H. de Wit

Effects of methamphetamine on the adjusting amount procedure, a model of impulsive behavior in rats

Abstract Rationale: Moderate doses of d-amphetamine (given both acutely and chronically) have been shown to decrease impulsivity in children with attention deficit hyperactivity disorder (ADHD) and to improve attention and learning in normal adults. In contrast, chronic doses of methamphetamine (METH) in drug abusers have been associated with increased impulsivity, and impairments in learning and attention. Objectives: We report the effects of METH on an animal model of impulsive behavior. Methods: Rats were tested using the adjusting amount (AdjAmt) procedure in which the animals choose between a delayed fixed (large) amount of water and an immediate adjusting (small) amount of water. In the acute METH study, rats were given a single dose of 0.5, 1.0, 2.0, and 4.0 mg/kg METH or saline 30 min before testing. In the chronic METH study, we determined the effects of the 4.0 mg/kg dose of METH injected chronically 1 h after behavioral testing for 14 days. Thus the rats were tested using the AdjAmt procedure 22 h after injections of METH or saline. Results: After 0.5, 1.0 and 2.0 mg/kg METH, the rats valued the delayed large rewards more than after saline, indicating that the METH decreased impulsiveness. At the 4.0 mg/kg dose, the rats failed to respond. Rats treated repeatedly with the post-session large behaviorally disruptive dose of METH valued the delayed large rewards less than the saline-treated rats, indicating that this dosing regimen of METH increased impulsiveness. Conclusions: In these experiments, the rats became less impulsive after acute non-disruptive doses of pre-session METH, whereas they became more impulsive after receiving repeated post-session injections of a dose that was behaviorally disruptive when administered acutely.

INDIVIDUAL DIFFERENCES IN THE REINFORCING AND SUBJECTIVE EFFECTS OF AMPHETAMINE AND DIAZEPAM

This study explored the relation between the reinforcing properties of different drugs and their subjective effects. Preference for a drug (amphetamine or diazepam) over placebo was measured in a choice procedure, and mood changes after drug administration were monitored by self-report questionnaires. Individual differences in behavioral drug preferences were then examined for their relationships to subjective drug responses as well as other subject variables. In Part I, the subjective effects of amphetamine were compared in those subjects who consistently preferred (i.e. chose) amphetamine over placebo, and those who preferred placebo over amphetamine. The two subject groups showed markedly different subjective responses to the stimulant drug: the choosers reported increased positive mood and euphoria, whereas the non-choosers reported only increased anxiety and depression. In Part II, the subjective effects of diazepam in consistent choosers of diazepam were compared to the subjective effects in consistent non-choosers of the drug. The non-choosers showed appreciable subjective effects, which were predominantly sedative in quality. In contrast to the results with amphetamine, the choosers showed negligible subjective drug effects. These results underline the importance of considering more than one response measure when attempting to characterize the reinforcing effects of drugs.

Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women

Rationale: Little is known about the interactions between ovarian hormones across the menstrual cycle and responses to psychoactive drugs in humans. Preclinical studies suggest that ovarian hormones such as estrogen and progesterone have direct and indirect central nervous system actions, and that these hormones can influence behavioral responses to psychoactive drugs. Objectives: In the present study, we assessed the subjective and behavioral effects of d-amphetamine (AMPH; 15 mg orally) at two hormonally distinct phases of the menstrual cycle in women. Methods: Sixteen healthy women received AMPH or placebo capsules during the follicular and mid-luteal phases of their cycle. During the follicular phase, estrogen levels are low initially and then rise while progesterone levels remain low. During the mid-luteal phase, levels of both estrogen and progesterone are relatively high. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Results: Although there were no baseline differences in mood during the follicular or luteal phase, the effects of AMPH were greater during the follicular phase than the luteal phase. During the follicular phase, subjects reported feeling more “High”, “Energetic and Intellectually Efficient”, and “Euphoric” after AMPH than during the luteal phase, and also reported liking and wanting AMPH more. Further analyses showed that during the follicular phase, but not the luteal phase, responses to AMPH were related to levels of estrogen. Higher levels of estrogen were associated with greater AMPH-induced increases in “Euphoria” and “Energy and Intellectual Efficiency”. During the luteal phase, in the presence of both estrogen and progesterone, estrogen levels were not related to the effects of AMPH. Conclusions: These findings suggest that estrogen may enhance the subjective responses to a stimulant drug in women, but that this effect may be masked in the presence of progesterone.

Comparison of the subjective effects of Δ9-tetrahydrocannabinol and marijuana in humans

Rationale. There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Δ9-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form.Objective. Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.Methods. In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC.Results. In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences.Conclusion. These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.

Increased ethanol choice in social drinkers following ethanol preload.

