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Biomedical subjects

H de Wit

Publications and source records attributed to H de Wit.

At least 55 records · Page 3Linked to original sources
PubMed1999

Delay or probability discounting in a model of impulsive behavior: effect of alcohol.

Little is known about the acute effects of drugs of abuse on impulsivity and self-control. In this study, impulsivity was assessed in humans using a computer task that measured delay and probability discounting. Discounting describes how much the value of a reward (or punisher) is decreased when its occurrence is either delayed or uncertain. Twenty-four healthy adult volunteers ingested a moderate dose of ethanol (0.5 or 0.8 g/kg ethanol: n = 12 at each dose) or placebo before completing the discounting task. In the task the participants were given a series of choices between a small, immediate, certain amount of money and $10 that was either delayed (0, 2, 30, 180, or 365 days) or probabilistic (i.e., certainty of receipt was 1.0, .9, .75, .5, or .25). The point at which each individual was indifferent between the smaller immediate or certain reward and the $10 delayed or probabilistic reward was identified using an adjusting-amount procedure. The results indicated that (a) delay and probability discounting were well described by a hyperbolic function; (b) delay and probability discounting were positively correlated within subjects; (c) delay and probability discounting were moderately correlated with personality measures of impulsivity; and (d) alcohol had no effect on discounting.

Adult↗
PubMed1999

Ethanol impairs saccadic and smooth pursuit eye movements without producing self-reports of sedation.

It has been suggested that eye movements provide a sensitive tool to assess the sedative-like properties of drugs. However, the relationship between sedative-like subjective effects and impairment in eye movements is not clear. For example, it is not clear whether drugs with stimulant-like effects can also impair eye movements. This study evaluated whether ethanol, a drug with both sedative-like and stimulant-like properties, impairs eye movements, and whether the impairment observed after ethanol is related to its sedative properties. Twenty healthy men and women, aged 21 to 35, consumed beverages containing placebo or ethanol (0.4 or 0.8 g/kg) on three separate laboratory sessions, in randomized order. Eye movement and psychomotor and subjective responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. Subjects were divided post hoc into two groups, based on their sedative-like or stimulant-like subjective responses to ethanol. Nine subjects reported increases in sedative-like effects after ethanol and 11 reported decreases in sedative-like effects, and increases in stimulant-like effects, after alcohol. Despite their distinctly different subjective responses to ethanol, the groups did not differ in the magnitude, time-course or quality of responses on the eye movement measures. In both groups, ethanol decreased peak saccadic eye velocity and smooth pursuit gain. These results demonstrate the dissociation between impairment in eye movements and subjective feelings of sedation after ethanol, and show that eye movements can be impaired even when subjects are reporting stimulant-like effects. The findings suggest that impaired eye movements are not a nonselective index of sedation, but may be related to specific drug actions on brain regions involved in generating these eye movements.

Adult↗
PubMed1998

Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines.

The transcription factor NF-kappaB plays an important role in the regulated expression of cytokines in human monocytes. A p100 subunit of NF-kappaB has IkappaB-like properties by sequestering the p65 transactivating subunit in the cytosol of cells. In transient transfection assays we demonstrated that p100 has an inhibitory effect on the NF-kappaB-dependent IL-6 promoter activity. In view of this finding, we studied the regulation of the p100 subunit in human monocytes in response to LPS, the inflammatory cytokines IL-1beta and TNF-alpha and lymphokines. The results demonstrate that LPS, IL-1beta, and TNF-alpha induce p100 expression at mRNA and protein level while IFN-gamma, IL-3 and IL-4/IL-10 have no effect. The induction of p100 expression was shown to be mediated by a two-fold increase in the p100 transcription rate and a two-fold increase in p100 mRNA stability. Furthermore the p100 mediated upregulation was dependent on a tyrosine kinase dependent pathway rather than the protein kinase C pathway. NF-kappaB is a complex of either p50 homodimers or a p50/p65 heterodimer. The latter is known to strongly autoregulate p100 transcription. We therefore examined the composition of NF-kappaB induced by LPS vs the different lymphokines. LPS-induced NF-kappaB showed a distinct p65 supershift whereas the composition of NF-kappaB induced by different lymphokines did not show a change in p65. We conclude that the p100 subunit of the transcription factor NF-kappaB is induced by different inflammatory mediators while lymphokines fail to induce p100 expression which may be caused by the induction of NF-kappaB predominantly consisting of p50 homodimers.

Cells, Cultured↗
PubMed1998

Interclass drug effects and changes in regional brain glucose metabolism.

