be a clear statement in the Abstract and main text.

The study design was the same for both groups i.e. both groups underwent PET scans on the same day as acute psychosocial stress. Whilst we cannot exclude the possibility of an interaction (see below), it is unlikely that acute changes in dopamine synthesis are driving our results.

The Abstract has been amended as follows:

"The PET scan took place two hours after the induction of acute psychosocial stress using the Montréal Imaging Stress Task to induce acute psychosocial stress."

We have also added the following text in the limitations section of the Discussion:

"The PET scan was conducted following exposure to acute psychosocial stress exposure. Whilst this increases dopamine release (Pruessner et al., 2004), it is not clear if this has an acute effect on striatal dopamine synthesis capacity. […] A further study is needed to determine if acute stress alters dopamine synthesis capacity.”

The authors need to provide a power analyses. This study has a low number of subjects (I know that this might be common for PET studies), hence the authors need to show convincingly that the effects are well powered.

We have added a power calculation as follows:

"In a study of test-retest reliability of [¹⁸F]-DOPA PET (Egerton et al., 2010) striatal Kp^er had an intraclass correlation coefficient of approximately 0.9 [mean (SD) = 0.01417(0.00127)min-1 (test) and 0.01381(0.00127)min-1 (re-test)]. […] Therefore, to achieve a power of 0.8, with an effect size of 1.0, a=0.05, using independent t-tests, n=17 participants would be required per group. "

An additional factor, which needs to be considered (e.g., by covariation) is the amount of smoking in both groups. Even though the numbers of smokers is equal in both groups, the amount of smoking differs and has been shown to influence dopamine neurotransmission.

The following has been inserted into the text:

"As the amount of smoking differed in the groups and heavy smoking can influence dopamine function (Bloomfield et al., 2014; Salokangas et al., 2000) we performed an ANCOVA to examine whether smoking was influencing our findings. When co-varying for amount of current cigarette use, the group difference remained significant in the limbic striatum only 5.2, p=.029, "Ép=. 15)."

In the mediation analysis, the limbic subdivision of the striatum was chosen (subsection “The relationships between physiological and subjective measures”). The motivation for this subregion in the text ("connectivity to the threat system") and in the Materials and methods ("Exploratory analyses were performed in the functional subdivisions of the striatum.") is not very strong. I would suggest to perform regression analyses to identify which subregion is actually the best predictor for the physiological measures.

The limbic striatum was chosen because of its role in the stress response, its functional connectivity to the threat detection system and the largest effects sizes for group differences observed in our study. However, regression analyses did not identify which sub-region was the best predictor of the physiological measures (p>.08). We have therefore removed the mediation analysis from the manuscript and inserted the following into the text:

"Regression analyses did not identify which striata/ sub-region was the best predictor of the physiological measures (p>.08)".

Reviewer #3:

[…] Any PET study is a serious investment in time and resources and therefore authors should be commended to have undertaken this endeavor. The research question is not completely new as previous studies have investigated the possible role of stress in dopamine function, also using PET (and the authors make reference to this).

What is unusual is the combination of early life and adult stressors to create a high cumulative lifetime adversity group; I have not come across this before. One can certainly argue whether this represents a useful approach as it confounds the early life (likely programming) effects with the later in life acute stressors which occur past the critical development periods. In fact, some authors (e.g., Ellis and colleagues with their work on life history theory) argue that early life adversity changes the stress systems to better prepare you for the adult life that is likely to be similar. In that sense, early life stress that is followed by adult stress might thus represent the expected outcome for the organism, that it is now better prepared for.

Be that as it may, I would simply have wished for a stronger justification for the particular chosen experimental approach as I was unclear on what exactly made the authors select these criteria. Also, why minority ethnic status was considered an adult stressor per se which was considered to be on par with bereavement or unemployment was not immediately clear to me and I would like to see more references justifying this approach.

We are grateful to the reviewer for raising these important points. Findings from epidemiological studies have found that early developmental adversity increases the risk of psychopathology in response to stressors in adulthood (e.g. McLaughlin et al., 2010) are not consistent with the theory that experiencing childhood trauma is protective against risk of mental illness in response to adult stressors.

We have revised the justification for our experimental approach, including the rationale for including minority ethnic status, in the Introduction as follows:

"Studies of psychosocial stressors and dopamine function have typically investigated risk factors in isolation, despite the fact that the risk factors cluster together and may share common underlying mechanisms (Hjern, Wicks, and Dalman; Morgan and Fisher; Wicks et al., 2005). […] Given the findings of dopaminergic dysfunction associated with childhood maltreatment presented above, we hypothesised that healthy humans with a high cumulative exposure to psychosocial stressors would have altered striatal dopamine synthesis, compared to humans with a low exposure."

We have added the following to the Discussion:

"We chose to recruit participants with high levels of stress exposure in early development and adulthood, because early developmental stressors increase the risk of psychopathology following adult stressors (McLaughlin et al., 2010). However, a potential limitation of our combination of early developmental and adult stressors is that it may confound the early life (i.e. likely programming) effects with the later in life acute stressors which occur after developmental sensitive periods. "

What might be a potentially bigger concern had to do with the methodological approach chosen by the authors – if I understood the Materials and methods section correctly, authors did the stress task (the MIST) two hours prior to the PET scanning. Is the assumption that the stress would have the effect on the dopamine synthesis two hours after stress cessation? If that was the case, this should be made very explicit to the reader, and then I would like to see a section in the manuscript where this is systematically explained; right now, the reader is left in the dark about the choice of this exact rationale. Further, there was no stress – control comparison; subjects performed the first block of control followed by directly the experimental condition of the MIST; how can the authors be sure that what they then observe in the PET is specific to the stress part of the experimental manipulation? This is completely unclear to me, and I (and I am assuming the average reader as well) would benefit from a more thorough explanation of this part of the study.

