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1.  Effect of social stress during acute nicotine abstinence 
Psychopharmacology  2011;218(1):39-48.
Rationale
Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response.
Objectives
The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal.
Methods
Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured.
Results
The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups.
Conclusions
The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement.
doi:10.1007/s00213-010-2150-y
PMCID: PMC3094594  PMID: 21234550
Nicotine withdrawal; Stress; Nicotine replacement; Cortisol
2.  Nicotine Effects on Immediate and Delayed Verbal Memory After Substance Use Detoxification 
Decrements in verbal memory are commonly reported by detoxified treatment-seeking individuals. Although acute nicotine has been shown to improve attentional performance, its effects on verbal memory in substance abusers have not been addressed. Treatment-seeking alcohol dependent (ALCS N=29; 14 male), illicit stimulant (predominantly cocaine) dependent (STIMS N = 25; 15 male) and alcohol and illicit stimulant dependent (ALC/STIMS N = 50; 35 male) participants with co-morbid nicotine dependence were studied. Subjects had been abstinent from their drugs of choice for 41(±18) days and were in short-term abstinence from tobacco (~8–10 hours). Subjects received double-blind administration of either transdermal nicotine (High dose: 21/14 mg for men and women, respectively or Low dose: 7 mg) or placebo. The Logical Memory (LM) subtest from the Wechsler Memory Scale -Revised (WMS-R) was used to assess immediate and delayed verbal memory recall. Results indicated that STIMS receiving the high dose of nicotine recalled more words at immediate recall than STIMS who received placebo. Trend level differences were also noted at delayed recall between STIM nicotine and placebo doses. Nicotine failed to impact either recall in alcoholic subgroups. Although not the primary focus, results also revealed differences in the forgetting rates between the groups with the ALC/STIMS demonstrating the steepest forgetting slope. In summary, this study suggests that nicotine effects may be differentially experienced by substance using subgroups; that nicotine may have a direct effect on memory and, that considering neurocognitive processes (e.g., encoding vs. retrieval) underlying endpoint indicators (e.g. correct recall) may be critical in predicting outcomes.
doi:10.1080/13803395.2010.543887
PMCID: PMC3146969  PMID: 21526444
3.  Cortisol secretion patterns in addiction and addiction risk 
Addiction to alcohol or nicotine involves altered functioning of the brain's motivational systems. Altered functioning of the hypothalamic–pituitary–adrenocortical (HPA) axis may hold clues to the nature of the motivational changes accompanying addiction and vulnerability to addiction. Alcohol and nicotine show at least three forms of interaction with HPA functioning. Acute intake of both substances causes stress-like cortisol responses. Their persistent use may dysregulate the HPA. Finally, the risk for dependence and for relapse after quitting may be associated with deficient cortisol reactivity to a variety of stressors. The HPA is regulated at the hypothalamus by diurnal and metabolic signals, but during acute emotional states, its regulation is superseded by signals from the limbic system and prefrontal cortex. This top–down organization makes the HPA responsive to inputs that reflect motivational processes. The HPA is accordingly a useful system for studying psychophysiological reactivity in persons who may vary in cognitive, emotional, and behavioral tendencies associated with addiction and risk for addiction. Chronic, heavy intake of alcohol and nicotine may cause modifications in these frontal–limbic interactions and may account for HPA response differences in seen in alcoholics and smokers. In addition, preexisting alterations in frontal–limbic interactions with the HPA may reflect addiction-proneness, as shown in studies of offspring of alcohol- and drug-abusing parents. Continuing research on the relationship between HPA function, stress responsivity, and the addictions may yield insights into how the brain's motivational systems support addictions and risk for addictions.
doi:10.1016/j.ijpsycho.2005.10.007
PMCID: PMC2257874  PMID: 16434116
Hypothalamic–pituitary–adrenal axis; Addictions; Nicotine; Alcohol; Cortisol; Stress
4.  Recent depressive and anxious symptoms predict cortisol responses to stress in men 
Psychoneuroendocrinology  2009;34(7):10.1016/j.psyneuen.2009.02.005.
Summary
Individuals with major depressive disorder show blunted cortisol responses to psychosocial stressors, but the extent to which this pattern of dampened responding characterizes individuals experiencing sub-clinical levels of depressive symptoms is unknown. This study investigated whether self-reports of depressive and anxious symptoms over the previous two weeks were associated with cortisol responses to a laboratory social stress task. In addition, we tested whether these associations were mediated by baseline cortisol, subjective responses to the task, or health behaviors. Healthy adults (N = 76) completed the Mood and Anxiety Symptom Questionnaire prior to engaging in the Trier Social Stress Task. Salivary cortisol was measured at 8 points before and after the task to assess cortisol responding. Linear regressions revealed that men reporting more distress and somatic symptoms had smaller cortisol responses, but anhedonic symptoms were not related to cortisol. Distress was associated with lower baseline cortisol, which in turn statistically mediated the relationship between distress and cortisol response. These results demonstrate that the recent experience of depressive and anxious symptoms is associated with smaller cortisol responses to a psychosocial stressor in a nonclinical population.
doi:10.1016/j.psyneuen.2009.02.005
PMCID: PMC3845823  PMID: 19272714
cortisol; stress; negative emotion; men; depression; anxiety
5.  Effect of transdermal nicotine replacement on alcohol responses and alcohol self-administration 
Psychopharmacology  2007;196(2):189-200.
