PubMed Health⌕ Search

Biomedical subjects

Harriet de Wit

Publications and source records attributed to Harriet de Wit.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effects of d-amphetamine and smoking abstinence on cue-induced cigarette craving.

In this study, the authors investigated the effects of the indirect dopamine agonist d-amphetamine (AMPH) on cue-induced cigarette craving in smokers. Abstinent or nonabstinent cigarette smokers (N=21) rated their cravings for cigarettes and for food (control) after pretreatment with AMPH (15 mg) or placebo and before and after viewing blocks of smoking-related, food-related, and neutral pictures. Before the cues were presented, AMPH increased cigarette craving and decreased food craving. Smoking and food cues increased craving for cigarettes and for food, respectively. AMPH also further increased cigarette craving (and decreased food craving) after cue presentation, but it did so regardless of cue type (food or smoking). Smoking abstinence markedly increased craving regardless of cue presentation or drug condition. These results suggest that both AMPH and smoking abstinence can increase cigarette craving, but they do not appear to specifically affect responses to conditioned smoking-related cues.

Adult↗
PubMed2005

Dopamine transporter gene associated with diminished subjective response to amphetamine.

Individual variability in responses to stimulant drugs may influence risk of stimulant abuse and treatment response. However, the genetic determinants of this variability have yet to be elucidated. The dopamine transporter is an important site of amphetamine action. Therefore, the dopamine transporter gene (DAT1) is a logical candidate gene to study. Using a drug challenge approach, we tested for association between DAT1 genotype and subjective responses to amphetamine in healthy adults. Volunteers participated in a double-blind, crossover design, randomly receiving placebo, 10 mg, and 20 mg oral D-amphetamine, and completed self-report measures on subjective effects including anxiety and euphoria. Subjects were genotyped for the DAT1 3'-untranslated region VNTR polymorphism and divided into groups based on genotype: homozygous for nine repeats (9/9, N=8), heterozygous (9/10, N=36) and homozygous for 10 repeats (10/10, N=52). The effects of amphetamine on ratings of Feel Drug, Anxiety, and Euphoria were examined with ANCOVA. In 9/10 and 10/10 subjects, amphetamine produced its expected effects of increased Euphoria, Anxiety, and Feel Drug (p<0.01). However, in 9/9 subjects, the effects of amphetamine were indistinguishable from placebo, suggesting that the 9/9 genotype has diminished subjective response to acute amphetamine. Interestingly, recent findings also implicate the 9/9 genotype in decreased therapeutic response to the stimulant methylphenidate in ADHD children. The current findings have important implications for understanding the genetic determinants of variability in stimulant response and risk of abuse.

3' Untranslated Regions↗
PubMed2005

Mecamylamine and ethanol preference in healthy volunteers.

BACKGROUND: Recent evidence suggests that some of the behavioral effects of alcohol may be mediated through actions on nicotinic acetylcholine receptors. Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduces alcohol preference and consumption in alcohol-preferring rats, and in humans, mecamylamine dampens some of the subjective, or mood-altering, effects of alcohol. This experiment was designed to investigate the effects of mecamylamine on consumption of alcohol in healthy social drinkers. METHODS: Healthy volunteers (12 men, 12 women) participated in a choice procedure in which they chose between an alcoholic beverage and money (low, medium, or high amounts) after pretreatment with mecamylamine (7.5 or 15 mg) or placebo. Outcome measures were the number of alcoholic beverages consumed and the subjective effects of alcohol. RESULTS: Mecamylamine (15 mg) decreased blood alcohol levels (BALs) after a small fixed dose of alcohol (0.2 g/kg). Even when the lower BALs were taken into account, mecamylamine reduced ratings of stimulation after alcohol (Addiction Research Center Inventory A scale). Mecamylamine did not significantly reduce choice for alcohol versus money. However, there was a tendency for the drug to decrease alcohol choice among participants who reported the greatest stimulant-like effects from alcohol. CONCLUSION: These results provide only limited support for the idea that nicotinic acetylcholine receptors are involved in the rewarding effects of alcohol.

