Biomedical subjects

Harriet de Wit

Publications and source records attributed to Harriet de Wit.

At least 19 recordsLinked to original sources

PubMed2006

Preference for immediate over delayed rewards is associated with magnitude of ventral striatal activity.

Discounting future outcomes as a function of their deferred availability underlies much of human decision making. Discounting, or preference for immediate over delayed rewards of larger value, is often associated with impulsivity and is a risk factor for addictive disorders such as pathological gambling, cigarette smoking, and drug and alcohol abuse. The ventral striatum (VS) is involved in mediating behavioral responses and physiological states associated with reward, and dysregulation of the VS contributes to addiction, perhaps by affecting impulsive decision-making. Behavioral tests of delay discounting (DD), which index preference for smaller immediate over larger delayed rewards, covary with impulsive tendencies in humans. In the current study, we examined the relationship between individual differences in DD, measured in a behavioral assessment, and VS activity measured with blood oxygenation level-dependent functional magnetic resonance imaging, in 45 adult volunteers. VS activity was determined using a task involving positive and negative feedback with monetary reward. Analyses revealed that individual differences in DD correlate positively with magnitude of VS activation in response to both positive and negative feedback, compared with a no-feedback control condition. Variability in DD was also associated with differential VS activation in response to positive, compared with negative, feedback. Collectively, our results suggest that increased preference for smaller immediate over larger delayed rewards reflects both a relatively indiscriminate and hyper-reactive VS circuitry. They also highlight a specific neurocognitive mechanism that may contribute to increased risk for addiction.

Adult↗

PubMed2006

An association study of the brain-derived neurotrophic factor Val66Met polymorphism and amphetamine response.

Although genetic factors are known to be important in addiction, no candidate genes have yet been consistently linked to drug use or abuse. Brain-derived neurotrophic factor (BDNF), which has been implicated in the behavioral response to psychomotor stimulants and potentiates neurotransmitters that are strongly linked to addiction, is a logical candidate gene to study. Using a drug challenge approach, we tested for association between BDNF G196A (val66met) genotype and subjective responses to amphetamine (AMPH). Healthy volunteers participated in a double blind, crossover design in which they received placebo, 10 mg, and 20 mg oral d-amphetamine in random order. Subjective and physical responses to ingestion of AMPH were measured at 30-min intervals after drug ingestion. Each subject was genotyped for the BDNF G196A polymorphism and grouped and analyzed accordingly. The effects of AMPH on ratings of arousal, energy, and heart rate were compared in subjects with the val/val genotype (N = 67) and the subjects with either the val/met or met/met genotypes (N = 32). AMPH produced less pronounced self-ratings of arousal and energy, yet higher increases in heart rate, in the val/met and met/met compared to the val/val group. These results suggest that BDNF is related to the subjective and physical response to low doses of AMPH.

Adult↗

PubMed2006

Cortisol effects of D-amphetamine relate to traits of fearlessness and aggression but not anxiety in healthy humans.

UNLABELLED: The current study utilized personality measures thought to relate to noradrenergic and catecholamine function (i.e., sensation seeking, anxiety and aggression) to investigate individual differences in amphetamine-induced increases in cortisol. The goal of the study was to better understand variations in responses to psychostimulants in healthy volunteers. METHOD: A placebo-controlled within-subjects investigation of salivary cortisol responses to oral D-amphetamine (20 mg) was conducted in seventy (N=70) young adults. Personality traits were assessed using the Eysenck Personality Inventory (EPI), Sensation Seeking Scale Form V (SSS-V) and the Multidimensional Personality Questionnaire-Brief Form (MPQ-BF). RESULTS: A more rapid rise in salivary cortisol after d-amphetamine was associated with SSS-V Thrill Seeking (r=-0.32 with time to peak, p<0.05). A greater peak increase in cortisol and a greater recovery after amphetamine was positively associated with MPQ-BF Aggression (r=+0.35, p<0.05; r=+0.38, p<0.05). In contrast, cortisol responses were unrelated to a composite measure of trait anxiety (EPI/MPQ-BF Anxiety Index). CONCLUSIONS: The findings suggest that the personality traits of aggression and thrill seeking are related to cortisol responses to d-amphetamine, raising the possibility that personality may predispose certain individuals to use drugs through a glucocorticoid pathway. The data also suggest a distinction between fear and anxiety, as amphetamine-induced cortisol responses were associated with measures of trait fear but not measures of trait anxiety in the current sample.

