Highlights • Healthy young men and women (in the follicular phase of the menstrual cycle) completed the Trier Social Stress Test. • Post-stress hypothalamic–pituitary–adrenal (HPA) axis hormone ...responses were greater in men than women. • Pre-stress testosterone levels were negatively associated with post-stress salivary cortisol response in men. • Pre-stress progesterone levels were negatively associated with post-stress ACTH and serum cortisol responses in women. • Pre-stress progesterone in men and estradiol in women were not associated with post-stress HPA axis response.
ABSTRACT
A challenging question that continues unanswered in the field of addiction is why some individuals are more vulnerable to substance use disorders than others. Numerous risk factors for ...alcohol and other drugs of abuse, including exposure to various forms of stress, have been identified in clinical studies. However, the neurobiological mechanisms that underlie this relationship remain unclear. Critical neurotransmitters, hormones and neurobiological sites have been recognized, which may provide the substrates that convey individual differences in vulnerability to addiction. With the advent of more sophisticated measures of brain function in humans, such as functional imaging technology, the mechanisms and neural pathways involved in the interactions between drugs of abuse, the mesocorticolimbic dopamine system and stress systems are beginning to be characterized.
This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from occasional drug use to drug dependence. We also review factors that contribute to different levels of hormonal/brain stress activation, which has implications for understanding individual vulnerability to drug dependence. Ultimately, these efforts may improve our chances of designing treatment strategies that target addiction at the core of the disorder.
Background
Stress and anxiety are widely considered to be causally related to alcohol craving and consumption, as well as development and maintenance of alcohol use disorder (AUD). However, numerous ...preclinical and human studies examining effects of stress or anxiety on alcohol use and alcohol‐related problems have been equivocal. This study examined relationships between scores on self‐report anxiety, anxiety sensitivity, and stress measures and frequency and intensity of recent drinking, alcohol craving during early withdrawal, as well as laboratory measures of alcohol craving and stress reactivity among heavy drinkers with AUD.
Methods
Media‐recruited, heavy drinkers with AUD (N = 87) were assessed for recent alcohol consumption. Anxiety and stress levels were characterized using paper‐and‐pencil measures, including the Beck Anxiety Inventory (BAI), the Anxiety Sensitivity Index‐3 (ASI‐3), and the Perceived Stress Scale (PSS). Eligible subjects (N = 30) underwent alcohol abstinence on the Clinical Research Unit; twice daily measures of alcohol craving were collected. On day 4, subjects participated in the Trier Social Stress Test; measures of cortisol and alcohol craving were collected.
Results
In multivariate analyses, higher BAI scores were associated with lower drinking frequency and reduced drinks/drinking day; in contrast, higher ASI‐3 scores were associated with higher drinking frequency. BAI anxiety symptom and ASI‐3 scores also were positively related to Alcohol Use Disorders Identification Test total scores and AUD symptom and problem subscale measures. Higher BAI and ASI‐3 scores but not PSS scores were related to greater self‐reported alcohol craving during early alcohol abstinence. Finally, BAI scores were positively related to laboratory stress‐induced cortisol and alcohol craving. In contrast, the PSS showed no relationship with most measures of alcohol craving or stress reactivity.
Conclusions
Overall, clinically oriented measures of anxiety compared with perceived stress were more strongly associated with a variety of alcohol‐related measures in current heavy drinkers with AUD.
Stress and anxiety are widely believed to contribute to drinking; however, prior research findings have been inconsistent. In this study, measures of anxiety and anxiety sensitivity as compared with perceived stress were more strongly associated with frequency and intensity of drinking, alcohol craving during withdrawal, and alcohol craving and cortisol levels following the Trier Social Stress Test. These findings highlight the importance of maintaining distinctions among these terms given unique relationships with drinking, craving, and stress reactivity among heavy drinkers.
There is evidence for hypercortisolemia playing a role in the generation of psychiatric symptoms and for epigenetic variation within hypothalamic-pituitary-adrenal (HPA) axis genes mediating ...behavioral changes. We tested the hypothesis that expression changes would be induced in Fkbp5 and other HPA axis genes by chronic exposure to corticosterone and that these changes would occur through the epigenetic mechanism of loss or gain of DNA methylation (DNAm). We administered corticosterone (CORT) to C57BL/6J mice via their drinking water for 4 wk and tested for behavioral and physiological changes and changes in gene expression levels using RNA extracted from hippocampus, hypothalamus, and blood for the following HPA genes: Fkbp5, Nr3c1, Hsp90, Crh, and Crhr1. The CORT mice exhibited anxiety-like behavior in the elevated plus maze test. Chronic exposure to CORT also caused a significant decrease in the hippocampal and blood mRNA levels of Nr3c1 and a decrease in Hsp90 in blood and caused an increase in Fkbp5 for all tissues. Differences were seen in Fkbp5 methylation in hippocampus and hypothalamus. To isolate a single-cell type, we followed up with an HT-22 mouse hippocampal neuronal cell line exposed to CORT. After 7 d, we observed a 2.4-fold increase in Fkbp5 expression and a decrease in DNAm. In the CORT-treated mice, we also observed changes in blood DNAm in Fkbp5. Our results suggest DNAm plays a role in mediating effects of glucocorticoid exposure on Fkbp5 function, with potential consequences for behavior.