Rationale
Nicotine replacement is commonly used to treat tobacco use in heavy-drinking smokers. However, few studies have examined the effect of nicotine replacement on subjective and physiological responses to alcohol and alcohol drinking behavior.
Objective
The primary aim of this within-subject, double-blind study was to examine whether transdermal nicotine replacement (0 mg vs 21 mg/day) altered response to a low-dose priming drink and subsequent ad libitum drinking behavior.
Materials and methods
Subjects (n=19) were non-treatment-seeking, non-dependent heavy drinkers who were daily smokers. Six hours after transdermal patch application, subjective and physiological responses to a priming drink [designed to raise blood alcohol levels (BALs) to 0.03 g/dl] were assessed. This was followed by a 2-h self-administration period where subjects could choose to consume up to eight additional drinks (each designed to raise BALs by 0.015 g/dl) or to receive monetary reinforcement for drinks not consumed.
Results
We found that 6 h after patch application, tobacco craving associated with withdrawal relief was decreased, and systolic blood pressure and heart rate were increased in the active patch condition compared to the placebo patch condition. Subjective intoxication in response to the priming drink was attenuated in the active nicotine patch condition compared to 6 h of nicotine deprivation (i.e., placebo patch). During the self-administration period, subjects had longer latencies to start drinking and consequently appeared to consume fewer drinks when administered the active patch compared to the placebo patch.
Conclusions
In heavy drinkers, transdermal nicotine replacement compared to mild nicotine deprivation attenuated subjective and physiological alcohol responses and delayed the initiation of drinking.
doi:10.1007/s00213-007-0952-3
PMCID: PMC2862181  PMID: 17912500
Transdermal nicotine replacement; Alcohol; Drinking; Self-administration; Craving; Monetary reinforcement
6.  Nicotine Patch vs. Nicotine Lozenge for Smoking Cessation: An Effectiveness Trial Coordinated by the Community Clinical Oncology Program 
Drug and alcohol dependence  2009;107(2-3):237-243.
Background:
Nicotine replacement therapies are efficacious for treating nicotine dependence. However, limited data exist on benefits of different NRTs and predictors of treatment outcome. This study compared the effectiveness of transdermal nicotine vs. nicotine lozenge for smoking cessation and identified predictors of treatment response.
Methods:
A randomized, open-label effectiveness trial was conducted at twelve medical sites participating in the National Cancer Institute's Community Clinical Oncology Program. The sample consisted of 642 treatment-seeking smokers randomized to twelve weeks of transdermal nicotine or nicotine lozenge.
Results:
Smoker characteristics were assessed at baseline, and 24-hour point prevalence abstinence confirmed with breath carbon monoxide (CO) was evaluated at end of treatment (EOT) and at a 6-month follow-up. There was a trend for higher quit rates for transdermal nicotine vs. nicotine lozenge at EOT (24.3% vs. 18.7%, p = .10) and 6-months (15.6% vs. 10.9%, p = .10). A logistic regression model of EOT quit rates showed smokers who preferred transdermal nicotine, were not reactive to smoking cues, and did not use nicotine to alleviate distress or stimulate cognitive function had higher quit rates on transdermal nicotine. A logistic regression model of 6-month quit rates showed smokers who preferred transdermal nicotine had higher quit rates on transdermal nicotine, and smokers who used nicotine to alleviate distress or stimulate cognitive processes had lower quit rates on nicotine lozenge.
Conclusions:
Transdermal nicotine may be more effective than nicotine lozenge for smokers who prefer transdermal nicotine and do not smoke to alleviate emotional distress or stimulate cognitive function.
doi:10.1016/j.drugalcdep.2009.11.001
PMCID: PMC2834192  PMID: 20004065
smoking cessation; nicotine replacement therapy; nicotine dependence; moderators
7.  Chronic psychosocial stressors and salivary biomarkers in emerging adults 
Psychoneuroendocrinology  2011;37(8):1158-1170.