We have developed an innovative use of positron emission tomography that has broad applications in drug development. Based on the FDG method (Phelps et al. 1979) for assessing glucose metabolism, the method requires rigorous experimental control of subjects and standardized data acquisition and analyses. In localizing net metabolic drug effects, measured in quantifiable terms, we have derived a new conceptual basis for examining pharmacologically induced changes in brain function and a new model for predicting drug effectiveness. We applied this method to studies of drugs in three different classes and noted marked differences in distribution and magnitude of metabolic effects. This approach presents an opportunity to selectively examine measurements of the glucose metabolic changes induced by specific pharmacological probes on intermediary metabolic pathways, including regulation of gene expression and the metabolic consequences of neurotransmitter alteration in pharmacologically targeted neuronal systems. Development of these methods provides new approaches for studying neurobiological mechanisms, and can contribute significantly to the process of new drug development.

Brain↗
PubMed1998

Individual differences in the biphasic effects of ethanol.

Ethanol exerts both stimulant-like and sedative-like subjective and behavioral effects in humans depending on the dose, the time after ingestion and, we will argue, also on the individual taking the drug. This study assessed stimulant-like and sedative-like subjective and behavioral effects of ethanol during the ascending and descending limbs of the blood alcohol curve across a range of doses in nonproblem social drinkers. Forty-nine healthy men and women, 21 to 35 years old, consumed a beverage containing placebo or ethanol (0.2, 0.4, or 0.8 g/kg) on four separate laboratory sessions, in randomized order and under double-blind conditions. Subjective and behavioral responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. The lowest dose of ethanol (0.2 g/kg) only produced negligible subjective effects compared to placebo. The moderate dose (0.4 g/kg) increased sedative-like effects 90 min after ethanol ingestion but did not increase ratings of stimulant effects at any time. The highest dose (0.8 g/kg) increased ratings of both stimulant- and sedative-like effects during the ascending limb and produced only sedative-like effects during the descending limb. Closer examination of the data revealed that individual differences in response to the highest dose of ethanol accounted for this unexpected pattern of results: about half of the subjects reported stimulant-like effects on the ascending limb and sedative-like effects on the descending limb after 0.8 g/kg ethanol, whereas the other half did not report stimulant-like effects at any time after administration of ethanol. These results challenge the simple assumption that ethanol has biphasic subjective effects across both dose and time, and extend previous findings demonstrating individual differences in response to ethanol.

Adult↗
PubMed1997

Behavioral responses to ethanol in light and moderate social drinkers following naltrexone pretreatment.

The opioid antagonist naltrexone has been shown to be effective in the treatment of alcoholism, possibly by dampening the subjective effects of ethanol. However, naltrexone does not consistently attenuate the effects of ethanol in social drinkers in laboratory-based challenge studies. In the present study, 25 healthy volunteers, who were either light drinkers (mean = 3 drinks per week) or moderate drinkers (mean = 16 drinks per week), participated in six evening sessions. At each session, subjects ingested a capsule containing naltrexone (25 or 50 mg) or placebo, and 1 hr later they consumed a beverage containing ethanol (0.25 g/kg, equivalent to about two standard alcoholic drinks) or placebo. Subjects received all combinations of pretreatments and beverages. They completed self-report mood questionnaires and psychomotor tests at regular intervals. This low dose of ethanol produced modest but significant effects on self-report measures such as ratings of feeling a drug effect and of liking the drug effect. However, naltrexone (25 or 50 mg) pretreatment had no dampening effect on subjects' responses to ethanol. These results indicate that acute doses of naltrexone that are effective when administered chronically to alcoholics do not attenuate the acute effects of a low dose of ethanol in non-problem drinkers.

Administration, Oral↗
PubMed1997

Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data.

Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.

Amphetamine↗
PubMed1997

Acute effects of triazolam in women: relationships with progesterone, estradiol and allopregnanolone.

This study investigated hormone levels and mood in normal women to explore relationships between levels of circulating hormones and i) baseline mood states and ii) effects of triazolam on mood. Certain ovarian hormones or their metabolites have direct actions on neuronal receptors. These actions may result in changes in mood state, or changes in responses to psychoactive drugs which act on the same receptors. The present study explored relationships between estrogen, progesterone and a metabolite of progesterone, allopregnanolone, and the mood-altering and performance effects of an acute dose of triazolam. Triazolam is a short-acting benzodiazepine which acts via the GABAA receptor complex. Twenty women received triazolam (0.25 mg) or placebo at the follicular, ovulatory and luteal phases of their menstrual cycle. Each subject participated in six conditions (i.e., drug and placebo at each of the three phases), across two menstrual cycles. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of estradiol, progesterone, allopregnanolone, and triazolam. Mood and performance measures were not clearly related to hormone levels when data from all three phases were examined. However, within the luteal phase, higher levels of allopregnanolone were associated with lower self-reported arousal before any drug administration (i.e., at baseline). After administration of triazolam, most subjects reported the expected decreases in rating of arousal. However, the subjects with the highest levels of allopregnanolone reported increases in ratings of arousal. Thus, hormone levels were related to mood and responses to triazolam, particularly during the luteal phase of the cycle. However, the drug-hormone interactions on mood and behavior were complex.