DNA methylation decreased, expression of the glucocorticoid signaling-related gene Fkbp5 increased, in response to corticosterone administration, suggesting epigenetic influences in the glucocorticoid–Fkbp5 interaction.
Abstract Objective The transition from microscopic to a fully endoscopic transsphenoidal surgery requires a surgeon to assess how the change in technique will affect the extent of tumor resection ...(EOR), outcomes, and complications. We compared a single surgeon’s experience transitioning from one technique to the other, and examined the operative outcomes and EOR between microscopic versus endoscopic transsphenoidal surgery. Methods Retrospective data analysis of adult patients who were treated surgically for a pituitary adenoma between August 2005 and May 2015 by a single neurosurgeon, who was originally trained and practiced in the microscopic transsphenoidal approach. Patient demographics, perioperative conditions, tumor characteristics, operative times, volumetric EOR, postoperative outcome, and the endoscopic learning curve were evaluated. Results One hundred nine patients underwent microscopic transsphenoidal surgery and two hundred seventy-five patients underwent a fully endoscopic approach. The patient characteristics were similar in the two groups. Operative room time was significantly shorter in the endoscopic group than in the microscopic group (180.2 vs. 215.6mins, p<0.001 ). The endoscopic and microscopic groups had similar volumetric EOR (85.1% vs 82.8%,p=0.371) as well as residual tumor volume(1.06cm3 vs 1.15cm3 ,p=0.765). The mean length of hospital stay was 2.4 days in the endoscopic group and 3.2 days in the microscopic group( p=0.03 ). Conclusion During the transition from the microscopic to the endoscopic approach, similar surgical outcomes and EOR were achieved in the two cohorts. In our experience, the endoscopic approach offers the advantage of shorter operative times and lengths of hospital stays after the surgeon has developed more experience with the technique.
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
Craclopride. 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.
Rationale
Chronic dysregulation of hypothalamus–pituitary–adrenal (HPA) axis activity is related to several neuropsychiatric disorders. Studies suggest that cortisol response to stress has a strong ...genetic etiology, and that FK506 binding protein 5 (FKBP5) and G-protein coupled type-I CRH receptor (CRHR1) are key proteins regulating response. Variations in the genes encoding these proteins,
FKBP5
and
CRHR1
, have been associated with several neuropsychiatric disorders.
Objectives
We examined variation in these genes in relation to cortisol response to psychological stress in one of the largest Trier Social Stress Test (TSST) cohorts yet examined.
Methods
A total of 368 healthy, young adults underwent the TSST. Salivary cortisol was measured at multiple time points before and after the stressor. Nine variants in
FKBP5
and four in
CRHR1
were assessed. Single marker analyses were conducted. Secondary analyses assessed haplotypes and interaction with stress-related variables.
Results
The strongest association was for rs4713902 in
FKBP5
with baseline cortisol (
p
dom
= 0.0004). We also identified a male-specific effect of
FKBP5
polymorphisms on peak response and response area under the curve (
p
= 0.0028 for rs3800374). In
CRHR1,
rs7209436, rs110402, and rs242924 were nominally associated with peak response (
p
rec
= 0.0029–0.0047). We observed interactions between trait anxiety and rs7209436 and rs110402 in
CRHR1
in association with baseline cortisol (
p
LRT
= 0.0272 and
p
LRT
= 0.0483, respectively).
Conclusions
We show association of variants in
FKBP5
and
CRHR1
with cortisol response to psychosocial stress. These variants were previously shown to be associated with neuropsychiatric disorders. These findings have implications for interindividual variation in HPA axis activity and potentially for the etiology of neuropsychiatric disorders.