Adolescent↗

PubMed2006

Does stress reactivity or response to amphetamine predict smoking progression in young adults? A preliminary study.

Recent studies with laboratory animals indicate that a constellation of behavioral factors predict progression to self-administer drugs. Relatively little is known about behavioral or biological factors that predict the progression in drug use from initial experimentation to regular use in human drug users. The present exploratory study examined reactivity to an acute stressor and reactivity to a single dose of a dopaminergic drug as predictors in progression to heavier smoking in young cigarette smokers over a 6-month period. Forty-four college students who were light to moderate smokers participated in three laboratory sessions, followed by a follow-up interview 6 months later to determine smoking level. On one of the laboratory sessions subjects underwent the Trier Social Stress Test, and on the others they ingested capsules containing placebo or 20 mg D-amphetamine. Outcome measures included subjective ratings of mood and measures of heart rate and salivary cortisol. We found modest positive relationships between stress reactivity and certain responses to amphetamine. Further, stress-induced increases in cortisol were positively related to increases in cigarette smoking in the 31 subjects who we were able to contact at 6 months. Although these results are highly preliminary, they resemble the relationships previously reported in laboratory animals, suggesting that some of the same factors that predict drug-self-administration in rodents predict progression in drug use among young adults.

Adolescent↗

PubMed2006

Nucleus accumbens lesions decrease sensitivity to rapid changes in the delay to reinforcement.

Both humans and non-humans discount the value of rewards that are delayed or uncertain, and individuals that discount delayed rewards at a relatively high rate are considered impulsive. To investigate the neural mechanisms that mediate delay discounting, the present study examined the effects of excitotoxic lesions of the nucleus accumbens (NAC) on discounting of reward value by delay and probability. Rats were trained on delay (n=24) or probability discounting (n=24) tasks. Following training, excitotoxic lesions of the NAC were made by intracranial injections of 0.5 microl 0.15 M quinolinic acid (n=12) or vehicle (n=12) aimed at the NAC (AP +1.6, ML +/-1.5, DV -7.1). NAC lesions did not alter performance in animals tested with a constant delay (4s) or probability (0.4) of reinforcement. However, when tested with between session changes in the delay (0, 1, 2, 4, and 8s) of reinforcement, the lesioned rats had flatter discount curves than the sham group, indicating that they were less sensitive to frequent changes in the delay to reward. In contrast, the NAC lesions did not affect discounting of probabilistic rewards. NAC lesions impaired the ability to adapt to frequent between session changes in the delay to reward but did not increase or decrease discounting when the delay was held constant across sessions. NAC lesions may disrupt the ability of the animals to predict the timing of delayed rewards when the delay to reward is changed frequently.

Animals↗

PubMed2006

Differential effects of nicotine on alcohol consumption in men and women.

RATIONALE: Nicotine and alcohol are frequently co-used, suggesting that use of one drug may facilitate use of the other. Furthermore, because men and women differ in their responses to both drugs, it is possible that men and women also differ in their responses to the combination of nicotine and alcohol. OBJECTIVE: This experiment was designed to investigate the effects of nicotine on consumption and subjective and physiological effects of alcohol in healthy male and female social drinkers. MATERIALS AND METHODS: Healthy light smoking, social drinkers (22 men and 12 women) participated in a three-session, double-blind within-subject study. They were pretreated with transdermal nicotine (7 or 14 mg) or placebo, followed two h later by an alcoholic beverage, and subsequent opportunities to "purchase" and consume more of the same drink. Outcome measures included the number of alcoholic beverages consumed and subjective and physiological effects. RESULTS: Nicotine increased alcohol consumption in men, whereas it decreased alcohol consumption in women. These effects were even more pronounced after excluding participants reporting nausea after nicotine administration. Nicotine alone increased subjective arousal in men but decreased positive mood in women. Nicotine increased the sedative-like effects of alcohol in both sexes. CONCLUSIONS: These findings indicate that both the subjective effects of nicotine and the effects of nicotine on alcohol consumption differ markedly in men and women. The findings extend existing data on sex differences in the effects of either nicotine or cigarette smoking on alcohol consumption, and support the idea that the pharmacological effects of nicotine may differ in men and women.

