Emma Childs

Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

Caffeine produces mild psychostimulant and sometimes anxiogenic effects by antagonizing adenosine at A1 and A2A receptors, and perhaps through interactions with other transmitter systems. Adenosine receptors are colocalized and functionally interact with dopamine receptors in the brain. Thus, functional polymorphisms in the genes for either adenosine or dopamine receptors may affect responses to caffeine. In this study, we examined associations between self-reported anxiogenic effects of caffeine and variation in the genes for A2A (ADORA2A) and DRD2 (DRD2) receptors. Healthy male and female individuals (n=102), who consumed less than 300 mg caffeine per week, ingested capsules containing 0, 50, 150, and 450 mg caffeine under double-blind conditions in four separate experimental sessions. Subjective anxiety was measured before and at repeated times after capsules were consumed. At the 150 mg dose of caffeine, we found a significant association between caffeine-induced anxiety (Visual Analog Scales, VAS) and ADORA2A rs5751876 (1976C/T), rs2298383 (intron 1a) and rs4822492 (3′-flank), and DRD2 rs1110976 (intron 6). Caffeine-induced anxiety (VAS) was also associated with two-loci interactions of selected ADORA2A and DRD2 polymorphisms. The lowest dose of caffeine did not increase ratings of anxiety while the highest dose increased anxiety in the majority of subjects. These findings provide support for an association between an ADORA2A polymorphism and self-reported anxiety after a moderate dose of caffeine. It is likely that other ADORA2A and DRD2 polymorphisms also contribute to responses to caffeine.

Acute Stress Increases Circulating Anandamide and Other N-Acylethanolamines in Healthy Humans

Stress plays an important role in psychiatric disorders, and preclinical evidence indicates that the central endocannabinoid system modulates endocrine and neuronal responses to stress. This study aimed to investigate the effect of acute stress on circulating concentrations of endocannabinoids (eCBs) in healthy humans. A total of 71 adults participated in two sessions in which they were exposed to either a standardized psychosocial stress procedure (Trier Social Stress Test) or a control task. Blood samples for eCB and cortisol assays and cardiovascular and subjective measures were obtained before and at regular intervals after the tasks. Serum concentrations of the eCBs, N-arachidonylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), as well as of the N-acylethanolamides (NAEs), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA), and of the O-acylglycerol, 2-oleoylglycerol (2-OG), were determined. Compared with the control condition, stress increased serum concentrations of AEA and the other NAEs immediately after the stress period. Increases in PEA were positively correlated with increases in serum cortisol after stress. Furthermore, anxiety ratings at baseline were negatively correlated with baseline concentrations of AEA. The sex and menstrual cycle status of the subject affected the NAE responses to stress. Interestingly, subjects of Asian and African-American races exhibited different patterns of stress responses compared with the Caucasian subjects. These results indicate that stress increases circulating NAEs in healthy human volunteers. This finding supports a protective role for eCBs in anxiety. Further research is needed to elucidate the function of these lipid mediators, and to determine the mechanisms that regulate their appearance in the circulation.

Hormonal, cardiovascular, and subjective responses to acute stress in smokers.

RationaleThere are complex relationships between stress and smoking; smoking may reduce the emotional discomfort of stress, yet nicotine activates stress systems and may alter responses to acute stress. It is important to understand how smoking affects physiological and psychological outcomes after stress and how these may interact to motivate smoking.ObjectivesThis study aimed to examine the magnitude and time course of hormonal, cardiovascular, and psychological responses to acute psychosocial stress in smokers and non-smokers to investigate whether responses to acute stress are altered in smokers.Materials and methodsHealthy male non-smokers (n = 20) and smokers (n = 15) participated in two experimental sessions involving a standardized public speaking stress procedure and a control non-stressful task. The outcome measures included self-reported mood, cardiovascular measures (heart rate and blood pressure), and plasma hormone levels (noradrenaline, cortisol, progesterone, and allopregnanolone).ResultsSmokers exhibited blunted increases in cortisol after the Trier Social Stress Test, and they reported greater and more prolonged subjective agitation than non-smokers. Stress-induced changes in progesterone were similar between smokers and non-smokers, although responses overall were smaller among smokers. Stress did not significantly alter levels of allopregnanolone, but smokers exhibited lower plasma concentrations of this neurosteroid.ConclusionsThese findings suggest that smoking dampens hormonal responses to stress and prolongs subjective discomfort. Dysregulated stress responses may represent a breakdown in the body’s ability to cope efficiently and effectively with stress and may contribute to smokers’ susceptibility to acute stress, especially during abstinence.

