Effects of Early Life Trauma on Risks for Adult Opioid Use Disorder Are Mediated by Stress and Occur Independent of Depression and Anxiety.

OBJECTIVES: Adverse childhood experiences, or early life trauma (ELT), may be a potential risk factor for opioid use disorders (OUDs) that could be further influenced by depression, anxiety, and stress. The prevalence and strength of these associations are largely unknown. METHODS: This study examined the association between current OUD severity and lifetime history of ELT, and the degree to which current depression, anxiety, and stress influenced this association, in persons (n = 310) with at least 1 lifetime exposure to opioids using an online survey. RESULTS: Ninety-three percent of respondents experienced at least 1 trauma in their lifetime, and 65% met the criteria for OUD. Early life trauma was largely unassociated with demographics but demonstrated an almost "dose-dependent" association among all forms of ELT (total, general, physical, emotional, sexual), whereby more ELT was associated with more severe current OUD. A multivariate mediation model found perceived stress to be a robust mediator of this association. Current psychiatric functioning did not significantly moderate the relationship between ELT and OUD, suggesting that ELT may impact OUD severity at varying levels of psychiatric functioning. CONCLUSIONS: These data support existing evidence that greater ELT may influence adult OUD severity and identify perceived stress as a potential mechanistic contributor to this association. Results are preliminary in nature but support continued research into mechanisms underlying the association between ELT and OUD, particularly conformational changes in the stress system resultant from ELT, and interventions to mitigate the impact of ELT on OUD development and/or develop trauma-informed OUD treatment approaches.

Adverse childhood experiences and burn pain: a review of biopsychosocial mechanisms that may influence healing.

Adverse childhood experiences (ACEs) affect over half of the adults in the United States and are known to contribute to the development of a wide variety of negative health and behavioral outcomes. The consequences of ACE exposure have been studied in patient populations that include individuals with gynecologic, orthopedic, metabolic, autoimmune, cardiovascular, and gastrointestinal conditions among others. Findings indicate that ACEs not only increase risks for chronic pain but also influence emotional responses to pain in many of these individuals. A growing body of research suggests that these effects may be the result of long-lasting changes induced by ACEs in neurobiological systems during early development. However, one area that is still largely unexplored concerns the effects of ACEs on burn patients, who account for almost 450,000 hospitalizations in the United States annually. Patients with severe burns frequently suffer from persistent pain that affects their well-being long after the acute injury, but considerable variability has been observed in the experience of pain across individuals. A literature search was conducted in CINAHL and PubMed to evaluate the possibility that previously documented ACE-induced changes in biological, psychological, and social processes might contribute to these differences. Findings suggest that better understanding of the role that ACEs play in burn outcomes could lead to improved treatment strategies, but further empirical research is needed to identify the predictors and mechanisms that dictate individual differences in pain outcomes in patients with ACE exposure and to clarify the role that ACE-related alterations play in early healing and recovery from burn injuries.

Early Life Stress and Risks for Opioid Misuse: Review of Data Supporting Neurobiological Underpinnings.

A robust body of research has shown that traumatic experiences occurring during critical developmental periods of childhood when neuronal plasticity is high increase risks for a spectrum of physical and mental health problems in adulthood, including substance use disorders. However, until recently, relatively few studies had specifically examined the relationships between early life stress (ELS) and opioid use disorder (OUD). Associations with opioid use initiation, injection drug use, overdose, and poor treatment outcome have now been demonstrated. In rodents, ELS has also been shown to increase the euphoric and decrease antinociceptive effects of opioids, but little is known about these processes in humans or about the neurobiological mechanisms that may underlie these relationships. This review aims to establish a theoretical model that highlights the mechanisms by which ELS may alter opioid sensitivity, thereby contributing to future risks for OUD. Alterations induced by ELS in mesocorticolimbic brain circuits, and endogenous opioid and dopamine neurotransmitter systems are described. The limited but provocative evidence linking these alterations with opioid sensitivity and risks for OUD is presented. Overall, the findings suggest that better understanding of these mechanisms holds promise for reducing vulnerability, improving prevention strategies, and prescribing guidelines for high-risk individuals.