Summary
We investigated whole saliva as a source of biomarkers to distinguish individuals who have, and who have not, been chronically exposed to severe and threatening life difficulties. We evaluated RNA and DNA metrics, expression of 37 candidate genes, and cortisol release in response to the Trier Social Stress Test, as well as clinical characteristics, from 48 individuals stratified on chronic exposure to psychosocial stressors within the last year as measured by the Life Events and Difficulties Schedule. Candidate genes were selected based on their differential gene expression ratio in circulating monocytes from a published genome-wide analysis of adults experiencing different levels of exposure to a chronic stressor.
In univariate analyses, we observed significantly decreased RNA integrity (RIN) score (P = 0.04), and reduced expression of glucocorticoid receptor-regulated genes (Ps < 0.05) in whole saliva RNA from individuals exposed to chronic stressors, as compared to those with no exposure. In those exposed, we observed significantly decreased BMI (P < 0.001), increased ever-smoking and increased lifetime alcohol abuse or dependence (P ≤ 0.03), and a reduction of cortisol release. In post hoc multivariate analyses including clinical and biospecimen-derived variables, we consistently observed significantly decreased expression of IL8 (Ps < 0.05) in individuals exposed, with no significant association to RIN score. Alcohol use disorders, tobacco use, a reduced acute stress response and decreased salivary IL8 gene expression characterize emerging adults chronically exposed to severe and threatening psychosocial stressors.
doi:10.1016/j.psyneuen.2011.11.010
PMCID: PMC3774595  PMID: 22172638
Human; Saliva; Gene expression; IL8; qPCR
8.  Blunted stress cortisol reactivity and failure to acclimate to familiar stress in depressed and sub-syndromal children 
Psychiatry research  2013;210(2):10.1016/j.psychres.2013.06.038.
Depressed adults have shown blunted or elevated cortisol reactivity in response to various forms of psychosocial stress. However, there have been few studies of cortisol reactivity in children who had early onset depression or a history of depression during the preschool-school period. The present study utilized a laboratory stress paradigm and collected salivary cortisol from preschoolers at baseline (age 3–5) and 24-month follow-up (age 5–7). Repeated-measures MANOVAs were used to compare cortisol reactivity to mild stress between children with major depressive disorder (MDD), elevated symptoms of depression (sub-syndromal MDD), and healthy controls. For healthy children, a quadratic cortisol reactivity curve was found at baseline (n=73), which appeared flatter under similar stressful situations at follow-up (n=14), which may reflect acclimation to the paradigm. In contrast, children with MDD (n=46) and sub-syndromal MDD (n=76) showed a peak cortisol response to the novelty of lab arrival and then reduced and blunted responses to stressors at baseline. These cortisol responses persisted at follow-up in children with any history of MDD (n=41) or sub-syndromal MDD (n=73). These results suggest that the hypothalamic-pituitary-adrenal (HPA) axis shows a blunted response to stress and failed to acclimate to familiar stressful situations in depressed and sub-syndromal depressed children.
doi:10.1016/j.psychres.2013.06.038
PMCID: PMC3818484  PMID: 23876281
Hypothalamic-pituitary-adrenal axis; Salivary cortisol; Child; Major depressive disorder; Preschool; High-risk
9.  Cortisol Responses to Mental Stress and the Progression of Coronary Artery Calcification in Healthy Men and Women 
PLoS ONE  2012;7(2):e31356.
Background
Psychosocial stress is a risk factor for coronary heart disease (CHD). The mechanisms are incompletely understood, although dysfunction of the hypothalamic pituitary adrenal (HPA) axis might be involved. We examined the association between cortisol responses to laboratory-induced mental stress and the progression of coronary artery calcification (CAC).
Methods and Results
Participants were 466 healthy men and women (mean age = 62.7±5.6 yrs), without history or objective signs of CHD, drawn from the Whitehall II epidemiological cohort. At the baseline assessment salivary cortisol was measured in response to mental stressors, consisting of a 5-min Stroop task and a 5-min mirror tracing task. CAC was measured at baseline and at 3 years follow up using electron beam computed tomography. CAC progression was defined as an increase >10 Agatston units between baseline and follow up. 38.2% of the sample demonstrated CAC progression over the 3 years follow up. There was considerable variation in the cortisol stress response, with approximately 40% of the sample responding to the stress tasks with an increase in cortisol of at least 1 mmol/l. There was an association between cortisol stress reactivity (per SD) and CAC progression (odds ratio = 1.27, 95% CI, 1.02–1.60) after adjustments for age, sex, pre-stress cortisol, employment grade, smoking, resting systolic BP, fibrinogen, body mass index, and use of statins. There was no association between systolic blood pressure reactivity and CAC progression (odds ratio per SD increase = 1.03, 95% CI, 0.85–1.24). Other independent predictors of CAC progression included age, male sex, smoking, resting systolic blood pressure, and fibrinogen.