Adult↗

PubMed2006

Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users.

RATIONALE: Caffeine produces mild psychostimulant effects that are thought to underlie its widespread use. However, the direct effects of caffeine are difficult to evaluate in regular users of caffeine because of tolerance and withdrawal. Indeed, some researchers hypothesize that the psychostimulant effects of caffeine are due largely to the reversal of withdrawal and question whether there are direct effects of caffeine consumption upon mood, alertness, or mental performance in nondependent individuals. OBJECTIVE: This study investigated the physiological, subjective, and behavioral effects of 0, 50, 150, and 450 mg caffeine in 102 light, nondependent caffeine users. METHODS: Using a within-subjects design, subjects participated in four experimental sessions, in which they received each of the four drug conditions in random order under double blind conditions. Participants completed subjective effects questionnaires and vital signs were measured before and at repeated time points after drug administration. Forty minutes after the capsules were ingested, subjects completed behavioral tasks that included tests of sustained attention, short-term memory, psychomotor performance, and behavioral inhibition. RESULTS: Caffeine significantly increased blood pressure, and produced feelings of arousal, positive mood, and high. Caffeine increased the number of hits and decreased reaction times in a vigilance task, but impaired performance on a memory task. CONCLUSION: We confirm that acute doses of caffeine, at levels typically found in a cup of coffee, produce stimulant-like subjective effects and enhance performance in light, nondependent caffeine users. These findings support the idea that the drug has psychoactive effects even in the absence of withdrawal.

Adolescent↗

PubMed2006

Acute-alcohol effects on the Experiential Discounting Task (EDT) and a question-based measure of delay discounting.

Alcohol is widely believed to increase impulsive behavior. However, this has been difficult to demonstrate for impulsive choice using existing measures of delay discounting. We hypothesized a new real-time discounting task would be more sensitive to acute effects of alcohol. Measures included were a (a) question-based measure of delay discounting, the (b) Experiential Discounting Task (EDT), the (c) Balloon Analogue Risk Task (BART), the (d) Stop Task, and the (e) Go/No-Go Task. A three-session, double-blind, placebo-controlled, within-subjects design was used. Placebo, 0.4, or 0.8 g/kg alcohol doses were administered in a counterbalanced order over the three testing sessions. Twenty four (13 females) healthy social drinkers between the ages of 21 and 35 participated. Alcohol increased impulsive responding only on the EDT and the Stop Task. On the EDT, participants performed more impulsively after the 0.8 g/kg dose compared to placebo, whereas on the Stop Task, both the 0.4 and 0.8 g/kg doses increased impulsive responding. Alcohol had no significant effects on the other measures. The EDT was more sensitive to the acute effects of alcohol than previously used discounting tasks. Procedural differences between the EDT and question-based measures are discussed in the context of these divergent findings.

Adult↗

PubMed2006

Menstrual cycle phase and responses to drugs of abuse in humans.

Researchers have recently become aware of the importance of including women in research, including drug abuse research. With this increased awareness has come an increased scientific interest in the potential influence of menstrual cycle phase on responses to drugs. In this review, we discuss recent studies that have examined subjective and physiological responses to drugs of abuse in relation to menstrual cycle phase. With most of the drugs reviewed, including alcohol, benzodiazepines, caffeine, marijuana, nicotine and opioids, responses to the drugs were not different were inconsistent across cycle phases. However, with psychomotor stimulant drugs, such as amphetamine and cocaine, responses to the drugs were greater during the follicular, compared to the luteal, phase of the cycle. These findings suggest that, consistent with certain pre-clinical findings, circulating levels of ovarian hormones influence the central effects of stimulant drugs in women. With other drugs, the evidence to date suggests that ovarian hormones have modest, if any, effects on responses to abused drugs. We discuss methodological issues relating to inclusion of women with regular menstrual cycles.