Adolescent↗
PubMed1997

Determination of discount functions in rats with an adjusting-amount procedure.

An adjusting-amount procedure was used to measure discounting of reinforcer value by delay. Eight rats chose between a varying amount of immediate water and a fixed amount of water given after a delay. The amount of immediate water was systematically adjusted as a function of the rats' previous choices. This procedure was used to determine the indifference point at which each rat chose the immediate amount and the delayed amount with equal frequency. The amount of immediate water at this indifference point was used to estimate the value of the delayed amount of water. In Experiment 1, the effects of daily changes in the delay to the fixed reinforcer (100 microliters of water delivered after 0, 2, 4, 8, or 16 s) were tested. Under these conditions, the rats reached indifference points within the first 30 trials of each 60-trial session. In Experiment 2, the effects of water deprivation level on discounting of value by delay were assessed. Altering water deprivation level affected the speed of responding but did not affect delay discounting. In Experiment 3, the effects of varying the magnitude of the delayed water (100, 150, and 200 microliters) were tested. There was some tendency for the discounting function to be steeper for larger than for smaller reinforcers, although this difference did not reach statistical significance. In all three experiments, the obtained discount functions were well described by a hyperbolic function. These experiments demonstrate that the adjusting-amount procedure provides a useful tool for measuring the discounting of reinforcer value by delay.

Animals↗
PubMed1997

The effects of ethanol on the relative preference for cigarettes.

This study examined the effects of ethanol preloading on preference for tobacco cigarettes in 10 nicotine-dependent volunteers. The crossover, double-blind study involved pretreating participants with 0, 0.2, 0.4 or 0.8 g/kg ethanol immediately prior to a task in which cigarettes and/or money could be earned. Tobacco cigarette preference was measured using the number of responses performed and reinforcers earned on a series of concurrent random-ratio schedules that yielded tobacco and money reinforcers. In addition to the preference measures, subjective effects and psychomotor performance were assessed before beverage ingestion and at regular intervals afterwards. Ethanol induced alterations in mood and psychomotor performance in a dose-related fashion. However, preference for tobacco cigarettes was not affected by ethanol pretreatment. The present study suggests that the increase in cigarette smoking that is associated with ethanol consumption does not involve changes in smokers' preference for cigarettes.

Adult↗
PubMed1996

Subjective responses to d-amphetamine alone and after pimozide pretreatment in normal, healthy volunteers.

The role of dopamine in d-amphetamine-induced euphoria has not been systematically examined in normal volunteers. Therefore, we examined the effects of the dopamine antagonist, pimozide, on responses to d-amphetamine in healthy volunteers, using a within-subjects, double-blind design. Ten subjects received single oral doses of d-amphetamine (0, 10, 20 mg) 2 hours following pretreatment with pimozide (0, 1, 2 mg). Subjective, behavioral, and physiological effects were assessed predrug and for 3 hours after d-amphetamine administration. d-Amphetamine alone produced prototypic effects on a variety of measures, including euphoria and drug liking. Pimozide did not produce any effects when administered alone and produced inconsistent effects on responses to d-amphetamine. Although higher doses of pimozide may be needed to antagonize the euphorigenic effects of d-amphetamine, these results raise the possibility that the role of dopamine in the subjective effects of stimulants may be more complex than initially appreciated.

Adult↗
PubMed1996

Interaction of expectancy and the pharmacological effects of d-amphetamine: subjective effects and self-administration.