Amphetamine-induced place preference in humans

BACKGROUND The conditioned place preference procedure is a widely used animal model of rewarding drug effects that, to date, has not been tested in humans. In this study, we sought to demonstrate that humans, like nonhumans, would exhibit a preference for a place previously associated with amphetamine. Further, we investigated the relationship between conditioned place preference and the mood-altering effects of the drug. METHODS Thirty-one healthy individuals participated in a five-session procedure during which they experienced the effects of d-amphetamine (20 mg) or placebo on two occasions in two distinctive environments (sessions 1-4). One group of subjects (paired group, n = 19) received amphetamine consistently in one room and placebo in another room, whereas a second group (unpaired group, n = 12) received amphetamine and placebo without regard to room. During the sessions, participants completed questionnaires to rate their mood. On the fifth session, they rated their preference for the two rooms. RESULTS Individuals in the paired group rated their liking of the amphetamine-paired room significantly higher than the placebo-associated room, whereas there was no difference between ratings of the two rooms for individuals in the unpaired group. In the paired group, drug-liking ratings during the conditioning sessions positively predicted preference for the drug-associated room, whereas reports of amphetamine-induced anxiety and dysphoria negatively predicted room-liking scores. CONCLUSIONS This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.

Effects of acute psychosocial stress on cigarette craving and smoking.

INTRODUCTION Stress is thought to influence use of drugs, including cigarette smoking, but the mechanisms by which it does so are not clear. In this study, we investigated the effects of acute psychosocial stress on cigarette craving, the subjective effects of smoking, and smoking behavior in daily smokers. METHODS Healthy male and female smokers participated in two experimental sessions in which they were exposed to the Trier Social Stress Test or a nonstressful control task. For 2 hr after each task, they had repeated opportunities to either smoke or earn money. Physiological (heart rate, cortisol, and alpha-amylase) and subjective (anxiety and desire to smoke) measures were obtained before and after the tasks and after each smoking opportunity. RESULTS Stress significantly increased cigarette craving but it did not increase smoking. When individual differences in nicotine dependence were taken into account, stress influenced CO boost and pleasure from smoking the first cigarette. DISCUSSION Our results support previous evidence that acute psychosocial stress increases smoking desire.

Cardiovascular, hormonal, and emotional responses to the TSST in relation to sex and menstrual cycle phase.

The prevalence of stress disorders differs between men and women. An understanding of how men and women vary in acute stress responses may help to understand these sex differences. We compared responses to the TSST and a control task in healthy men (N=28) and women tested in two phases (Follicular N=29, Luteal N=23) of the menstrual cycle. Men exhibited greater cortisol responses to stress than women in either phase. Luteal women exhibited the greatest subjective and allopregnanolone responses to stress, whereas follicular women exhibited blunted noradrenaline responses. Partial correlations controlling for group differences revealed that individuals who were most sensitive to the subjective effects of stress exhibited the largest salivary cortisol, noradrenaline, and allopregnanolone responses and the smallest progesterone responses to stress. We discuss our findings in the context of sex differences in the prevalence of stress-linked disorders.

Enhanced mood and psychomotor performance by a caffeine-containing energy capsule in fatigued individuals.

Caffeine produces mild psychostimulant effects that may be particularly evident in individuals whose mood or performance is impaired by sleep restriction or caffeine withdrawal. Caffeinated energy drinks have been shown to improve energy and cognition but expectancy effects cannot be ruled out in these studies. Very few studies have examined the effects of caffeine-containing energy capsules upon behavioral and subjective measures. This study compared the effects of a caffeine-containing (200 mg) supplement (CAF) or placebo in capsule form after prolonged wakefulness, in participants who varied in their level of habitual caffeine use. Thirty-five healthy volunteers (16 male, 19 female) participated in two experimental sessions in which they remained awake between 5 p.m. and 5 a.m. At 3:30 a.m. they consumed CAF or placebo in random order under double-blind conditions. Participants completed subjective effects questionnaires and performed computerized attention tasks before and after consuming capsules. Heart rate and blood pressure were monitored at regular intervals. Compared to measures at 5 p.m., participants reported more tiredness and mood disturbance at 3 a.m., and exhibited longer reaction times and more attentional lapses. Heavier caffeine consumers exhibited the greatest decreases in Profile of Mood States (POMS) Vigor. CAF produced stimulant-like effects and significantly improved mood and reaction times upon the tasks. These effects did not vary with level of habitual caffeine consumption. These findings indicate that consumption of a caffeine-containing food supplement improves subjective state and cognitive performance in fatigued individuals that is likely a result of its caffeine content.