Adult↗
PubMed2004

Effects of morphine and naltrexone on impulsive decision making in rats.

RATIONALE: It has been reported that human opiate addicts discount delayed rewards more than non-addicts, indicating that they are more impulsive. However, it is not clear whether this difference reflects pre-existing traits, or the effects of exposure to the opiates. OBJECTIVES: This study was designed to investigate the effects of an opioid agonist and antagonist on delay discounting in rats. The study had three objectives: to determine (1) the acute effects of the opioid agonist morphine (MOR) on delay discounting, (2) the acute effects of the opioid antagonist naltrexone (NAL) on delay discounting, and (3) whether NAL reverses the effects of MOR on delay discounting. METHODS: An adjusting amount procedure (AdjAmt) was used to determine how much animals discounted the value of delayed rewards. Acute doses of MOR (0.3, 1.0, and 1.8 mg/kg SC), NAL (0.01, 0.1, 1.0, and 10 mg/kg SC) and NAL (0.1 mg/kg SC) prior to MOR (1.8 mg/kg SC) were tested in 15 rats. RESULTS: MOR dose dependently increased the rate of delay discounting (i.e., made the animals more impulsive). NAL alone had no effect on the value of delayed rewards, but NAL blocked the effects of MOR. CONCLUSIONS: These results suggested that the direct effects of MOR may contribute to the high level of impulsive behavior seen among opiate users.

Analgesics, Opioid↗
PubMed2004

Therapeutic doses of diazepam do not alter impulsive behavior in humans.

This study examined the effects of low, therapeutic doses of diazepam on several measures of impulsive behavior in healthy volunteers. Volunteers (N=35) participated in a three-session double-blind randomized design in which they received diazepam (5 or 10 mg) or placebo. The volunteers were classified as high and low impulsive based on the Barratt Impulsiveness Scale-11 (BIS-11). One hour after ingesting the capsule on each session, participants completed mood questionnaires and five impulsivity tasks: go/no-go task, delay discounting task, time estimation task, stop task, and the balloon analogue risk task (BART). Diazepam (5 and 10 mg) produced its prototypic sedative-like mood effects. However, the drug did not affect performance on any of the measures of impulsive behavior in either the high or low BIS participants. These results suggest that low doses of diazepam, including doses that are used therapeutically, do not increase impulsive behavior. Whether higher doses would increase impulsivity remains to be determined.

Adolescent↗
PubMed2004

Biological and behavioral markers of alcohol sensitivity.

This article summarizes a symposium that was organized by Dr. Kim Fromme and presented at the 2003 annual meeting of the Research Society on Alcoholism in Ft. Lauderdale, Florida. The four presentations illustrate the emerging technologies and methods that are now being used to investigate the genetic basis of differential sensitivity to alcohol and their behavioral manifestations. Combining human genotyping with laboratory measures of behavior and subjective reports, these presentations represent state-of-the-art approaches to crossing the bridge from the Decade of the Brain to the Decade of Behavior. Dr. De Wit's paper describes her research on the neurobiological basis for individual differences in sensitivity to the stimulant and sedative effects of alcohol. Evidence suggests that activity of the dopaminergic and GABAergic neurotransmitters underlie these stimulant and sedative effects, respectively. Both Drs. Hutchison's and Corbin's papers describe their research on polymorphisms for the serotonin transporter (SLC6A4) as a determinant of the subjective effects of alcohol challenge. Dr. Hutchinson's and Ms. Ray's findings indicate that individuals with the short form of the SLC6A4 alleles (S) demonstrated a low level of response to alcohol, thus supporting previous research that the S allele may be associated with increased risk for alcohol dependence. In contrast, Dr. Corbin did not find a reliable association between the SLC6A4 genotype and subjective response to alcohol. Mr. Cook's and Dr. Wall's paper adds another dimension to this article by presenting research on both the aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH2) genetic variants and their association with the alcohol-related flushing response that is prevalent in Asian populations. Dr. David Goldman provides concluding remarks.