Early Life Stress as a Predictor of Co-Occurring Alcohol Use Disorder and Post-Traumatic Stress Disorder.

During the critical developmental periods of childhood when neural plasticity is high, exposure to early life stress (ELS) or trauma may lead to enduring changes in physiological stress systems and enhanced vulnerability for psychopathological conditions such as post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) in adulthood. Clinical and preclinical studies have sought to understand the possible mechanisms linking ELS, PTSD, and AUD. Preclinical studies have employed animal models of stress to recapitulate PTSD-like behavioral deficits and alcohol dependence, providing a basic framework for identifying common physiological mechanisms that may underlie these disorders. Clinical studies have documented ELS-related endocrine dysregulation and genetic variations associated with PTSD and AUD, as well as disruption in crucial neural circuitry throughout the corticomesolimbic region. Despite limitations and challenges, both types of studies have implicated three interrelated mechanisms: hypothalamic pituitary adrenal (HPA) axis and glucocorticoid signaling dysregulation, genetics, and epigenetics. ELS exposure leads to disruption of HPA axis function and glucocorticoid signaling, both of which affect homeostatic cortisol levels. However, individual response to ELS depends on genetic variations at specific genes that moderate HPA axis and brain function, thus influencing susceptibility or resilience to psychopathologies. Epigenetic-influenced pathways also are emerging as a powerful force in helping to create the PTSD and AUD phenotypes. Dysregulation of the HPA axis has an epigenetic effect on genes that regulate the HPA axis itself, as well as on brain-specific processes such as neurodevelopment and neurotransmitter regulation. These studies are only beginning to elucidate the underpinnings of ELS, PTSD, and AUD. Larger human cohorts, identification of additional genetic determinants, and better animal models capable of recapitulating the symptoms of PTSD and AUD are needed.

Comments and controversies: Piecing together the neurobiology of decision-making.

In this paper, we address issues raised by Tierney and Hart (Assessing Complex Cognitive Functioning Requires Multiple Tasks) in response to our recently published findings showing that less advantageous decision-making on the Iowa Gambling Task (IGT) was associated with enhanced right ventral striatal dopamine response to intravenous amphetamine (Oswald et al., 2015). We agree with the overall premise of the paper, which was that decision-making involves multiple components, which may not be tapped by a single measure. While Tierney and Hart also bring up some important issues related to the construct validity of the IGT, we suggest that they are failing to put the findings within the context of the growing body of research that has highlighted the role of DA function in risk-taking behavior across species using a variety of tasks. It should also be noted that it was not our goal to "cover all bases" within the context of a single study. Nevertheless, we appreciate the discussion, which we believe highlights the need for further empirical refinement of the construct to facilitate detection and understanding of the differential role that specific molecular mechanisms may play in the component processes.

Risky decision-making and ventral striatal dopamine responses to amphetamine: a positron emission tomography [(11)C]raclopride study in healthy adults.

Recent functional magnetic resonance imaging (fMRI) studies have provided compelling evidence that corticolimbic brain regions are integrally involved in human decision-making. Although much less is known about molecular mechanisms, there is growing evidence that the mesolimbic dopamine (DA) neurotransmitter system may be an important neural substrate. Thus far, direct examination of DA signaling in human risk-taking has centered on gambling disorder. Findings from several positron emission tomography (PET) studies suggest that dysfunctions in mesolimbic DA circuits may play an important role in gambling behavior. Nevertheless, interpretation of these findings is currently hampered by a need for better understanding of how individual differences in regional DA function influence normative decision-making in humans. To further our understanding of these processes, we used [(11)C]raclopride PET to examine associations between ventral striatal (VS) DA responses to amphetamine (AMPH) and risky decision-making in a sample of healthy young adults with no history of psychiatric disorder, Forty-five male and female subjects, ages 18-29 years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second, by intravenous AMPH (0.3mg/kg). Findings of primary analyses showed that less advantageous decision-making was associated with greater right VS DA release; the relationship did not differ as a function of gender. No associations were observed between risk-taking and left VS DA release or baseline D2/D3 receptor availability in either hemisphere. Overall, the results support notions that variability in striatal DA function may mediate inter-individual differences in risky decision-making in healthy adults, further suggesting that hypersensitive DA circuits may represent a risk pathway in this population.