The study examined the effects of expectation on the subjective effects and oral self-administration of 15 mg d-amphetamine (AMP) and placebo in 40 volunteers who reported no prior use of stimulants other than caffeine. A balanced placebo design was used to create four groups: told Placebo/got Placebo (P/P), told Placebo/got Stimulant (P/S), told Stimulant/got Placebo (S/P), told Stimulant/got Stimulant (S/S). There were three sessions. On one session (INFO), participants received a capsule containing AMP or placebo and were given information about the contents of the capsule according to the balanced placebo design. On another session (NO INFO), participants received no information about the capsule's contents and were given placebo. On the final session, participants were allowed to choose either the INFO or NO INFO capsule. Participants came to the laboratory to ingest their capsules, and then returned to their normal environments where they completed subjective effects questionnaires every 2 h for 8 h. Expectancies influenced the subjective effects reported during the INFO session, regardless of whether subjects actually received AMP or placebo: subjects who expected a stimulant had higher ratings of "feel drug" and "like drug". The pharmacological effects of AMP were also evident on the INFO sessions: AMP produced its prototypic subjective effects regardless of subjects' expectancies. Significant interactions between drug and expectancy were obtained on self-report measures of anxiety and arousal: anxiety was higher for groups who received substances that did not match their expectations (P/S and S/P) and arousal increased most in volunteers who expected placebo but received stimulant. Choice of drug was determined primarily by pharmacology: participants who received AMP on the INFO session usually chose that capsule, regardless of information about its identity (P/S: 8/10; S/S: 9/10). In contrast, participants who received placebo on the INFO session chose this capsule at chance levels, regardless of information about its identity (S/P: 3/10; P/P: 6/10). Thus, expectancy influenced some of the subjective effects of AMP and placebo, but the pharmacological effects of the AMP were instrumental in determining whether volunteers would self-administer the drug.

Adult↗
PubMed1996

Preference for diazepam, but not buspirone, in moderate drinkers.

The purpose of the present study was to determine the preference for buspirone, an anxiolytic predicted to have minimal abuse potential, in comparison with diazepam in moderate drinkers. Preference for diazepam and buspirone was assessed in 55 moderate drinkers using a seven-session procedure consisting of four sampling sessions followed by three choice sessions. On each sampling session subjects ingested five capsules, one every 30 min. Color-coded capsules contained placebo on two sessions and drug on two sessions. Each drug capsule contained diazepam (4 mg) for 30 subjects and buspirone (5 mg) for 25 subjects. On choice sessions subjects chose whichever of the two color-coded capsules, i.e., drug or placebo, they wished to take. After ingesting one capsule, every 30 min they had the option of ingesting another capsule of the same color and content, for a maximum of seven capsules over the session (maximum of 28 mg diazepam or 35 mg buspirone). In the diazepam group 70% of subjects chose diazepam over placebo on at least two of the three choice sessions, whereas in the buspirone group only 24% of subjects chose buspirone over placebo on at least two sessions. Both diazepam and buspirone increased measures of sedation. Only diazepam increased ratings of liking and impaired performance, whereas only buspirone decreased ratings of feeling Friendly. These results replicate previous findings indicating that diazepam has reinforcing effects in moderate drinkers. Further, these results demonstrate the pharmacological specificity of this effect by showing that buspirone did not function as a reinforcer under these same conditions.

Adult↗
PubMed1996

Evaluation of phentermine and fenfluramine, alone and in combination, in normal, healthy volunteers.

Recent clinical reports indicate that combined administration of phentermine and fenfluramine may have useful effects in the treatment of drug abuse. The present study was designed to evaluate the subjective and mood-altering effects of these drugs, alone and in combination, in normal healthy volunteers. Seven male and five female volunteers participated in an eight-session, double-blind study in which each subject received each of the following drug conditions: d-amphetamine (10 and 20 mg), phentermine (30 mg), fenfluramine (40 and 80 mg), phentermine (30 mg) with fenfluramine (40 mg), phentermine (30 mg) with fenfluramine (80 mg), and placebo. Sessions were conducted in a laboratory setting two or three days a week. Subjects completed standardized self-report questionnaires and psychomotor tests before and at regular intervals after each drug administration. Phentermine produced effects that were similar to those of d-amphetamine, whereas fenfluramine produced different and apparently aversive effects (e.g., it increased measures of anxiety and confusion). Phentermine reduced the apparently aversive effects of fenfluramine when the two drugs were given together. These results suggest that the combination of phentermine and fenfluramine would have a low potential for abuse.

Adult↗
PubMed1996

Interferon-gamma modulates the lipopolysaccharide-induced expression of AP-1 and NF-kappa B at the mRNA and protein level in human monocytes.

