Stress-induced Dopamine Release Research Articles

The relation between stress-induced dopamine release in the ventromedial prefrontal cortex, fronto-striatal functional connectivity, and negative urgency: A multimodal investigation using [18F]Fallypride PET, MRI and experience sampling

Negative urgency (NU), or the tendency to act rashly when stress of negative affect is high, could be the result of an insufficient control of the ventromedial prefrontal cortex (vmPFC) over the striatum, through an impaired dopamine (DA) transmission. Therefore, we investigated in vivo human stress-induced DA release in the vmPFC, its relation with fronto-striatal functional connectivity (FC), and NU in daily life. In total, 12 female healthy participants performed a simultaneous [18 F]fallypride PET and fMRI scan during which stress was induced. Regions displaying stress-induced DA release were identified and used to investigate stress-induced changes in fronto-striatal FC. Additionally, participants enrolled in an experience sampling study, reporting on daily life stress and rash actions over a 12-month-long period. Mixed models explored whether stress-induced DA release and FC moderated NU in daily life. Stress led to a lower FC between the vmPFC and dorsal striatum, but a higher FC between the vmPFC and contralateral ventral striatum. Participants with a higher FC between the vmPFC and dorsal striatum displayed more NU in daily life. A higher stress-induced DA release in the vmPFC was related to a higher stress-induced change in FC between the vmPFC and striatum. Participants with a higher DA release in the vmPFC displayed more NU in daily life. In conclusion, stress could differentially impact fronto-striatal FC whereby the connectivity with the dorsal striatum is especially important for NU in daily life. This could be mediated by a higher, but not a lower, stress-induced DA release in the vmPFC.

Chronic restraint stress increases sensitivity to punishment during cocaine self-administration via a dopamine D1-like receptor-mediated mechanism in prelimbic medial prefrontal cortex

We recently reported that male rats displayed less sensitivity to punishment during cocaine self-administration compared to females. Moreover, daily restraint stress increased sensitivity to punishment in males, while having no effect in females. The purpose of the present study was to extend these findings by determining whether chronic stress-induced dopamine release in prelimbic medial prefrontal cortex mediates the effect of stress on punished cocaine self-administration. Thus, male rats were trained to press a lever for i.v. cocaine infusions (0.50 mg/kg/infusion) paired with a discrete tone + light cue in daily 3-hr sessions. Subsequently, 50 % of the lever presses were punished by a mild footshock that gradually increased in intensity over 7 days. During the punishment phase, rats were exposed to a chronic restraint stress procedure (3 h/day) or control procedure (unstressed). Rats also received bilateral microinjections of the D1-like receptor antagonist SCH-23390 (0.25 μg/0.5 μl/side) or vehicle (0.5 μl/side) delivered to prelimbic cortex prior to daily treatments. Relapse tests were conducted 1 and 8 days after the last punishment session. Chronically stressed rats displayed reduced cocaine self-administration during punishment relative to unstressed rats, an effect prevented by co-administration of SCH-23390 to prelimbic cortex with daily restraint. Neither stress nor SCH-23390 treatment had significant effects on subsequent relapse-like behavior. These results establish a specific role for prelimbic D1-like receptors in chronic stress-induced suppression of punished cocaine self-administration in male rats. As such, these findings may inform novel methods to facilitate self-imposed abstinence in cocaine-dependent men.

Racism and the Social Defeat Hypothesis of Psychosis

IntroductionThe social defeat hypothesis of psychosis posits that an outsider status or subordinate position is a common denominator of several psychosis risk factors, leads to elevated striatal dopamine function and thereby to an increased risk for the disorder. The purpose of this paper is to examine whether this hypothesis offers a good explanation for the increased psychosis risk for migrants from developing countries. Method: Review of literature. Results: The outsider status and subordinate position of many migrants from developing countries in Europe, and of Africans in particular, is evident. It is also clear that racism contributes to this situation. An interpretation of racism as psychotogenic is supported by findings of increased risks for other discriminated groups, such as homosexuals, individuals with a low IQ or a hearing impairment. The single study that examined dopamine function in migrants reported indeed elevated stress-induced dopamine release and dopamine synthesis capacity (Egerton et al., 2017). Recently, we examined the time course of the RR of treatment for psychosis for all migrants to the Netherlands (Termorshuizen & Selten, submitted). Contrary to our expectations, the RR for migrants from sub-Saharan Africa was already increased in the year of arrival (RR=2.5; 2.0-3.1), particularly for those aged 10-20 years (RR=6.1; 2.9-12.6). Conclusion: The social defeat hypothesis accords well with a psychotogenic effect of racism, but replications of the dopamine study are needed. The finding of an increased risk for Africans in the year of arrival suggests that racism is not the single cause of their increased risk.DisclosureNo significant relationships.

Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex

The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress.

Stress-induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis.

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBPND ) was defined as percent change in D2/3 receptor binding potential between both scans using a novel correction for injected mass of [11 C]FLB457. ΔBPND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBPND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUCI ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBPND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBPND . Length of cannabis use was negatively associated with ΔBPND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth.

Preliminary data indicating a connection between stress-induced prefrontal dopamine release and hippocampal TSPO expression in the psychosis spectrum

Prolonged stress can cause neuronal loss in the hippocampus resulting in disinhibition of glutamatergic neurons proposed to enhance dopaminergic firing in subcortical regions including striatal areas. Supporting this, imaging studies show increased striatal dopamine release in response to psychosocial stress in healthy individuals with low childhood maternal care, individuals at clinical high risk for psychosis (CHR) and patients with schizophrenia. The prefrontal cortex (PFC) is connected to the hippocampus and a key region to control neurochemical responses to stressful stimuli. We recently reported a disrupted PFC dopamine-stress regulation in schizophrenia, which was intact in CHR. Given the available evidence on the link between psychosocial stress, PFC dopamine release and hippocampal immune activation in psychosis, we explored, for the first time in vivo, whether stress-induced PFC dopamine release is associated with hippocampal TSPO expression (a neuroimmune marker) in the psychosis spectrum. We used an overlapping sample of antipsychotic-naïve subjects with CHR (n = 6) and antipsychotic-free schizophrenia patients (n = 9) from our previously published studies, measuring PFC dopamine release induced by a psychosocial stress task with [11C]FLB457 positron emission tomography (PET) and TSPO expression with [18F]FEPPA PET. We observed that participants on the psychosis spectrum with lower stress-induced dopamine release in PFC had significantly higher TSPO expression in hippocampus (β = −2.39, SE = 0.96, F(1,11) = 6.17, p = 0.030). Additionally, we report a positive association between stress-induced PFC dopamine release, controlled for hippocampal TSPO expression, and Global Assessment of Functioning. This is the first exploration of the relationship between PFC dopamine release and hippocampal TSPO expression in vivo in humans.

26.2 CORTICAL STRESS REGULATION IS DISRUPTED IN SCHIZOPHRENIA BUT NOT IN CLINICAL HIGH-RISK FOR PSYCHOSIS

BackgroundWhile striatal dopamine in psychosis and stress has been well studied, the role of dopamine in the prefrontal cortex (PFC) is poorly understood. To date no study has investigated the PFC dopamine response to stress exclusively in schizophrenia or its putative prodrome, even though medial PFC is known as a key area in stress regulation. The present study uses the high-affinity dopamine D2/3 receptor radiotracer [11C]FLB457 and positron emission tomography (PET) together with a validated psychosocial stress challenge to investigate if the PFC dopamine response to stress is dysregulated in schizophrenia and clinical high risk (CHR) for psychosis.MethodsFourteen antipsychotic-free patients with schizophrenia, 14 CHR and 12 matched healthy volunteers underwent two [11C]FLB457 PET scans, one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). PET data were analyzed using the Simplified Reference Tissue Model with non-displaceable binding potential (BPND) as outcome measure. Dopamine release was defined as percent change in BPND between control and stress scan (ΔBPND).ResultsWe observed an increased dopamine release, indexed by ΔBPND, in the medial PFC in schizophrenia patients but not CHR compared to healthy volunteers. Further, associations between stress-induced dopamine release and increase in cortisol levels observed in healthy volunteers and CHR, were absent in schizophrenia, similar to associations with symptoms, distress and anxiety.DiscussionThese findings provide first direct evidence of a disrupted cortical dopamine-stress regulation in schizophrenia.

Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naïve Schizophrenia.

Striatal dopamine (DA) synthesis capacity and release are elevated in schizophrenia (SCZ) and its putative prodrome, the clinical high risk (CHR) state. Striatal DA function results from the activity of midbrain DA neurons projecting mainly from the substantia nigra (SN). Elevated stress-induced DA release in SCZ and CHR was observed in the striatum; however, whether it is also elevated in the SN is unclear. The current study aims to determine whether nigral DA release in response to a validated stress task is altered in CHR and in antipsychotic-naïve SCZ. Further, we explore how DA release in the SN and striatum might be related. 24 CHR subjects, 9 antipsychotic-naïve SCZ and 25 healthy volunteers (HV) underwent 2 positron emission tomography (PET) scans using the DA D2/3 agonist radiotracer, [11C]-(+)-PHNO, which allows simultaneous investigations of DA in the SN and striatum. Psychosocial stress-induced DA release was estimated as the percentage differences in BPND (%[11C]-(+)-PHNO displacement) between stress and sensory-motor control sessions. We observed a significant diagnostic group by session interaction, such that SCZ exhibited greater stress-induced [11C]-(+)-PHNO % displacement (25.90% ± 32.2%; mean ± SD), as compared to HVs (-10.94% ± 27.1%). Displacement in CHRs (-1.13% ± 32.2%) did not differ significantly from either HV or SCZ. Our findings suggest that elevated nigral DA responsiveness to stress is observed in antipsychotic-naïve SCZ.

203. Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naive Schizophrenia

203. Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naive Schizophrenia

Elevated Striatal Dopamine Function in Immigrants and Their Children: A Risk Mechanism for Psychosis.

Migration is a major risk factor for schizophrenia but the neurochemical processes involved are unknown. One candidate mechanism is through elevations in striatal dopamine synthesis and release. The objective of this research was to determine whether striatal dopamine function is elevated in immigrants compared to nonimmigrants and the relationship with psychosis. Two complementary case–control studies of in vivo dopamine function (stress-induced dopamine release and dopamine synthesis capacity) in immigrants compared to nonimmigrants were performed in Canada and the United Kingdom. The Canadian dopamine release study included 25 immigrant and 31 nonmigrant Canadians. These groups included 23 clinical high risk (CHR) subjects, 9 antipsychotic naïve patients with schizophrenia, and 24 healthy volunteers. The UK dopamine synthesis study included 32 immigrants and 44 nonimmigrant British. These groups included 50 CHR subjects and 26 healthy volunteers. Both striatal stress-induced dopamine release and dopamine synthesis capacity were significantly elevated in immigrants compared to nonimmigrants, independent of clinical status. These data provide the first evidence that the effect of migration on the risk of developing psychosis may be mediated by an elevation in brain dopamine function.

Dopamine dynamics during emotional cognitive processing: Implications of the specific actions of clozapine compared with haloperidol

Clozapine has improved efficacy relative to typical antipsychotics in schizophrenia treatment, particularly regarding emotional symptoms. However, the mechanisms underlying its therapeutic benefits remain unclear. Using a methamphetamine-sensitised rat model, we measured changes in dopamine levels in the amygdalae in response to a fear-conditioned cue, serving as a biochemical marker of emotional cognitive processing disruption in psychosis, for analysing the biochemical mechanisms associated with the clinical benefits of clozapine. We also compared how clozapine and haloperidol affected basal dopamine levels and phasic dopamine release in response to the fear-conditioned cue. Extracellular dopamine was collected from the amygdalae of freely moving rats via microdialysis and was analysed by high-performance liquid chromatography. Clozapine or haloperidol was injected during microdialysis, followed by exposure to the fear-conditioned cue. We analysed the ratio of change in dopamine levels from baseline. Haloperidol treatment increased the baseline dopamine levels in both non-sensitised and sensitised rats. Conversely, clozapine only increased the basal dopamine levels in the non-sensitised rats, but not in the sensitised rats. Although both antipsychotics attenuated phasic dopamine release in both the non-sensitised and sensitised rats, the attenuation extent was greater for clozapine than for haloperidol under both dopaminergic conditions. Our findings indicate that stabilized dopamine release in the amygdalae is a common therapeutic mechanism of antipsychotic action during emotional processing. However, the specific dopaminergic state-dependent action of clozapine on both basal dopamine levels and stress-induced dopamine release may be the underlying mechanism for its superior clinical effect on emotional cognitive processing in patients with schizophrenia.

No evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder.

Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [18F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [18F]fallypride displacement and the spatial extent of stress-induced [18F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [18F]fallypride displacement nor the spatial extent of stress-induced [18F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.

Stress-induced dopamine release in human medial prefrontal cortex-18F-Fallypride/PET study in healthy volunteers

In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [(18)F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BP ND ) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BP ND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. The psychological stressor significantly decreased [(18)F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress-induced decrease in [(18)F]fallypride binding in the dmPFC, the greater the stress-induced increases in heart rate. The present study provides evidence of stress-induced dopamine release in the mPFC in humans, in vivo.

Increased Stress-Induced Dopamine Release in Psychosis

Increased Stress-Induced Dopamine Release in Psychosis

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

A number of addictions have been linked with decreased striatal dopamine (DA) receptor availability and DA release. Stress has a key role in cannabis craving, as well as in modulation of dopaminergic signaling. The present study aimed to assess DA release in response to a laboratory stress task with [(11)C]-(+)-PHNO positron emission tomography in cannabis users (CU). Thirteen healthy CU and 12 healthy volunteers (HV) were scanned during a sensorimotor control task (SMCT) and under a stress condition using the validated Montreal imaging stress task (MIST). The simplified reference tissue model (SRTM) was used to obtain binding potential (BP(ND)) in striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Stress-induced DA release (indexed as a percentage of reduction in [(11)C]-(+)-PHNO BP (ND)) between CU and HV was tested with analysis of variance. SMCT BP(ND) was significantly higher in CU compared with HV in the AST (F=10.38, p=0.003), LST (F=4.95, p=0.036), SMST (F=4.33, p=0.048), and whole striatum (F=9.02, p=0.006). Percentage of displacement (change in BP(ND) between SMCT and MIST PET scans) was not significantly different across groups in any brain region, except in the GP (-5.03±14.6 in CU, compared with 6.15±12.1 in HV; F=4.39, p=0.049). Duration of cannabis use was significantly associated with stress-induced [(11)C]-(+)-PHNO displacement by endogenous DA in the LST (r=0.566, p=0.044), with no effect in any other brain region. In conclusion, despite an increase in striatal BP(ND) observed during the control task, chronic cannabis use is not associated with alterations in stress-induced DA release.

Leptin Regulates Dopamine Responses to Sustained Stress in Humans

Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity.

Oxytocin Gene Polymorphisms Influence Human Dopaminergic Function in a Sex-Dependent Manner

Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin's interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample. Fifty-five young healthy volunteers were scanned using [¹¹C]raclopride positron emission tomography while they underwent a standardized physical and emotional stressor that consisted of moderate levels of experimental sustained deep muscle pain, and a baseline, control state. Four haplotype tagging single nucleotide polymorphisms located in regions near OXT were genotyped. Measures of pain, affect, anxiety, well-being and interpersonal attachment were also assessed. Female rs4813625 C allele carriers demonstrated greater stress-induced dopamine release, measured as reductions in receptor availability from baseline to the pain-stress condition relative to female GG homozygotes. No significant differences were detected among males. We also observed that female rs4813625 C allele carriers exhibited higher attachment anxiety, higher trait anxiety and lower emotional well-being scores. In addition, greater stress-induced dopamine release was associated with lower emotional well-being scores in female rs4813625 C allele carriers. Our results suggest that variability within the oxytocin gene appear to explain interindividual differences in dopaminergic responses to stress, which are shown to be associated with anxiety traits, including those linked to attachment style, as well as emotional well-being in women.

DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience

Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine inter-individual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced DA release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R “Openness to Experience” and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders.