Central Nervous System Stimulants↗

PubMed2006

Diazepam impairs behavioral inhibition but not delay discounting or risk taking in healthy adults.

There are reports that diazepam can increase, decrease, or have no effect on measures of impulsive behavior, which may be related, in part, to differences among the tasks used to measure impulsivity. This study examined the effects of a relatively high dose of diazepam (20 mg) on 5 measures of impulsive behavior in healthy adult men and women. Volunteers (N = 18) participated in a 2-session double-blind randomized design in which they received 20 mg diazepam or placebo. One hour after ingesting the capsule, participants completed mood questionnaires and several impulsivity tasks to measure subtypes of impulsive behavior, including behavioral inhibition, delay and probability discounting, and risk taking. Diazepam impaired behavioral inhibition but had no effect on measures of discounting or risk taking. These results are discussed in the context of other recent findings suggesting that different behavioral indices of impulsivity are dissociable and governed by separate underlying mechanisms.

Adolescent↗

PubMed2006

Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine.

Animal models suggest that the casein kinase 1 epsilon gene (Csnk1e) contributes to variability in stimulant response. Csnk1e is a key component in the Darpp-32 (Dopamine-And-cAMP-Regulated-Phosphoprotein-32 kDa) second messenger pathway and has been implicated in previous pharmacological and pharmacogenetic studies in mice. Mice bred for methamphetamine sensitivity showed linkage to the region of chromosome 15 that contains Csnk1e and also showed a 10-fold increase in expression of Csnk1e. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNK1E region and subjective response to placebo, 10, or 20 mg of oral D-amphetamine. Repeated-measures ANOVA was used to analyze interactions between genotype and drug response. The primary outcome measure, subjects' ratings of whether they felt a drug effect (Drug Effects Questionnaire (DEQ)), revealed a significant effect (p=0.010) at one single-nucleotide polymorphism (rs135745). Subjects with more copies of the rs135745 C allele were more sensitive to the low dose of D-amphetamine (p=0.001), which corresponded to a leftward shift in the dose-response curve. These findings demonstrate the successful translation of pharmacogenetic results from mice to humans.

Adolescent↗

PubMed2006

Personality and the subjective effects of acute amphetamine in healthy volunteers.

Individual differences in the positive mood and other subjective effects of d-amphetamine have been linked to personality traits related to sensation seeking. The current study extends these associations to separate personality traits of reward sensitivity, physical fearlessness, and impulsivity. A total of 128 healthy volunteers received oral doses of d-amphetamine (10 and 20 mg) or placebo in counterbalanced order. Their responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Participants completed the Multidimensional Personality Questionnaire Brief Form to assess personality traits related to reward sensitivity (Agentic Positive Emotionality and Social Potency (SP)), physical fear (Harm Avoidance (HA)), and impulsivity (Control (CL)). Participants were rank ordered on each trait, and individuals with scores in the top and bottom thirds of scores on each trait were compared using ANCOVA. High trait physical fearlessness (low HA) was associated with greater positive activational effects of 10 mg d-amphetamine. High trait reward sensitivity (high SP) was marginally associated with greater positive activational effects of 20 mg d-amphetamine. High trait impulsivity (low CL) was unrelated to positive drug effects in response either dose. The two separate personality traits of physical fearlessness and reward sensitivity are associated with d-amphetamine effects on mood in healthy volunteers. Implications for the vulnerability to psychostimulant addiction in healthy nonaddicts are discussed.

Adolescent↗

PubMed2006

Efficacy of naltrexone in smoking cessation: a preliminary study and an examination of sex differences.