Interferon-gamma (IFN-gamma) modulates the expression of several cytokines by human monocytes at the transcriptional level. In view of these findings, we analyzed the effects of IFN-gamma on the expression of different transcription factors in activated human monocytes. Priming of human monocytes with IFN-gamma resulted in the down regulation of c-fos and c-jun mRNA in response to stimulation with lipopolysaccharide (LPS) compared to the effects of LPS alone. Not only was this effect observed at the mRNA level, but activator protein-1 (AP-1) DNA binding capacity was affected as well, A strong reduction was observed in the LPS-induced DNA-binding activity of AP-1 in the presence of IFN-gamma. LPS-stimulated monocytes showed an increased expression of p105 mRNA, the precursor of the p50 subunit of the transcription factor nuclear factor-kappa B (NF-kappa B), while no effect was noticed on the expression of p65 mRNA. In contrast, IFN-gamma priming did not affect the expression of p105 transcripts but enhanced the expression of p65 mRNA (two-fold). Priming with IFN-gamma followed by LPS stimulation resulted in a further increase in the expression of p65 mRNA. This was due to an increase in the half-life of p65 mRNA (75 vs 150 minutes). Electrophoretic mobility shift assays (EMSAs) demonstrated that unstimulated monocytes predominantly expressed p50 NF-kappa B. Stimulation with LPS or IFN-gamma resulted in the expression of p50 and p65 subunits, while the combination of IFN-gamma plus LPS caused a further increase in the expression of NF-kappa B. With Western blotting, it was shown that nuclear extracts from monocytes contained p50 and p65 protein in response to LPS and IFN-gamma stimulation. However, the combined stimulation did not result in enhanced p50 and p65 protein expression. The effects of IFN-gamma on the transcription factors were specific, since no change was observed in the expression of NF-IL-6 or I kappa B alpha, the inhibitor of NF-kappa B. We conclude that the effects of IFN-gamma on the expression of the transcription factors AP-1 and NF-kappa B may be important for the modulatory effects of IFN-gamma on the cytokine expression in activated human monocytes.

Base Sequence↗
PubMed1995

Effect of setting on the reinforcing and subjective effects of ethanol in social drinkers.

The reinforcing and subjective effects of two doses of ethanol [0.5 g/kg (LOW) and 0.8 g/kg (HIGH)] were evaluated under two conditions, a social condition (SOC), in which subjects were tested with two or three other subjects, and a socially isolated condition (ISO), in which subjects were tested alone. Forty-one social drinkers participated in a double-blind, seven-session choice procedure. Subjects were randomly assigned to one of four experimental groups: SOC-LOW, SOC-HIGH, ISO-LOW, or ISO-HIGH. On the first four sessions, subjects sampled ethanol (0.5 or 0.8 g/kg) on two occasions and placebo on the other two occasions. On the three remaining sessions, subjects selected and consumed whichever of the two previously sampled substances they preferred. The number of sessions on which they chose ethanol was the primary measure of the reinforcing effects of ethanol. Standardized self-report questionnaires and a psychomotor test were used to measure subjective and objective drug effects. Subjects in the SOC condition chose ethanol over placebo on significantly more sessions than subjects in the ISO condition. Ethanol produced positive subjective effects (e.g., increased ratings of drug liking and euphoria) for subjects in the SOC condition, but for subjects in the ISO condition, it produced apparently negative effects (e.g., increased ratings of dysphoria). These results extend previous reports that the behavioral effects of ethanol depend upon the social condition in which it is consumed.

Adult↗
PubMed1995

Preferences for ethanol and diazepam in anxious individuals: an evaluation of the self-medication hypothesis.

The self-medication hypothesis of addictive disorders postulates that individuals with psychiatric symptoms use drugs to alleviate their symptoms. Although commonly cited to explain the etiology of substance abuse, self-medication has not been experimentally validated. This study evaluated one version of the self-medication hypothesis by formulating it into a testable hypothesis: are highly anxious volunteers more likely to self-administer anxiolytic drugs than non-anxious controls. Anxious (ANX, n = 22) and control (CTL, n = 23) subjects participated in two double-blind placebo-controlled experiments, one testing ethanol (0.8 g/kg) and the other testing diazepam (20 mg). Subjects sampled and then chose between ethanol and placebo in one experiment, and diazepam and placebo in the other. The main dependent measures were choice of drug over placebo and subjective responses to the drugs. Ethanol decreased self-reported anxiety in ANX subjects, but ANX subjects did not choose ethanol more often than CTL subjects. Diazepam did not measurably reduce anxiety, but ANX subjects nevertheless chose diazepam more often than did CTL subjects. Thus, there were some differences in drug responses between the ANX and CTL subjects, and the study provided limited support for the self-medication hypothesis. However, drug choice was not directly related to anxiolytic drug effects with either ethanol or diazepam. The procedure may be used to test other formulations of the self-medication hypothesis (e.g., examining other psychiatric risk factors).

Adult↗