Alcohol Drinking↗
PubMed2003

Effects of reinforcer magnitude on an animal model of impulsive behavior.

The effects of altering sucrose solution concentration on discounting of delayed rewards in rats were examined. Five different delays were used (0, 1, 2, 4, and 8s) and three different sucrose solution concentrations (3, 10, and 30%). It was hypothesized that high value sucrose solution concentrations would be discounted less than low value sucrose solution concentrations. The results indicated that the rats discounted the 30% sucrose solution concentration at a higher rate than the 3 or 10% sucrose solution concentration, a finding that apparently contradicted the hypothesis that higher value sucrose solution concentrations would be discounted less than lower value sucrose solution concentrations. However, a follow up experiment indicated that the 3 and 10% sucrose solution concentrations were preferred over the 30% concentration. Thus the results of Experiment 1 can be interpreted as supporting the hypothesis that high valued sucrose solution concentrations are discounted less than lower valued sucrose solution concentrations.

Journal Article↗
PubMed2003

Effects of stress on responses to methamphetamine in humans.

RATIONALE: Studies with laboratory animals indicate that acute stress can modify both the direct effects of drugs of abuse and the tendency to self-administer drugs. Similarly, stress may also alter the acute subjective effects of drugs or the tendency to seek and consume drugs in humans. OBJECTIVES: This laboratory-based study was designed to determine whether an acute social stressor (Trier Social Stress Test; TSST) alters subjective responses to a low oral dose of methamphetamine (METH; 10 mg) in humans. METHODS: The study utilized a mixed within- and between-subjects design. Healthy young men ( n=28) participated in two sessions, one with stress and the other without. They were randomly assigned to two groups who received either METH ( n=16) or placebo ( n=12) on both sessions. On each session, subjects underwent the TSST or no TSST, and then ingested a beverage containing drug (10 mg METH) or placebo (PLAC). Over the next 1.5 h various self-reported mood measures and physiological measures, including salivary cortisol levels, were obtained at regular intervals. RESULTS: Both acute stress and METH produced mood-altering and physiological effects. Stress increased ratings of anxiety immediately after the stressful task, and increased salivary cortisol levels 20 min later. METH increased feelings of stimulation, and decreased fatigue and sedation, beginning about 20 min after drug administration and peaking at 60 and 90 min. Stress dampened the early responses to METH (i.e. at 20 min), but not the later effects (60 or 90 min). CONCLUSIONS: These results demonstrate that acute stress can dampen subjective responses to a low dose of METH, but these effects are short-lived. It remains to be determined what mechanisms mediate this effect.

Adolescent↗
PubMed2003

Association between A2a receptor gene polymorphisms and caffeine-induced anxiety.

The adenosine receptor system, which mediates the psychoactive effects of caffeine, is also thought to be involved in the regulation of anxiety. In this study, we examined the association between variations in anxiogenic responses to caffeine and polymorphisms in the A1 and A2a adenosine receptor genes. Healthy, infrequent caffeine users (N=94) recorded their subjective mood states following a 150 mg oral dose of caffeine freebase or placebo in a double-blind study. We found a significant association between self-reported anxiety after caffeine administration and two linked polymorphisms on the A2a receptor gene, the 1976C>T and 2592C>Tins polymorphisms. Individuals with the 1976T/T and the 2592Tins/Tins genotypes reported greater increases in anxiety after caffeine administration than the other genotypic groups. The study shows that an adenosine receptor gene polymorphism that has been associated with Panic Disorder is also associated with anxiogenic responses to an acute dose of caffeine.

Adult↗
PubMed2003

Effects of THC on behavioral measures of impulsivity in humans.

