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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.

Rationale Given the contribution of cortisol dysregulation to neuropsychiatric and metabolic disorders, it is important to be able to accurately compute glucocorticoid burden, a measure of allostatic load. One major problem in calculating cortisol burden is that existing measures reflect cortisol exposure over a short duration and have not been proven to reliably quantify cortisol burden over weeks or months. Method We treated two cohorts of mice with corticosterone in the drinking water and determined the relationship between serial plasma corticosterone levels drawn over 4 weeks and the whole-blood DNA methylation (DNAm) changes in a specific glucocorticoid-sensitive gene, Fkbp5 , determined at the end of the treatment period. Results We observed that the percent reduction in DNAm in the intron 1 region of Fkbp5 determined from a single blood draw strongly reflected average glucocorticoid burden generated weekly during the prior month of glucocorticoid exposure. There were also strong correlations in DNAm with glucocorticoid-induced end organ changes in spleen weight and visceral fat. We tested a subset of these animals for anxiety-like behavior in the elevated plus maze and found that DNAm in the blood also has predictive value in determining the behavioral consequences of glucocorticoid exposure. Conclusion A whole-blood assessment of Fkbp5 gene methylation is a biomarker that integrates 4 weeks of glucocorticoid exposure and may be a useful measure in states of excess exposure. It will be important to determine if Fkbp5 DNAm changes can also be a biomarker of glucocorticoid burden during chronic social stress.

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 [11C]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 18–29years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [11C]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. •Heightened RVS DA response to amphetamine is associated with poor decision-making.•Associations between decision-making and DA response did not differ between M and F.•Decision-making was not associated with LVS DA release or BPND in any striatal region.•Hyper-responsive striatal DA circuits may represent a risk pathway in healthy adults.

Background Subclinical hypercortisolism and hypothalamic-pituitary-adrenal (HPA) axis dysfunction are associated with type 2 diabetes (T2DM), cardiovascular disease, and metabolic dysfunction. Intronic methylation of FKBP5 has been implicated as a potential indicator of chronic cortisol exposure. Our overall objective in this study was to determine the association of chronic cortisol exposure, measured via percent methylation of FKBP5 at intron 2, with percent glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-cholesterol), waist circumference (WC), and body mass index (BMI), in a clinic-based sample of 43 individuals with T2DM. Results Greater percent methylation of the FKBP5 intron 2 at one CpG-dinucleotide region was significantly associated with higher HbA1c ( β  = 0.535, p  = 0.003) and LDL cholesterol ( β  = 0.344, p  = 0.037) and a second CpG-dinucleotide region was significantly associated with higher BMI and WC ( β  = 0.516, p  = 0.001; β  = 0.403, p  = 0.006, respectively). Conclusions FKBP5 methylation may be a marker of higher metabolic risk in T2DM, possibly secondary to higher exposure to cortisol. Further work should aim to assess the longitudinal association of FKBP5 with cardiovascular disease and glycemic outcomes in T2DM as a first step in understanding potential preventive and treatment-related interventions targeting the HPA axis.

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 [ 11 C]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.

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.

The Asn40Asp variant (A118G) of the μ opioid receptor (OPRM1) gene is thought to contribute to the development and treatment of alcohol dependence. Employing positron emission tomography (PET), we first examined whether the single nucleotide polymorphism (SNP) modifies binding potential (BPND) of the μ-selective ligand [11C]carfentanil in healthy control (Con) and 5-d abstinent alcohol-dependent (AD) subjects (unblocked basal scan). Second, we examined whether the allelic variants were associated with differences in OPRM1 occupancy by naltrexone (50 mg) in AD subjects. Con and AD carriers of the G allele (AG) had lower global BPND at the basal scan than subjects homozygous for the A allele (AA). In AD subjects, naltrexone occupancy was slightly higher in AG subjects (98.9%) compared to AA subjects (93.1%), but this was not significant. We are the first to demonstrate using PET in healthy normal and AD subjects that the A118G SNP alters OPRM1 availability.

A polymorphism in the mu-opioid receptor (MOR) (A118G) has been shown to increase beta-endorphin binding affinity, theoretically placing greater inhibitory tone on hypothalamic corticotropin-releasing hormone (CRH) neurons. We hypothesized that the minor allele (G) would predict cortisol responses to both pharmacological (naloxone) and psychological (stress) activation of the hypothalamic-pituitary-adrenal (HPA) axis. Healthy subjects (mean age 25.2 years, SD 9.2 years) completed a naloxone challenge (n=74) and/or the modified Trier Social Stress Test (TSST) (n=86). For the naloxone challenge, two baseline blood samples were obtained. Then, five increasing doses of i.v. naloxone were administered at 30-min intervals and 12 additional blood samples were collected at 15-min intervals. The TSST consisted of 5-min of public speaking and 5-min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Both the naloxone and TSST groups had significant adrenocorticotropin (ACTH) and cortisol responses to their respective challenges (P<0.001). There were no differences in baseline ACTH, baseline cortisol, or ACTH response by genotype in either the naloxone or the TSST group. Among subjects expressing a G allele, there was a higher cortisol response to naloxone (P=0.046), but a lower cortisol response to the TSST (P=0.044). In conclusion, the minor allele (G) was associated with a robust cortisol response to naloxone blockade, but a blunted response to psychosocial stress. We speculate that increased opioid avidity of the minor allele receptor contributes to the differential response to naloxone vs stress.

Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS. We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus. In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity). These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH. ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotrophin-releasing hormone CS = Cushing syndrome DDAVP = desmopressin EAS = ectopic ACTH secretion IJVS = internal jugular vein sampling IPSS = inferior petrosal sinus sampling JVS = jugular venous sampling MRI = magnetic resonance imaging.

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.