History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine.

RATIONALE: Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear. OBJECTIVES: This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans. METHODS: Following intake assessment, 28 healthy male and female adults, aged 18-29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg). RESULTS: Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress. CONCLUSIONS: Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.

Volunteerism and self-selection bias in human positron emission tomography neuroimaging research.

Scientists have known for decades that persons who volunteer for behavioral research may be different from those who decline participation and that characteristics differentiating volunteers from non-volunteers may vary depending on the nature of the research. There is evidence that volunteer self-selection can impact representativeness of samples in studies involving physically or psychologically stressful procedures, such as electric shocks, sensory isolation, or drug effects. However, the degree to which self-selection influences sample characteristics in "stressful" studies involving positron emission tomography (PET) has not been evaluated. Since estimation of population parameters, robustness of findings, and validity of inferred relationships can all be impacted by volunteer bias, it is important to determine if self-selection may act as an unrecognized confound in such studies. In the present investigation, we obtained baseline data on 114 (56M, 58F) subjects who participated in a study involving completion of several self-report questionnaires and behavioral performance tasks. Participants were later given the opportunity to enroll in an [11C]raclopride PET study involving intravenous amphetamine (AMPH) administration. Demographic characteristics, personality traits, and task performance of subjects who consented to the latter study were compared with those who declined participation. Findings showed that the principal personality trait that distinguished the two groups was sensation-seeking; volunteers scored significantly higher on this dimension than non-volunteers. Males were more likely to volunteer than females. However, results of mediation analysis suggested that the relationship between gender and volunteer status was mediated by greater sensation-seeking traits in the males. Implications of these findings are discussed.

Impulsivity and chronic stress are associated with amphetamine-induced striatal dopamine release.

A challenging question that continues to plague the field of addiction is why some individuals are more vulnerable for substance use disorders than others. Several important risk factors for substance abuse have been identified in clinical studies, including trait impulsivity and environmental stress. However, the neurobiological mechanisms that underlie the relationships remain poorly understood. The purpose of this study was to examine associations among impulsivity, stress, and striatal dopamine (DA) responses to amphetamine (AMPH) in humans. Forty healthy M, F adults, ages 18-29 years, completed self-report measures of trait impulsivity, life events stress, and perceived stress. Subjects subsequently underwent two consecutive 90-min positron emission tomography (PET) studies with high specific activity [11C]raclopride. The first scan was preceded by an intravenous injection of saline; the second was preceded by 0.3 mg/kg AMPH. Findings showed that high impulsivity was associated with blunted right ventral striatal DA release. However, effects were modified by a significant interaction with life events stress. Dopamine release was greater in low vs. high impulsivity subjects under conditions of low or moderate stress. Under conditions of high stress, both groups had low DA release. Subjects with high impulsivity reported more pleasant effects with AMPH than subjects with low impulsivity. In contrast, stress was negatively associated with pleasant drug effects. No associations were observed between impulsivity or stress and cortisol responses to AMPH. The findings are consistent with notions that blunted DA responses represent an endophenotype for substance use disorders.

Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress.

Preclinical studies have shown that stress and glucocorticoids increase mesolimbic dopamine (DA) and thereby facilitate psychostimulant self-administration. The relationship between stress-induced cortisol and mesolimbic DA responses to psychostimulants has not been studied in humans. To test the hypotheses that glucocorticoid responses to psychological stress are correlated with DA and subjective responses to psychostimulants in humans, 25 healthy adults (18-29 years) completed the Trier Social Stress Test (TSST) and two positron emission tomography (PET) scans with high-specific [11C]raclopride. The first scan was preceded by intravenous saline and the second by amphetamine (AMPH). Findings showed that stress-induced cortisol levels were positively associated with AMPH-induced DA release in the ventral striatum and other striatal regions. Subjects with higher cortisol responses to stress also reported more positive subjective drug effects with AMPH than subjects with lower responses. The results are consistent with preclinical findings showing an interrelationship between glucocorticoids and mesolimbic DA dynamics, which may influence psychostimulant self-administration in humans.