Conclusion
Results demonstrate an association between heightened cortisol reactivity to stress and CAC progression. These data support the notion that cortisol reactivity, an index of HPA function, is one of the possible mechanisms through which psychosocial stress may influence the risk of CHD.
doi:10.1371/journal.pone.0031356
PMCID: PMC3273460  PMID: 22328931
10.  Smoking Cessation during Alcohol Treatment: A Randomized Trial of Combination Nicotine Patch plus Nicotine Gum 
Addiction (Abingdon, England)  2009;104(9):1588-1596.
Aims
The primary aim was to compare the efficacy of smoking cessation treatment using the combination of active nicotine patch plus active nicotine gum versus therapy consisting of active nicotine patch plus placebo gum in a sample of alcohol dependent tobacco smokers in an early phase of outpatient alcohol treatment. A secondary aim was to determine whether or not there were any carryover effects of combination nicotine replacement on drinking outcomes.
Design
Small scale randomized double-blind placebo controlled clinical trial with one-year smoking and drinking outcome assessment.
Setting
Two outpatient substance abuse clinics provided a treatment platform of behavioral alcohol and smoking treatment delivered in three months of weekly sessions followed by three monthly booster sessions.
Participants
Participants were 96 men and women with a diagnosis of alcohol abuse or dependence and smoking 15 or more cigarettes per day.
Intervention
All participants received open-label transdermal nicotine patch and were randomized to receive either 2 mg nicotine gum or placebo gum under double blind conditions.
Findings
Analysis of 1-year follow-up data revealed that patients receiving nicotine patch plus active gum had better smoking outcomes than those receiving patch plus placebo gum on measures of time to smoking relapse and prolonged abstinence at 12 months. Alcohol outcomes were not significantly different across medication conditions.
Conclusions
Results of this study were consistent with results of larger trials of smokers without alcohol problems showing that combination therapy (nicotine patch plus gum) is more effective than monotherapy (nicotine patch) for smoking cessation.
doi:10.1111/j.1360-0443.2009.02624.x
PMCID: PMC2753831  PMID: 19549054
smoking; smoking cessation; nicotine; alcoholism; tobacco
11.  Suppression of the HPA Axis Stress-Response: Implications for Relapse 
This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the medication groups, but not the placebo group. Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects. Alterations in HPA axis responsivity may therefore have a negative impact upon clinical outcome in alcohol-dependent subjects, and disinhibition of the axis with medication may have therapeutic potential.
doi:10.1097/01.ALC.0000176356.97620.84
PMCID: PMC2584966  PMID: 16088999
Adrenal Cortex; Alcoholism; Pituitary-Adrenal System; Naltrexone
12.  Hormonal contraceptive use diminishes salivary cortisol response to psychosocial stress and naltrexone in healthy women 
The use of hormonal contraception (HC) may affect salivary cortisol levels at rest and in response to a pharmacological or stress challenge. Therefore, the current study used a secondary data analysis to investigate the effect of HC on salivary cortisol levels in response to the mu-opioid receptor antagonist naltrexone and a psychosocial stressor, and also across the diurnal curve. Two hundred and nine women (n = 72 using hormonal contraception; HC+) completed a two-session stress response study that consisted of a stress day, in which they were exposed to public speaking and mental arithmetic, and a rest day, in which unstimulated cortisol levels were measured to assess the diurnal rhythm. A subset of seventy women (n = 24 HC+) also completed a second study in which they were administered oral naltrexone (50 mg) or placebo in a randomized, placebo-controlled, double blind fashion. Women who were HC+ had a significantly reduced salivary cortisol response to both the psychosocial stressor (p < 0.001) and naltrexone (p < 0.05) compared to HC− women. Additionally, HC+ women had a significantly altered morning diurnal cortisol rhythm (p < 0.01), with a delayed peak and higher overall levels. The results of the current study confirm that HC attenuates salivary cortisol response to a psychosocial stressor and mu-opioid receptor antagonism, and also alters the morning diurnal cortisol curve.
doi:10.1016/j.pbb.2013.05.007
PMCID: PMC3683955  PMID: 23672966
Hormonal Contraception; Cortisol; Stress; Diurnal Rhythm; Naltrexone; HPA axis
13.  Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: The role of stress and of antipsychotic treatment 
Schizophrenia research  2009;116(2-3):234-242.
First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60 min after awakening, and at 12 and 8 pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p < 0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.
doi:10.1016/j.schres.2009.08.013
PMCID: PMC3513410  PMID: 19751968
First-episode psychosis; Cortisol; Stress; Antipsychotic; Childhood trauma; HPA axis
14.  Bidirectional interactions between acute psychosocial stress and acute intravenous alcohol in healthy men 
Background
The biological mechanisms by which acute stress increases alcohol consumption are unclear. One potential mechanism is that stress acts by altering the pharmacological and subjective effects of alcohol. Acute stress produces a cascade of physiological and psychological effects, each with a distinctive time course. In this study, we investigated whether different phases of response to an acute stress alter the subjective effects of intravenous alcohol, by administering the drug at two different times after the stress.