Population-based studies have been hampered in exploring hypothalamic-pituitary-adrenal axis (HPA) activity as a potential explanatory link between stressrelated and metabolic disorders due to their ...lack of incorporation of reliable measures of chronic cortisol exposure. The purpose of this review is to summarize current literature on the reliability of HPA axis measures and to discuss the feasibility of performing them in population-based studies. We identified articles through PubMed using search terms related to cortisol, HPA axis, adrenal imaging, and reliability. The diurnal salivary cortisol curve (generated from multiple salivary samples from awakening to midnight) and 11 p. m. salivary cortisol had the highest between-visit reliabilities (r = 0.63-0.84 and 0.78, respectively). The cortisol awakening response and dexamethasone-suppressed cortisol had the next highest between-visit reliabilities (r = 0.33-0.67 and 0.42-0.66, respectively). Based on our own data, the inter-reader reliability (r s ) of adrenal gland volume from non-contrast CT was 0.67-0.71 for the left and 0.47-0.70 for the right adrenal glands. While a single 8 a.m. salivary cortisol is one of the easiest measures to perform, it had the lowest between-visit reliability (R = 0.18-0.47). Based on the current literature, use of sampling multiple salivary cortisol measures across the diurnal curve (with awakening cortisol), dexamethasone-suppressed cortisol, and adrenal gland volume are measures of HPA axis tone with similar between-visit reliabilities which likely reflect chronic cortisol burden and are feasible to perform in populationbased studies.
•Among participants with diabetes.•Annual increases in cortisol features associated with increased glucose over time.•Flattening of cortisol decline associated with increased annual % change in ...glucose.•This suggests a detrimental role of cortisol contributing to glycemia in diabetes.
Little is known about the longitudinal association between fasting glucose (FG) and the diurnal cortisol profile among those with normal fasting glucose (NFG), impaired fasting glucose (IFG) and diabetes. To assess the temporality of the relationship between cortisol and glucose, we examined the association of: A) change (Δ) in diurnal cortisol curve features with ΔFG; B) prior annual percent change in FG with diurnal cortisol curve features; and C) baseline cortisol curve features with ΔFG over 6 years among participants with NFG, IFG and diabetes in the Multi-Ethnic Study of Atherosclerosis. The main outcome measures were: A) 6-year ΔFG (n = 512); B) diurnal cortisol curve features (wake-up cortisol levels, cortisol awakening response, total area under the curve, overall decline slope and bedtime cortisol) (n = 1275); and C) 6-year ΔFG (n = 700). After full multivariable adjustment among participants with diabetes, each annual percent change increase in wake-up cortisol, total area under the curve (AUC), and overall decline slope was associated with a significant increase in FG over 6 years in all models (all p < 0.05). A 1% prior annual increase in FG was associated with a 2.8 % lower (−2.8 %; 95 % CI: −5.3 % to −0.4 %) bedtime cortisol among participants with NFG at baseline. A 1 % flatter overall decline slope was associated with a 0.19 % increase in subsequent annual % change in FG over 6 years among participants with diabetes. Among participants with diabetes there was a positive association of change in wake-up cortisol, total AUC and overall decline slope with change in FG. Baseline overall decline slope was positively associated with change in FG among the baseline diabetes group. These results suggest a detrimental role of cortisol contributing to glycemia among individuals with diabetes.
► Dose dependent increase in FK506 binding protein 5 (Fkbp5) and decrease in DNA methyltransferase 1 (Dnmt1) expression by dexamethasone. ► Site-specific loss of methylation of Fkbp5 in pituitary ...cell line and hippocampus. ► Glucocorticoid-induced epigenetic activity in hippocampus enriched in dentate gyrus.
Glucocorticoids may play a significant role in the etiology of neuropsychiatric illnesses. Abnormalities in plasma cortisol levels, glucocorticoid sensitivity, and HPA-axis function often accompany clinical symptoms of stress-related illnesses such as PTSD and depression. Of particular interest are genetic association studies that link single nucleotide polymorphisms of HPA-axis genes with illnesses only in the context of an early-life trauma exposure such as child abuse. These studies suggest that dysregulation of HPA-axis function can have lasting repercussions in shaping mood and anxiety, long after termination of the traumatic experience. As persistent glucocorticoid-induced loss of DNA methylation in FK506 binding protein 5 (Fkbp5) was previously observed in the hippocampus and blood and in the neuronal cell line HT-22, we asked whether these epigenetic alterations occur in non-neuronal, HPA-axis relevant cells. We used the pituitary adenoma cell line AtT-20 to demonstrate that the intronic enhancer region of Fkbp5 undergoes loss of DNA methylation in response to dexamethasone treatment in a dose-dependent manner. We also focused on the mouse hippocampal dentate gyrus to test whether these changes would be enriched in a region implicated in the HPA-axis stress response, neurogenesis, and synaptic plasticity. We observed an increase in enrichment of DNA methylation loss in the dentate gyrus, as compared to whole hippocampal tissues that were similarly treated with glucocorticoids. We then asked whether DNA methyltransferase 1 (Dnmt1), a methyltransferase enzyme involved in maintaining DNA methylation following cell division, is involved in the observed epigenetic alterations. We found a dose-dependent decrease of Dnmt1 expression in the AtT-20 cells following dexamethasone treatment, and a similar decrease in corticosterone-treated mouse hippocampus. Taken together, we provide evidence that these glucocorticoid-induced epigenetic alterations have a broader validity in non-neuronal cells and that they may involve the DNA methylation machinery.
PDF