Increased Stress-Induced Dopamine Release in Psychosis

A pathologic response to common life stressors, in which a hyperresponsive dopaminergic system is thought to play a key role, is a potential etiologic factor in the triggering and relapse of psychosis. However, there is no direct evidence that brain dopaminergic response to stress is exaggerated in psychosis. Using the ability of endogenous dopamine (DA) to compete with [(11)C]-(+)-PHNO binding, as measured with positron emission tomography, we examined stress-induced DA release in response to a validated psychosocial stress task. We studied 12 clinical high-risk (CHR), 10 antipsychotic-naive subjects with schizophrenia (SCZ), and 12 matched healthy volunteers (HV). Stress-induced DA release was estimated as the percent change in binding potential between conditions (stress and control scan) in the striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). We found a significant difference between groups in the AST (F = 8.13, df = 2,31, p = .001), and at the SMST (F = 3,64, df = 2,31, p = .03) but not in the LST (F = .43, df = 2,31, p = .40) with CHR and SCZ having larger [(11)C]-(+)-PHNO displacement in response to the stress. Bonferroni-corrected comparisons confirmed that HV displacement (-2.86%) in the AST was significantly different in CHR (6.97%) and SCZ (11.44%) (with no significant difference between CHR and SCZ). This study reveals a sensitized dopaminergic response to stress in a psychiatric condition and may have important theoretical and clinical implications regarding efforts to abort or delay relapse and/or conversion to psychosis.

Advances in PET analyses of stress and dopamine

A deregulation of the stress response is a potential etiological factor in the development and relapse of dopamine (DA)-related human disorders, including addiction, drug-induced psychosis, and schizophrenia. Schizophrenia is characterized by a chronic relapsing nature and vulnerability to exacerbation following stress or dopaminergic drugs. Indeed, the most replicated finding so far in schizophrenia positron emission tomography (PET) research has been an increased DA release after the administration of amphetamine, and this DA increase has been associated with positive psychotic symptoms and active stages of the illness. As increased stimulant-induced DA release is a hallmark of sensitization, several pieces of evidence support the view that schizophrenia is associated with a process of dopamine sensitization (Laruelle and Abi-Dargham, 1999). Psychosis sufferers themselves often cite a link between the experience of stress and psychotic symptoms. The stress-vulnerability model suggests that an endogenous, organic diathesis or vulnerability interacts with internal or external stressors in the development of psychotic disorders. However, the underlying neurobiological condition/event that results in an exaggerated response to stressors is unknown. One proposed mechanism is neurochemical sensitization of the DA system—dopamine sensitization—, whereby repeated exposure to sensitizing life stressors (or DA drugs) progresses into increased stress-associated DA release. Hence, during active periods of the illness (that is, prodromal phase, initial episode, and subsequent relapses), dopaminergic neurons may be hyperresponsive to environmental stimuli, and exposure to even moderate levels of stress (or DA drugs) produces excessive DA release, precipitating illness in vulnerable individuals and relapse in those with schizophrenia. The phenomenon of DA sensitization to psychostimulants is subjected to cross-sensitization with stress. It is well established that repeated stress (maternal separation, social-defeat stress, foot shock, tail pinch, restraint) induces heightened sensitivity to low doses of dopaminergic drugs; and conversely, repeated dopaminergic drug exposure increases the stress response in animals. Consistent with these findings, prenatal and postnatal stress is associated with increased drug-induced DA release, and different types of acute and repeated stress increase DA release (Abercrombie et al, 1989; Kalivas et al, 1986). Similarly, recent studies in humans using PET have shown increased DA release after either a psychosocial or a metabolic stress task (Adler et al, 2000; Pruessner et al, 2004). However, this finding was not replicated in another study, which used a different stress paradigm, with no apparent negative feedback (that is, social stress) (Montgomery et al, 2006). The next logical step is to test whether stress produces a deregulated DA response in clinical populations, such as those with psychotic disorders, addictions, as well as in those at risk. We tested both drug-free patients with schizophrenia and clinical high risk (CHR) for psychosis (that is, putatively prodromal) diagnosed with the Criteria of Prodromal Syndromes in a two-scan protocol: one while doing a Sensory Motor Control Task and another one while doing the Montreal Imaging Stress Task. Our pilot data suggests an increased stress-induced DA release as compared with matched healthy volunteers (HVs) (Figure 1). This kind of studies has important theoretical and clinical implications regarding the prevention of relapse and efforts to abort or delay conversion to psychosis. Figure 1 Representative figure showing decreased [11C]-(+)-PHNO BPND in CHR following stress suggesting increased DA displacement, as compared with HV.