Methods
Healthy men (N=25) participated in two sessions; one with the Trier Social Stress Test, the other with a non-stressful control task, each followed by infusions of intravenous alcohol (targeting 40mg% in 5 min) and placebo. One group of participants received alcohol within 1 min of completing the tasks (Alc0, N=11), followed by placebo 30 min later. In the other group (Alc30, N=14), the order of alcohol and placebo infusions was reversed. Subjective effects (i.e., Anxiety, Stimulation, Want more) and physiological measures (heart rate, blood pressure, salivary cortisol) were measured before and at repeated intervals after the tasks and infusions.
Results
Stress did not change the subjective effects of alcohol in either group. However, when individual differences in alcohol responses were considered, stress differentially altered the stimulant-like and sedative effects of alcohol. Among individuals who exhibited predominantly stimulant responses to alcohol in the non-stressful condition, stress decreased the stimulant-like effects of alcohol and ‘wanting more’. By contrast, among participants who did not report stimulation after alcohol in the control session, stress decreased the sedative effects and increased ‘want more’. In addition, alcohol administered immediately after the TSST dampened cortisol responses yet prolonged negative subjective responses to the stress.
Conclusions
These findings demonstrate that there are bi-directional relationships between alcohol and stress. Alcohol influences responses to stress, and stress changes reactions to alcohol, depending on an individual's pattern of response to alcohol. This study highlights the fact that stress-alcohol interactions vary among individual drinkers, suggesting that the effects of stress on motivation to drink alcohol may also differ between individuals.
doi:10.1111/j.1530-0277.2011.01522.x
PMCID: PMC3183385  PMID: 21762177
Acute stress; Trier Social Stress Test; Alcohol; Anxiety; Cortisol
15.  Time lag between peak concentrations of plasma and salivary cortisol following a stressful procedure in dairy cattle 
Background
Measurement of salivary cortisol has been used extensively as a non-invasive alternative to blood sampling to assess adrenal activity in ruminants. However, there is evidence suggesting a considerable delay in the transfer of cortisol from plasma into saliva. Previous studies in cattle have used long sampling intervals making it difficult to characterise the relationship between plasma and salivary cortisol (PLCort and SACort, respectively) concentrations at different time points and determine whether or not such a time lag exist in large ruminants. Therefore, the objective of this study was to characterise the relationship between plasma and salivary cortisol and determine if there is a significant time lag between reaching peak cortisol concentrations in plasma and saliva across a 4.25 h time-period, using short sampling intervals of 10–15 min, following social separation in dairy cattle.
Five cows were separated from their calves at 4 days after calving, and six calves were separated from a group of four peers at 8 weeks of age. Following separation, the animals were moved to an unfamiliar surrounding where they could not see their calves or pen mates. The animals were catheterised with indwelling jugular catheters 1 day before sampling. Blood and saliva samples were obtained simultaneously before and after separation.
Results
In response to the stressors, PLCort and SACort increased reaching peak concentrations 10 and 20 min after separation, respectively. This suggested a 10 min time lag between peak cortisol concentrations in plasma and saliva, which was further confirmed with a time-series analysis. Considering the 10 min time lag, SACort was strongly correlated with PLCort (P < 0.0001).
Conclusions
Salivary cortisol correlates well with plasma cortisol and is a good indicator of the time-dependent variations in cortisol concentrations in plasma following acute stress. However, there is a time lag to reach peak cortisol concentrations in saliva compared to those in plasma, which should be considered when saliva samples are used as the only measure of hypothalamic-pituitary-adrenal axis response to stress in cattle.
doi:10.1186/s13028-014-0061-3
PMCID: PMC4194406  PMID: 25297979
Calves; Cattle; Cortisol; Cows; Dairy; Plasma; Saliva; Stress
16.  Role of the HPA Axis and the A118G Polymorphism of the μ-Opioid Receptor in Stress-Induced Drinking Behavior 
Aims: The present study sought to investigate the relationship between the HPA axis reactivity to stress, the endogenous opioid system and stress-induced drinking behavior. Methods: In the present study, 74 non-treatment-seeking alcohol-dependent subjects were tested under two mood conditions, neutral and stress, in separate testing sessions. Salivary cortisol measurements were obtained following stress induction and during the neutral control condition. Multiple measurements of alcohol intake, latency to access the alcohol cue and craving for alcohol were obtained during cue-availability testing. In addition, 52 of the study subjects were genotyped for the μ-opioid receptor. Results: A blunted cortisol response to stress was significantly correlated with increased alcohol intake following stress exposure compared to alcohol intake during the neutral session. There was not a clear correlation between the change in cortisol in response to stress and the change in latency to access alcohol or alcohol craving in response to stress. Carriers of the Asp40 variant of the μ-opioid receptor exhibited a dampened cortisol response to stress, higher alcohol intake and greater craving in response to stress compared to Asn40 homozygotes, although these differences were not statistically significant. Conclusions: The results of the present study indicate that a blunted biological stress response was correlated with increased drinking in response to stress. The Asp40 variant of the μ-opioid receptor may be associated with this HPA axis hyporeactivity although the small sample size used in the present study did not permit adequate evaluation of this association.