This study investigated the acute effects of delta(9)-tetrahydrocannabinol (THC) on four behavioral measures of impulsivity in recreational marijuana users. Although impulsive behavior has been studied using several different measures of impulsivity, few studies have utilized more than one of these measures on a single cohort. In this study, 37 healthy men and women participated in three sessions, in which they received capsules containing placebo, 7.5, or 15 mg THC in randomized order under double-blind conditions. Subjects were tested on the following four tasks: the Stop task, which measures the ability to inhibit a prepotent motor response; a Go/no-go task; a Delay discounting task, which measures the value of delayed or uncertain reinforcers; and a time estimation task, which measures alterations in time perception through a time reproduction procedure. Subjects also completed mood questionnaires and general measures of performance. THC produced its expected effects on subjective measures including increases in ARCI euphoria and marijuana scales. THC increased impulsive responding on the Stop task but did not affect performance on either the Go/no-go or Delay or Probability discounting tasks. On the time reproduction task, THC increased estimates of the duration of short intervals while not affecting estimates of longer intervals. There were no significant correlations between the four tasks either before or after drug administration. These results suggest that THC may increase certain forms of impulsive behavior while not affecting other impulsive behaviors. The dissociations between the four measures of impulsivity suggest that impulsivity is an assemblage of distinct components rather than a unitary process.

Adolescent↗
PubMed2003

Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers.

BACKGROUND: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. METHODS: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. RESULTS: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. CONCLUSIONS: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.

Adult↗
PubMed2003

Effects of acute social stress on alcohol consumption in healthy subjects.

BACKGROUND: There has been renewed interest in interactions between stress and use of drugs and alcohol. Although there is evidence that stress increases drug use in human drug users and in laboratory animals, the processes by which stress affects drug-motivated behavior are not understood. Here we examined the effects of an acute social stressor (performing a mental arithmetic task in front of an audience) on consumption of ethanol or placebo beverages in healthy social drinkers. METHODS: Thirty-seven men and women, ages 21-35, were randomly assigned to a placebo (n = 15) or ethanol group (n = 22). Subjects participated in two sessions, one with stress (Trier Social Stress Test) the other without stress. In each session, immediately after the stress or no-stress period, subjects consumed the first dose (placebo or 0.3 g/kg of ethanol for men or 0.2 g/kg for women). Then, subjects were allowed to choose up to six more beverages (0.1 g/kg each for the ethanol group or placebo beverages for the placebo group). Measures included percentage of beverage consumed, salivary cortisol level, heart rate, blood pressure, and subjective ratings of mood and drug effect. RESULTS: Subjects in both the placebo and ethanol groups consumed significantly more of their beverages after stress, compared to no stress. Stress increased anxiety, uneasiness, and produced some stimulant-like effects and, in the ethanol group, it dampened some of the acute subjective effects of ethanol. The direct physiologic and mood effects of the stress were fairly short-lived. CONCLUSIONS: It is concluded that acute stress may produce a modest increase in alcohol consumption in healthy, nonproblem social drinkers but that this increase is not directly related to the pharmacological effects of the drug. Nonpharmacological factors may include expectancies, thirst, or nonspecific facilitation of ongoing behaviors.

Adult↗
PubMed2002

Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism.

This study investigated the effects of acute serotonin depletion on two measures of impulsive behavior in healthy men with a family history of alcoholism. Serotonin has been implicated in several forms of impulsive behavior, as well as in the etiology of Type II alcoholism. The present study was designed to determine if an acute disturbance of serotonin function would increase impulsive responding on two behavioral indices of impulsivity, and whether this effect would be greater in individuals with a genetic predisposition to alcoholism. Forty healthy men, half of whom had an alcoholic father, participated in a two-session study. Subjects ingested a tryptophan-depleting diet on one session and a balanced diet on the other session, and completed tasks measuring behavioral inhibition and delay discounting. Tryptophan depletion impaired performance on the behavioral inhibition task in the males with a positive family history, relative to the males without alcoholic relatives, whereas it improved behavioral inhibition in the family history negative group. Tryptophan depletion had negligible effects on mood, and it did not alter performance on the delay discounting task. The results provide partial support for the hypothesis that impulsive behavior is related to low serotonin function, and further suggests that the role of serotonin depends on genetic factors related to alcoholism. The results complement the results of a parallel study investigating the effects of serotonin depletion on a similar behavioral inhibition procedure in rats. Parallel studies in rats and humans are important to validate the large body of neurobiological research with non-human species to humans.