Role of training dose in drug discrimination: a review.

Drug discrimination has been an important technique in behavioural pharmacology for at least 40 years. The characteristics of drug-produced discriminative stimuli are influenced by behavioural and pharmacological variables, including the doses used to establish discriminations. This review covers studies on the effects of varying the training dose of a drug in a search for general principles that are applicable across different drug classes and methodological approaches. With respect to quantitative changes, relationships between training dose and the rate of acquisition or magnitude of stimulus control were found for most drug classes. Acquisition accelerated with dose up to a point beyond which drug-induced impairments of performance had a deleterious impact. Sensitivity to the training drug as measured by ED50 values typically increased when the training dose was reduced. Qualitative changes were more complex and appeared to fall into three categories: (a) changes in profiles of generalization between partial and full agonists; (b) reduced specificity of some discriminations at small training doses; and (c) changes in the relative salience of actions mediated through different neurotransmitter systems or from central and peripheral sites. Three-lever discrimination procedures incorporating ‘drug versus drug’ or ‘dose versus dose’ contingencies enabled detection of more subtle differences than the simple ‘drug versus no drug’ approach when applied to the opioid, hallucinogen and barbiturate classes of drugs. These conclusions have implications for the interpretation of data from studies that use either within-subject or between-subject designs for studying the discriminative stimulus effects of drugs.

Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements.

BACKGROUND Varenicline (VAR) is a partial nicotinic receptor agonist that is an effective smoking cessation medication. Preliminary evidence indicates that it may also reduce alcohol consumption, but the underlying mechanism is not clear. For example, VAR may reduce alcohol consumption by attenuating its subjectively rewarding properties or by enhancing its aversive effects. In this study, we examined the effects of an acute dose of VAR upon subjective, physiological, and objective responses to low and moderate doses of alcohol in healthy social drinkers. METHODS Healthy men and women (N = 15) participated in 6 randomized sessions; 3 sessions each with 2 mg VAR and placebo (PL) followed 3 hours later by a beverage containing PL, low-dose alcohol (0.4 g/kg), or high-dose alcohol (0.8 g/kg). Subjective mood and drug effects (i.e., stimulation, drug liking), physiological measures (heart rate, blood pressure), and eye tracking tasks were administered at various intervals before and after drug and alcohol administration. RESULTS VAR acutely increased blood pressure, heart rate, ratings of dysphoria and nausea, and also improved eye tracking performance. After alcohol drinking (vs. PL), VAR increased dysphoria and tended to reduce alcohol liking ratings. It also attenuated alcohol-induced eye-tracking impairments. These effects were independent of the drugs effects on nausea before drinking. CONCLUSIONS Our data support the theory that VAR may reduce drinking by potentiating aversive effects of alcohol. VAR also offsets alcohol-induced eye movement impairment. The evidence suggests that VAR may decrease alcohol consumption by producing effects, which oppose the rewarding efficacy of alcohol.

Effects of acute progesterone administration upon responses to acute psychosocial stress in men.

Animal studies suggest that neuroactive steroids, in particular progesterone and its metabolites, have stress-dampening effects. However, few studies have explored these effects in humans. In this study, we investigated the effects of acute progesterone administration on responses to the Trier Social Stress Test (TSST). Healthy men participated in the TSST 3.5 hrs after intramuscular injection of 0, 50, or 100 mg progesterone (N = 16, 14, and 14). We measured cardiovascular (heart rate, blood pressure), hormonal (plasma adrenocorticotrophic hormone, cortisol, and noradrenaline), and subjective (e.g., anxiety, arousal) responses to stress in the three groups. Before the TSST, progesterone injections increased plasma levels without altering physiological or subjective states. Stress produced its expected physiological and subjective effects among placebo-treated individuals. Progesterone 50 mg attenuated peak increases in plasma cortisol and reduced changes in negative mood and alertness after stress, yet it increased plasma noradrenaline and systolic blood pressure. Progesterone 100 mg also attenuated stress-induced increases in alertness and arousal, yet it potentiated stress-induced increases in diastolic pressure. Thus, progesterone dampened some of the psychological effects of stress but produced inconsistent effects on physiological stress responses.