doi:10.1093/alcalc/agp007
PMCID: PMC2732914  PMID: 19240053
17.  Response to CRH Infusion in Cocaine-Dependent Individuals 
Archives of general psychiatry  2009;66(4):422-430.
Context
Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal (HPA) axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration.
Objective
The primary objective was to examine the HPA axis, subjective and physiologic response to CRH in cocaine-dependent individuals and controls.
Design
Case-control study
Setting
Subjects were admitted to a General Clinical Research Center (GCRC) for testing and abstinence verified with urine drug screening.
Participants
Participants were control males (n=23), control females (n=24), cocaine-dependent males (n=28), and cocaine-dependent females (n=25). Individuals with dependence on other substances (except caffeine, nicotine) or with major depression, PTSD, bipolar, psychotic and eating disorders were excluded.
Intervention
Subjects received i.v. CRH (1ug/kg).
Main Outcome Measures
Primary outcomes included plasma ACTH and cortisol, heart rate, and subjective measurements.
Results
Cocaine-dependent individuals exhibited higher stress (P < 0.001) and craving to CRH compared to controls. A positive correlation (rs=.51, P=0.0002) between stress and craving was found in cocaine dependent subjects. CRH elevated heart rates in all groups, however cocaine dependent females, demonstrated a significantly higher heart rate at all time points (P=0.05). Women had higher cortisol response to CRH (P=0.028). No effect of cocaine status was observed. ACTH response to CRH was independent of gender and cocaine. Cortisol and ACTH were positively correlated in the controls and cocaine-dependent males, but not in cocaine-dependent females (rs = 0.199; P = 0.4).
Conclusion
There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in HPA axis response between the cocaine and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of non-hypothalamic stress-responsive CRH systems.
doi:10.1001/archgenpsychiatry.2009.9
PMCID: PMC2696287  PMID: 19349312
18.  An acute psychosocial stressor does not potentiate alcohol cue reactivity in non-treatment-seeking alcoholics 
Background
Relapse risk factors, such as psychological stress and alcohol cues, are often encountered together. Understanding how they interact has the potential to improve alcoholism treatments. The present study was conducted to examine whether an acute psychosocial stressor enhanced alcohol cue reactivity in non-treatment-seeking alcoholics.
Methods
Seventy-nine alcohol dependent individuals (39 women) randomly received either the Trier Social Stress Test or a no-stress control condition. Stress reactivity was measured with serum ACTH and cortisol, mean arterial blood pressure, and subjective distress. Immediately following the stress manipulation, participants held and sniffed a neutral cue then their preferred alcoholic beverage. Cue reactivity was measured by two subjective measures of craving following each cue. Additionally, general craving was assessed with the Alcohol Urge Questionnaire (AUQ) at the beginning and end of the laboratory procedure.
Results
The stress manipulation showed internal validity on all measures of stress reactivity. There was not a main effect of stress nor a stress x cue interaction on either cue reactivity measure. As expected, there was a main effect of cue (alcohol > neutral cue) on both measures of cue reactivity. General craving increased during the challenge, but not differently by stress group. Magnitude of stress reactivity was not associated with magnitude of cue reactivity, and all results were independent of gender.
Conclusion
In this well-controlled clinical laboratory study of non-treatment-seeking alcoholics, an acute psychological stressor did not make an alcohol cue a more potent urge-inducing stimulus, and stress had no effect on general alcohol craving.
doi:10.1111/j.1530-0277.2010.01363.x
PMCID: PMC3117919  PMID: 21143244
alcohol; stress; craving; cue reactivity; gender
19.  Burnout and Hypocortisolism – A Matter of Severity? A Study on ACTH and Cortisol Responses to Acute Psychosocial Stress 
Background: Common consequences of long-term psychosocial stress are fatigue and burnout. It has been suggested that burnout could be associated with hypocortisolism, thus, inability to produce sufficient amounts of cortisol. This study aimed to investigate whether patients with clinical burnout exhibit aberrant ACTH and cortisol responses under acute psychosocial stress compared with healthy individuals.