Adolescent↗
PubMed2002

The reinstatement model of drug relapse: history, methodology and major findings.

RATIONAL AND OBJECTIVES: The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. CONCLUSIONS: The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.

Animals↗
PubMed2002

Delay of gratification and delay discounting in rats.

Delay discounting (DD) and delay of gratification (DG) are two measures of impulsive behavior often viewed as reflecting the same or equivalent processes. However, there are some key differences in the contingencies of reinforcement between the procedures that may have implications for understanding impulsivity. This study used DD and DG procedures to determine if differences in contingencies of reinforcement specified by DD and DG alters how much organisms discount the value of delayed reinforcers. Twenty-four water-deprived rats performed one of two Adjusting Amount procedures, which consisted of repeated choices between a fixed amount of water (250 &mgr;l) delivered after a delay (0, 4, 8, 16, or 32 s) and an adjusting, usually lesser amount delivered immediately. Half of the rats (n=12) performed a DD procedure designed to assess preference for immediate over delayed reinforcers in which they had discrete choices between the immediate and delayed amounts of water. A DG procedure was used for the other half of the rats (n=12). In the DG procedure rats also selected between immediate and delayed alternatives, but if they chose the delayed alternative they could switch to and receive the immediate alternative at any time during the delay to the larger reward. In the DD procedure switching responses were not reinforced but were still recorded and used for analyses. The DD functions of the two groups did not differ significantly. However, at the longer delays, the DG group made significantly fewer switching responses than the DD group. A possible role of response inhibition in the DG procedure is discussed.

Journal Article↗
PubMed2002

The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers.

Despite extensive evidence that selective dopamine antagonists attenuate the reinforcing effects of stimulants in laboratory animals, there is little evidence that dopamine antagonists block the positive subjective effects of stimulants in humans. However, recent evidence suggests that the subjective effects of stimulants in humans may depend in part on serotonin. The goal of this study was to examine the effects of haloperidol, a drug that primarily blocks dopamine receptors, and risperidone, a drug that blocks both dopamine and serotonin receptors, on the physiological and subjective effects of methamphetamine in healthy volunteers. Two groups of subjects participated in a placebo-controlled, within-subject, 2 x 2 repeated measures design. One group was tested with haloperidol (3 mg; N = 18), the other with risperidone (0.75 mg; N = 18). Each subject participated in four sessions receiving all combinations of antagonist or placebo and methamphetamine (20 mg) or placebo. Dependent measures included vital signs and standardized questionnaires of subjective effects. At these doses, both haloperidol and risperidone produced mild sedative-like effects compared to placebo. However, neither drug consistently reduced the stimulant-like effects of methamphetamine. These results add to the growing body of literature suggesting that D(2) dopamine receptor antagonists do not block the euphorigenic subjective effects of stimulant drugs in humans, and also do not support the idea that serotonin contributes significantly to these effects.

Adolescent↗
PubMed2002

GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings.

A growing preclinical and clinical literature suggests that GABA(B) receptor agonists promote abstinence and reduce the use of cocaine, heroin, alcohol and nicotine. The purpose of this paper is to critically review these data. GABA(B) receptor agonists, such as baclofen, appear to reduce the reinforcing effects of abused drugs in animal models under multiple experimental procedures. This occurs at doses that have little effect on responding for other positive reinforcers such as food or water. We review evidence that these potential therapeutic effects may be mediated by modulation of mesolimbic dopamine neurons. This review also examines the preliminary clinical data from studies of the efficacy of baclofen for treatment of cocaine, alcohol, and nicotine dependence. We suggest that these preliminary data provide a rationale for conducting more systematic studies of the effects of GABA(B) receptor agonists as treatment for drug abuse. This line of research may also improve our understanding of the neurochemical mechanisms underlying the drug dependence process.

Animals↗