This double-blinded, placebo-controlled trial evaluated the efficacy of naltrexone as an adjunct to standard smoking cessation treatment. Participants (N = 110) were adult male and female nicotine-dependent smokers who expressed interest in quitting smoking. All subjects received six sessions of behavioral counseling (1 hr/session for 6 weeks), and 1 month of the nicotine patch (21 mg for the first 2 weeks, 14 mg the third week, 7 mg the fourth week). Subjects were randomly assigned to the naltrexone or placebo group. The naltrexone group started at 25 mg daily for 3 days prior to the quit date, and increased to 50 mg/day on the quit date and following 8 weeks. At the end of medication treatment, the naltrexone group had better quit rates versus the placebo group (48% quit on naltrexone vs. 41% on placebo), but this difference was not statistically significant. However, men and women differed on several measures: in the placebo group, women had significantly lower quit rates than men (39% vs. 67%, p<.05), but in the naltrexone group, women had quit rates comparable with those of men (58% vs. 62%, p = ns). Further examination revealed that naltrexone significantly reduced men's and women's cessation-related weight gain and selectively reduced women's urge to smoke to relieve negative affect and withdrawal. The results suggest continued examination of naltrexone as an adjunct in smoking cessation, particularly in female smokers, who have historically shown worse outcomes with traditional treatment methods.

Adult↗

PubMed2006

Evaluation of the abuse potential of pagoclone, a partial GABAA agonist.

This study assessed the abuse potential of pagoclone, a partial agonist at the gamma-aminobutyric acid type A (GABAA) benzodiazepine receptor site, in healthy recreational drug users. Twenty-three young adults, who reported past recreational use of sedative drugs or alcohol, participated in 4 sessions during which capsules containing pagoclone (doses: 1.2 mg, the higher end of the proposed therapeutic dose range, and 4.8 mg, a 4-fold higher dose), diazepam (dose, 30 mg), or placebo were randomly administered under double-blind conditions. Subjective ratings of mood, drug effects, and psychomotor tests were completed at regular intervals after ingesting the capsules. On most of the standardized measures of abuse potential, pagoclone (dose, 4.8 mg) was rated as being similar to diazepam. Both drugs increased the ratings of good effects and drug liking. However, pagoclone also produced some adverse mood effects that might limit its potential to be used recreationally, and it produced fewer sedativelike effects on some measures. In general, the results with these doses indicate that the abuse potential of pagoclone is similar to that of diazepam, although its profile as a partial agonist suggests that differences between the drugs may emerge at higher doses.

Adolescent↗

PubMed2006

The alcohol clamp: applications, challenges, and new directions--an RSA 2004 symposium summary.

This article summarizes the proceedings of a symposium organized and cochaired by Vijay Ramchandani and Sean O'Connor and presented at the 2004 Research Society on Alcoholism meeting in Vancouver, BC, Canada. The objectives of this symposium were: (1) to provide a rationale for the development and use of the alcohol clamp and the requirements for its use in alcohol challenge studies; (2) to highlight recent studies conducted using the alcohol clamp to identify sources of variation in the pharmacokinetics and pharmacodynamics of alcohol, as well as to address important research questions related to the relationship between the response to alcohol and the risk for alcoholism; and (3) to provide a perspective on progress, address limitations of the clamp, and identify new directions for alcohol challenge research. The symposium began with an introduction and overview of the alcohol clamp, by Vijay Ramchandani. This was followed by 4 presentations that highlighted recent studies conducted using the clamp including: (1) determination of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in a male Jewish population, by Yehuda Neumark; (2) examination of family history of alcoholism, recent drinking history, and levels and rates of administration as determinants of the response to alcohol and risk for alcoholism, by Sean O'Connor; (3) evaluation of the time course of ethanol intoxication on neuroendocrine function in humans, by Ulrich Zimmermann; and (4) a study of the effects of steady-state blood alcohol levels on auditory event-related potentials in rats, by Sandra Morzorati. Harriet de Wit summarized and discussed the research presented at the symposium and provided her perspective on future directions for research using the alcohol clamp.

Alcohol Dehydrogenase↗

PubMed2005

Attenuated cortisol response to alcohol in heavy social drinkers.