Methods: Nineteen patients (9 men and 10 women) and 37 healthy subjects (20 men and 17 women), underwent the Trier Social Stress Test. Blood samples and saliva samples were collected before, after, and during the stress test for measurements of plasma ACTH, serum cortisol, and salivary cortisol. Several statistical analyses were conducted to compare the responses between patients and controls. In addition, in order to investigate the possibility that burnout patients with more severe symptoms would respond differently, sub-groups of patients reporting higher and lower burnout scores were compared.
Results: In both patients and healthy controls, we observed elevated levels of ACTH and cortisol after exposure to the stressor. There were no differences in responses of ACTH, serum cortisol, or salivary cortisol between patients and controls. Patients reporting higher burnout scores had lower salivary cortisol responses than controls, indicating that patients with more severe burnout symptoms may be suffering from hypocortisolism. In addition, patients with more severe burnout symptoms tended to have smaller ACTH responses than the other patients. However, there was no corresponding difference in serum cortisol.
Conclusion: This study indicates that hypocortisolism is not present in a clinical burnout patient group as a whole but may be present in the patients with more severe burnout symptoms.
doi:10.3389/fpsyt.2015.00008
PMCID: PMC4313581
chronic stress; burnout; Trier Social Stress Test; acute stress response; adrenocorticotropic hormone; cortisol; hypocortisolism
20.  Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats 
Drug and Alcohol Dependence  2011;121(3):240-246.
Background
Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.
Methods
Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone+light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug+cues to reinstate nicotine-seeking.
Results
Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests.
Conclusions
These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.
doi:10.1016/j.drugalcdep.2011.09.001
PMCID: PMC3258537  PMID: 21945235
female; nicotine; self-administration; reinstatement; relapse; yohimbine
21.  A Preliminary Study on the Effect of Combined Nicotine Replacement Therapy on Alcohol Responses and Alcohol Self-administration 
Background and Objectives
Limiting alcohol consumption may help prevent alcohol-mediated smoking relapse in heavy drinking smokers. This pilot study examined whether combining a nicotine patch with nicotine nasal spray has stronger attenuating effects on alcohol response and consumption than a nicotine patch alone.
Methods
Twenty-two non-alcohol dependent heavy drinking smokers completed the double-blind cross-over, placebo-controlled study (21mg nicotine patch + nicotine or placebo nasal spray). Six hours after 21mg nicotine patch application, subjective and physiological responses to a priming drink (0.3 g/kg) were assessed, followed by two 1-hr alcohol self-administration periods, with possible consumption of up to 4 drinks per period (each 0.15 g/kg). Nasal spray (1 mg [active] or 0 mg [placebo] per dose) was administered 10 min prior to the priming dose and each self-administration period.
Results
Active nasal spray did not increase serum nicotine levels, compared with placebo administration. The number of drinks consumed did not differ by the nasal spray conditions. However, positive subjective responses to the priming drink were lower in the active nasal spray condition than the placebo nasal spray condition. During the self-administration period, urge to drink was also lower in the active spray condition than the placebo condition.
Conclusions and Scientific Significance
Augmenting the nicotine patch with nicotine nasal spray attenuated positive subjective alcohol response and craving and suggests that future studies should investigate whether these findings translate to a clinical setting.
doi:10.1111/j.1521-0391.2013.12014.x
PMCID: PMC3934424  PMID: 24131167
Combined nicotine replacement therapy; alcohol self-administration; heavy drinkers; alcohol response; craving
22.  Transdermal Nicotine Administration and the Electroencephalographic Activity of Substance Abusers in Treatment 
Journal of addiction medicine  2008;2(4):202-214.
Objectives
It is widely recognized that individuals with alcohol or illicit substance abuse disorders often smoke cigarettes. However, few studies have examined the direct effects of nicotine among substance abuse subgroups. The current study examined patterns of electroencephalographic (EEG) activity in alcohol-dependent (AD), stimulant-dependent (StimD), alcohol- and stimulant-dependent (ASD) participants, as well as community controls (CC). All participants were regular smokers.
Methods
After overnight nicotine abstinence, subjects were administered either a high (14 or 21 mg) or low (7mg) dose transdermal nicotine patch. EEG data were collected during a 2 minute eyes open and 5 minute eyes closed baseline recording session, which occurred as part of a larger study of brain electrophysiology.
Results
The most interesting finding was a differential pattern of nicotine dose effects by group. EEGs of Controls and ASD participants did not distinguish between high and low nicotine doses; whereas, nicotine administration in the AD and StimD groups resulted in opposite findings across a range of spectral bands.
Conclusions
Although further research is warranted, these results may have implications for the study of smoking cessation and attentional functioning among substance abusers in treatment. These data suggest that nicotine–related changes in neurophysiology may be associated with specific brain areas and/or specific drug histories and reinforce the need for caution in generalizing among such groups.