We apologise that this was not clear enough. The rationale for conducting the PET scan on the same day as the stress task was to reduce the variance in the time between the measures. We did not have assumptions that acute stress exposure would alter subsequent dopamine synthesis capacity. Whilst we cannot exclude the possibility that such effects may be contributing to our results, we are not aware of evidence indicating that an acute stressor can alter two parameters that contribute to our index (i.e. the number of available dopamine vesicles and/or the activity of aromatic acid decarboxylase) in this timeframe. The rationale for exploring the relationships between stress-induced measures and dopamine synthesis capacity is implicit is provided in the manuscript. We have included these points as follows:

Materials and methods:

"The rationale for conducting the PET scan on the same day as the stress task was to reduce the variance in the time between the measures."

Discussion:

"However, we are not aware of evidence indicating that an acute stressor can alter the parameters that contribute to our index (i.e. the activity of aromatic acid decarboxylase) in the timeframe used in our study. "

[Editors' note: further revisions were requested prior to acceptance, as described below.]

The manuscript has been improved but there is one remaining issue that needs to be addressed before acceptance:

The data does not allow to say that DA synthesis is driven by early adversity alone, because it could be the interaction of childhood adversity and acute stress manipulation. The reviewers and the editor think that this does not lower the importance of this paper, but that it needs to be made clear in the paper, including the title (see below).

We are grateful to Professor Buchel and colleagues for their further review. We have made changes to the paper including the title.

Reviewer #2:

The author responded to my comments and made an effort to clarify critical points in the manuscript.

The authors agree that the current study cannot disentangle chronic and acute stress, which is why I will consult with the other reviewers if the term "chronic" should be removed/changed from the title.

We are grateful to the reviewer. We have removed the term "chronic" from the title. The title now reads: "The Effects of Psychosocial Stress on Dopaminergic Function and the Acute Stress Response".

Reviewer #3:

[…] For the major points, the first point that was raised by this reviewer, i.e. the question of why a high cumulative lifetime adversity group was created, was answered thoroughly and convincingly, resulting in helpful revision in both the Introduction and the Discussion.

The second point previously raised, i.e. why a stress task preceded the PET scan by two hours, was answered by stating that the rationale was to reduce the variance in time. Here I am less enthusiastic that this is a sufficient response. Why would it be important to reduce the variation in time? On the other hand, by putting these two tests so close to each other, my fear would be that potential after effects from the stressor might have influenced what was observed during the PET scan. Authors do clarify that they are not aware of any evidence indicating that an acute stressor can have an effect on the parameters looked at in the PET, but then again, a controlled study comparing stress and no stress prior to PET to investigate the effects probably does not exist at this point, so obviously it is not known. Any number of things can occur two hours after an acute stressor – e.g., immune system changes, genomic effects of glucocorticoids, refractory period of hpa axis responsivity, which might or might not have an effect on the subsequent PET scan.

Thus, the decision to induce acute stress so close before the PET scan is in my opinion problematic, in the absence of a good rationale. Just to avoid the impression that it isn't, and to prevent other researchers from copying this design, it might be worth adding that having more time pass after an acute stressor might have been the superior choice.

We are grateful to the reviewer for their feedback. In performing the PET scan so close to the stress task we sought to reduce the length of time between task and PET scan to reduce variance associated with normal fluctuations in dopamine synthesis capacity. We agree is possible that close temporal proximity of the stress task to the PET means that it is possible that what was observed during the PET scan could have been influenced by the stress task. Whilst we not aware of any evidence indicating that an acute stressor can have an effect on the parameters looked at in the PET, a controlled study comparing stress and no stress prior to PET to investigate the effects is needed to definitively address this possibility. Given this, it is possible therefore that an optimal experimental design would allow more time to pass between the stressor and the PET scan. These points have been clarified in the text as below:

"The PET scan was conducted following exposure to acute psychosocial stress exposure. […] Nonetheless, a controlled study comparing stress and no stress prior to PET to investigate the effects is needed to definitively determine if acute stress alters dopamine synthesis capacity. Given this, it is possible that an optimal experimental design would allow more time to pass between the stressor and the PET scan.”

Author details

1. Michael AP Bloomfield

   1. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
   2. Translational Psychiatry Research Group, Research Department of Mental Health Neuroscience, Division of Psychiatry, UCL Institute of Mental Health, University College London, London, United Kingdom
   3. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom
   4. Clinical Psychopharmacology Unit, Research Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom
   5. NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
   6. The Traumatic Stress Clinic, St Pancras Hospital, Camden and Islington NHS Foundation Trust, London, United Kingdom
   7. National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   m.bloomfield@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1972-4610

2. Robert A McCutcheon

   1. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
   2. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1102-2566

3. Matthew Kempton

   Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom

   Contribution

   Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

4. Tom P Freeman

   1. Translational Psychiatry Research Group, Research Department of Mental Health Neuroscience, Division of Psychiatry, UCL Institute of Mental Health, University College London, London, United Kingdom
   2. Clinical Psychopharmacology Unit, Research Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom
   3. Department of Psychology, University of Bath, Bath, United Kingdom

   Contribution

   Formal analysis, Writing—review and editing

   Competing interests

   No competing interests declared

5. Oliver Howes

   1. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
   2. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing

   For correspondence

   oliver.howes@kcl.ac.uk

   Competing interests

   Professor Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither Professor Howes nor his family have been employed by or have holdings/a financial stake in any biomedical company.

• 20,962

  Page views

• 1,030

  Downloads

• 45

  Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.