Individual differences in response to stress may play a role in the development and maintenance of addictive behaviors. While there is evidence that people with a biological family history for alcoholism have a blunted cortisol response to alcohol, data are lacking in other at-risk subgroups, such as heavy social drinkers. The present study examined salivary cortisol response to administration of 0.0, 0.4 (2 drink equivalent), and 0.8 g/kg (4 drink equivalent) alcohol in two groups of social drinkers: heavy drinkers (n=32) and light social drinkers (n=23). The study was conducted double-blind and drink-order was counterbalanced between groups. Salivary cortisol and subjective measures were obtained at predrink baseline, and 15, 45, 105, and 165 min after beverage consumption. Results showed a significant groupxdosextime interaction (p<0.005), with alcohol (0.8 g/kg) producing an attenuated cortisol response in heavy drinkers compared to the light drinkers during the declining phase of the BAC. This outcome remained even after controlling for the effects of smoking status, family history of alcoholism, sex, and negative affect ratings during the session. Neither placebo nor the lower dose of alcohol significantly increased cortisol levels. In sum, a relatively high dose of alcohol produced a smaller increase in cortisol in heavy drinkers compared to light drinkers. The reduced cortisol reactivity in the heavier drinkers is consistent with reports that individuals at risk for alcoholism are hyporesponsive to physical and psychological stress. Further research may help determine whether alteration in cortisol response to alcohol is a biological marker of the propensity to abuse alcohol.

Adult↗

PubMed2005

Interindividual variation in anxiety response to amphetamine: possible role for adenosine A2A receptor gene variants.

Amphetamine is thought to produce its stimulant effects mainly via the dopamine system, but its effects may also be influenced by other systems. Dopamine D1 and D2 receptors exist as heterodimers with adenosine A1 and A(2A) receptors, which modulate their responsiveness, suggesting that responses to amphetamine may also depend on adenosinergic function. We therefore studied the relevance of one adenosine A1 and three adenosine A(2A) receptor gene polymorphisms for the interindividual variability in amphetamine response in 99 healthy volunteers who received placebo or d-amphetamine (10 or 20 mg). The 1976C/T and 2592C/T(ins) polymorphisms of the adenosine receptor gene were associated with increases in anxiety at both doses. This is consistent with recent observations indicating a role for adenosine A(2A) receptor gene polymorphisms in anxiety.

Adolescent↗

PubMed2005

Moderate doses of ethanol fail to increase plasma levels of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one-like immunoreactivity in healthy men and women.

RATIONALE: The endogenous GABAergic neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP, allopregnanolone) has been proposed to contribute to ethanol actions. Humans synthesize 3alpha,5alpha-THP, but its role in response to systemic administration of ethanol is unclear. OBJECTIVE: The present study aims to determine the effect of a moderate dose of ethanol on progesterone and 3alpha,5alpha-THP concentrations in plasma samples of healthy male and female subjects and to determine if these levels are related to the subjective effects of ethanol. Females were tested in both the follicular and luteal phases of the menstrual cycle. METHODS: Healthy men (N=9) and women (N=12) aged 21-35 participated in the study. Men participated in two sessions on which they received ethanol (0.8 g/kg) or placebo. Women participated in four sessions on which they received ethanol (0.7 g/kg) or placebo during the follicular and luteal phases of their cycle. Subjective states and mood were measured by standardized self-report questionnaires and a measure of psychomotor performance. Steroid levels (progesterone, 3alpha,5alpha-THP, estradiol, and cortisol) were measured in plasma samples by radioimmunoassay. RESULTS: Ethanol significantly increased plasma levels of progesterone, but not 3alpha,5alpha-THP-like immunoreactivity, in women in the luteal phase. Ethanol had no effect on progesterone or 3alpha,5alpha-THP-like immunoreactivity levels in women in the follicular phase or in men, and it did not increase cortisol in men or women. Ethanol also did not affect estradiol in men or women. CONCLUSIONS: 3alpha,5alpha-THP-like immunoreactivity levels in human plasma are not increased following moderate ethanol consumption, suggesting that circulating levels of progesterone or its tetrahydro-reduced metabolites do not play a major role in ethanol action. However, the possibility remains that ethanol increases endogenous brain production of GABAergic neurosteroids without affecting plasma levels. Moreover, humans synthesize 5beta-reduced GABAergic steroids, and levels of these steroids may be altered in plasma or brain.

Adult↗