PMCID: PMC2665044  PMID: 19347067
Nicotine; Alcohol; Cocaine; Methamphetamine; Electroencephalogram
23.  GENE AND GENE BY SEX ASSOCIATIONS WITH INITIAL SENSITIVITY TO NICOTINE IN NONSMOKERS 
Behavioural pharmacology  2008;19(5-6):630-640.
Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 μg/kg) was administered via nasal spray followed by mood, nicotine reward (e.g. “liking”) and perception (e.g. “feel effects”) measures, physiological responses, sensory processing (pre-pulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine vs. placebo spray choice procedure. For the dopamine D4 receptor (DRD4 VNTR), presence of the 7 repeat allele was associated with greater aversive responses to nicotine (decreases in “vigor”, positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased “feel effects” and greater startle response, but in men only. Also observed in men but not women were other genetic associations, such as greater “feel effects” and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T SNP) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3’ VNTR (SLC6A3), and the mu opioid receptor A118G SNP (OPRM1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine prior to the onset of dependence and may do so differentially between men and women.
doi:10.1097/FBP.0b013e32830c3621
PMCID: PMC2743299  PMID: 18690117
nicotine; sensitivity; genetics; dopamine; reward; reinforcement
24.  Association of Smoking with Mu- Opioid Receptor Availability Before and During Naltrexone Blockade in Alcohol-Dependent Subjects 
Addiction biology  2012;10.1111/adb.12022.
Persons with a history of alcohol dependence are more likely to use tobacco and to meet criteria for nicotine dependence compared to social drinkers or nondrinkers. The high levels of comorbidity of nicotine and alcohol use and dependence are thought to be related to interactions between nicotinic, opioid and dopamine receptors in mesolimbic regions. The current study examined whether individual differences in regional mu-opioid receptor (MOR) availability were associated with tobacco use, nicotine dependence, and level of nicotine craving in 25 alcohol dependent (AD) subjects. AD subjects completed an inpatient protocol, which included medically supervised alcohol withdrawal, monitored alcohol abstinence, transdermal nicotine maintenance (21 mg/day), and Positron Emission Tomography (PET) imaging using the MOR agonist [11C]-carfentanil (CFN) before (basal scan) and during treatment with 50 mg/day naltrexone (naltrexone scan). Subjects who had higher scores on the Fagerström Nicotine Dependence Test had significantly lower basal scan binding potential (BPND) across mesolimbic regions including the amygdala, cingulate, globus pallidus, thalamus and insula. Likewise, the number of cigarettes per day was negatively associated with basal scan BPND in mesolimbic regions Higher nicotine craving was significantly associated with lower BPND in amygdala, globus pallidus, putamen, thalamus and ventral striatum. Although blunted during naltrexone treatment, the negative association was maintained for nicotine dependence and cigarettes per day, but not for nicotine craving. These findings suggest that intensity of cigarette smoking and severity of nicotine dependence symptoms are systematically related to reduced BPND across multiple brain regions in AD subjects.
doi:10.1111/adb.12022
PMCID: PMC3638047  PMID: 23252742
mu opioid receptors; nicotine; alcoholism; dependence; PET imaging; humans
25.  Acute Stress and Nicotine Cues Interact to Unveil Locomotor Arousal and Activity-Dependent Gene Expression in the Prefrontal Cortex 
Biological psychiatry  2006;61(1):127-135.
Background:
This study examines the interactive effects of acute stress and nicotine-associated contextual cues on locomotor activity and activity-dependent gene expression in subregions of the prefrontal cortex.
Methods:
Locomotor activity of rats was measured in a context associated with either low-dose nicotine or saline administration with or without 5 minutes of pre-exposure to ferrets, a nonphysical stressor. After 45 minutes in the test environment, plasma corticosterone levels and mRNA levels of the immediate-early genes Arc, NGFI-B, and c-Fos in prefrontal and primary motor cortical subregions were measured.
Results:
Stress alone increased plasma corticosterone and prefrontal cortex gene expression. Low-dose nicotine cues had no effect on corticosterone levels nor did they elicit conditioned motor activation, and they caused minor elevations in gene expression. Stress and low-dose nicotine cues, however, interacted to elicit conditioned motor activation and further increases in early response gene expression in prefrontal but not in the primary motor cortical subregions.
Conclusions:
Stress interacts with nicotine-associated cues to uncover locomotor arousal, a state associated with prefrontal neuronal activation and immediate early gene expression. Thus, in nicotine-experienced individuals, stress may be an important determinant of subjective reactivity and prefrontal cortex activation that occurs in response to nicotine-associated cues.
doi:10.1016/j.biopsych.2006.03.002
PMCID: PMC1698504  PMID: 16631128
Addiction; relapse; reinstatement; craving; cigarette; imaging

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