Striatal dopamine release and family history of alcoholism.

BACKGROUND: The offspring of alcohol-dependent individuals are at increased risk for alcoholism. The present study was designed to determine whether mesolimbic dopamine binding potential (BP), dopamine release, stress hormones, and subjective responses to intravenous amphetamine are different in nonalcoholic offspring from families with a history of alcohol dependence [family history positive (FHP)] than in nonalcoholic offspring without a family history of alcohol dependence [family history negative (FHN)]. METHODS: Participants were 41 healthy men and women (11 FHP, 30 FHN; age range 18-29). After completing baseline psychiatric symptom and personality measures, striatal D2/D3 dopamine BP and dopamine release in response to an amphetamine challenge were measured with positron emission tomography (PET) using the D2/D3 dopamine (DA) receptor radioligand [11C]raclopride. Binding potential was defined as Bmax/KD, percent change in BP from baseline defined dopamine release. During the scans, subjects rated the degree to which they were experiencing each of 10 possible drug effects. Plasma cortisol and growth hormone (GH) were also measured at scheduled intervals during the scans. RESULTS: Neither baseline BP nor dopamine release differed by family history. Similarly, subjective responses to amphetamine did not differ by a family history of alcoholism. Although both cortisol and GH increased following administration of amphetamine, these increases did not differ between family history groups. CONCLUSIONS: Using amphetamine to provoke mesolimbic dopamine, we did not show significant differences in dopamine release, subjective responses, or stress hormone measures as a function of family history of alcoholism.

Sex differences in striatal dopamine release in healthy adults.

BACKGROUND: Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. METHODS: Using positron emission tomography (PET) scans with high-specific-activity [11C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. RESULTS: Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, men's ratings of the positive effects of amphetamine were greater than women's. We found no sex difference in neuroendocrine hormone responses. CONCLUSIONS: We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.

Relationship between cortisol responses to stress and personality.

Although there is growing evidence of links between the cortisol stress response and personality, the nature of the relationships and the underlying mechanisms require further clarification. The purpose of this study was to examine associations between personality traits and cortisol responses to stress using the Revised NEO Personality Inventory five-factor model of personality. In total, 68 healthy adults, aged 18-30 years, completed the personality assessment and underwent a laboratory psychological stress test that consisted of a 5 min speech and 5-min of mental arithmetic. Findings showed that in the sample as a whole, less Openness was associated with lower cortisol responses to the challenge. Cortisol responses also corresponded to certain personality dimensions in a gender-specific manner. Blunted cortisol responses were associated with higher Neuroticism in women and with lower Extraversion in men. These findings suggest that personality traits that have been traditionally associated with greater psychopathology were also associated with blunted HPA axis responses to stress.

Hormone responses to social stress in abstinent alcohol-dependent subjects and social drinkers with no history of alcohol dependence.

BACKGROUND: Previous studies have described blunted stress hormone responses after pharmacological activation of the hypothalamic-pituitary-adrenal (HPA) axis in sober alcoholics. The aim of the present study was to compare ACTH, cortisol, and prolactin responses to a psychological stressor in abstinent alcohol-dependent subjects matched to healthy control subjects. METHODS: Individuals who met DSM-IV diagnostic criteria for a history of alcohol dependence but not for other axis I disorders were included in the study (n = 18; mean duration of abstinence +/- SEM, 3.5 +/- 5.7 years). Social drinkers (n = 23) served as control subjects. The sober alcohol-dependent and control subjects were matched for demographic measures including levels of stress symptoms. All subjects underwent the Trier Social Stress Test (TSST), a laboratory-based psychological stressor. Prestress and poststress plasma ACTH, cortisol, and prolactin levels, as well as a self-report measure of anxiety (State-Trait Anxiety Inventory), were obtained. RESULTS: Nondepressed, abstinent alcoholics and control subjects did not differ with regard to age, racial composition, or baseline or poststress ratings of anxiety. Whereas ACTH and cortisol levels increased in response to the TSST, prolactin levels did not. Stress hormone response curves for the three hormones did not differ between the alcoholics and control subjects. CONCLUSIONS: When matched for levels of stress, a laboratory-based psychological stress test did not induce differential hormone response curves for abstinent alcoholics and control subjects.

Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine.

There is evidence that stress and glucocorticoids alter drug self-administration and mesolimbic dopamine (DA) activity in preclinical models. The primary purpose of this study was to test the hypothesis that glucocorticoids are associated with psychostimulant reinforcement and DA release in humans. In total, 16 healthy adults, ages 18-27 years, underwent two consecutive 90-min PET studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline, and the second by intravenous amphetamine (AMPH 0.3 mg/kg). DA release was defined as the percent change in raclopride binding between the placebo and AMPH scans. Measures of subjective drug effects, plasma cortisol, and growth hormone (GH) were obtained. Findings showed that cortisol levels were positively associated with AMPH-induced DA release in the left ventral striatum (LVS) and the dorsal putamen. Subjects with higher cortisol responses to AMPH also reported more positive subjective drug effects than subjects with lower cortisol responses; no association was observed between cortisol levels and negative drug effects. Higher ratings of positive drug effects were also associated with greater DA release in the LVS, dorsal putamen, and dorsal caudate. A general lack of relationship was observed between GH responses to AMPH and DA release or subjective drug responses. Our findings provide evidence of interrelationships between glucocorticoid levels, subjective responses to IV AMPH, and brain DA release in humans. The results are consistent with those of preclinical studies, suggesting that individual differences in HPA axis function may influence vulnerability to alcohol and drug dependence in humans.

Catechol-O-methyltransferase polymorphism alters hypothalamic-pituitary-adrenal axis responses to naloxone: a preliminary report.

BACKGROUND: A common polymorphism in the catechol-O-methyltransferase gene involves a valine to methionine mutation that results in a threefold to fourfold decrease in enzyme activity. This polymorphism has been associated with altered mu-opioid receptor binding potential and prefrontal cognitive performance, as well as risk for several neuropsychiatric conditions. We hypothesized that subjects homozygous for the low-activity allele would have greater hypothalamic-pituitary-adrenal axis responses to opioid blockade than subjects with the high-activity allele. METHODS: Forty-six healthy adults were genotyped and underwent a procedure in which adrenocorticotropin hormone and cortisol responses to the opioid antagonist naloxone were examined. RESULTS: Findings showed that adrenocorticotropin hormone and cortisol responses were greater in subjects with the methionine/methionine genotype compared to subjects homozygous or heterozygous for the valine allele. CONCLUSIONS: These findings suggest that individual differences in catecholamine metabolism may impact hypothalamic-pituitary-adrenal axis function and may play a pharmacogenetic role in responses to naloxone.

Comparison of HPA axis hormonal responses to naloxone vs psychologically-induced stress.

Although the naloxone challenge has been used to draw inferences about the dynamics of the stress response, this procedure has never actually been compared "head to head" with a psychological stressor. In the present study, we asked 14 healthy volunteers to complete the naloxone challenge and the Trier Social Stress Test in an outpatient GCRC laboratory setting so that the degree of correspondence between the two procedures could be examined. Findings indicated that subjects who had greater ACTH responses to naloxone also had greater ACTH responses to the psychologically-induced stressor. This was true for both ACTH peak (r=0.57; p<0.04) and ACTH AUC response (r=0.64; p<0.02) measures; none of the cortisol summary score measures correlated significantly across the two challenges. Associations were also found between subjects' baseline personality characteristics and their ACTH responses to each of the challenges. Furthermore, the kinds of characteristics that predicted greater ACTH response to the pharmacological challenge were similar to the kinds of characteristics that predicted ACTH response to the psychological challenge. In general, higher scores on the NEO dimensions of Extraversion and Openness predicted greater ACTH responses. These findings give preliminary evidence that novelty-seeking behavior may be associated with HPA axis lability. The commonalities in personality predictors between the two challenges further support the notion that a common biological substrate may be, at least partially, responsible for the similarities in responses. However, caution should be used in assuming that responses to naloxone directly parallel responses to physiological stress.