This study showed that normal social drinkers were more likely to consume ethanol after receiving a priming (preload) dose of ethanol. Twenty-eight non-problem drinkers (average consumption 9 drinks/week) participated in a six-session, double-blind choice procedure. On the first two sessions they sampled beverages containing ethanol (0.8 g/kg) or placebo (mix alone), between which they would choose on subsequent choice sessions. On the third session (dummy choice session) subjects were first asked to indicate verbally which beverage they preferred. If they chose the ethanol-containing beverage the experimenter negotiated with each subject to determine the minimum amount of money (from 1 to 30) needed to switch his or her choice from ethanol to placebo. Once this amount was determined it remained fixed for the subsequent three preload/choice sessions. Thus, on choice sessions subjects chose between the beverage which contained ethanol, and placebo plus the amount of money established in Session 3. On the preload/choice test sessions (Sessions 4–6) subjects received preloads of ethanol (0, 0.25 or 0.5 g/kg) 1 h before being given the choice between the sampled ethanol beverage and the placebo beverage plus money. The frequency of ethanol choice was the primary dependent variable. Subjective drug effects, including ratings of desire for the sampled substances, were also measured. Twenty subjects initially chose ethanol on Session 3 and switched their choice with a monetary incentive. Of these 20 subjects, four chose ethanol after the placebo preload, seven chose ethanol after the low-dose ethanol preload, and 11 chose ethanol after the higher ethanol preload (significant linear trend, Mantel-Haenszel test p > 0.03). Ratings of desire for the ethanol-containing beverage increased after the higher preload. These results suggest that ingestion of a moderate dose of ethanol increases the tendency to continue drinking, even among normal social drinkers.

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.

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.

Non-specific effect of naltrexone on ethanol consumption in social drinkers.

Abstract Rationale: Clinical studies have shown that the opioid antagonist naltrexone is effective in the treatment of alcoholism. However, the mechanism by which it produces this effect is not understood. Objective: This study was designed to investigate the effect of acute naltrexone on consumption of ethanol in healthy, non-problem social drinkers. Methods: Subjects (n=24) participated in an eight-session, within-subject, placebo-controlled choice procedure which measured ethanol preference and consumption. The procedure consisted of two blocks of four sessions in which subjects received either naltrexone (50 mg oral) or placebo 1 h before consuming an ethanol or placebo beverage. On the first two sessions of each block, subjects received a color-coded beverage containing ethanol (0.75 g/kg) or placebo, in five equal portions at 15-min intervals. On the next two sessions of each block, subjects chose which beverage they preferred (i.e., placebo or ethanol) and how much they wished to take, in unit doses (placebo or ethanol 0.15 g/kg/dose). The primary behavioral measures were (1) the number of times subjects chose ethanol over placebo, and (2) the number of doses they consumed. Subjects rated their mood states and subjective drug effects at regular intervals during each session. Results: Naltrexone did not alter the frequency of ethanol (versus placebo) choice. Although naltrexone did decrease the total number of ethanol doses subjects took (mean 2.7 doses after naltrexone; 3.4 doses after placebo), it also decreased the number of placebo ”doses” subjects took on sessions when they chose the placebo beverage (mean 1.6 placebo doses after naltrexone; 2.8 doses after placebo). Ethanol produced its prototypic subjective effects (e.g., increased ratings of ”feel drug”, ”like drug” and ”high”), and these effects were not altered by naltrexone. Naltrexone produced mild sedative-like effects, and several subjects reported adverse effects such as nausea. Conclusions: These findings show that naltrexone reduces ethanol consumption in healthy volunteers, as it does in alcoholics. However, this reduction was not specific to alcohol; subjects also consumed less of a non-alcoholic, placebo beverage. These findings suggest that naltrexone may reduce alcohol consumption by a non-specific mechanism.

Lack of preference for flurazepam in normal volunteers.

The reinforcing efficacy of flurazepam (15 and 30 mg) in humans was assessed using an experimental choice procedure. Twelve healthy volunteers were tested in two 3-week choice experiments, in which each dose of the drug was compared to placebo. Subjective effects of the drug (and placebo) were monitored using the Profile of Mood States and a 49-item version of the Addiction Research Center Inventory. The lower dose of flurazepam was chosen equally as often as placebo and produced no significant subjective effects. The higher dose (30 mg) was chosen significantly less often than chance, and produced typical tranquilizer-like effects (e.g., sedation). These results are consistent with previous results using other benzodiazepines such as diazepam and lorazepam, and suggest that the reinforcing efficacy of these drugs in normal volunteers is low.

Drug preference in normal volunteers: Effects of age and time of day

These experiments assessed the influence of two variables, age of subjects and time of drug administration, on the reinforcing properties of amphetamine and of diazepam in normal volunteers. Three groups of subjects were tested: i) a group of 40–55-year-old subjects (AGE group; N=11) who were tested in the morning, ii) a group of 21–35-year-old subjects (CTL group; N=12) who were also tested in the morning, and iii) a group of 21–35-year-olds who were tested in the late afternoon (AFT group; N=13). All subjects participated in three separate experiments comparing one drug (5 mg d,l-amphetamine, 5 mg diazepam or 10 mg diazepam) to placebo. Each experiment consisted of nine sessions: On the first four sessions subjects sampled two color-coded capsules on alternate sessions and on the following five sessions they chose and ingested the capsule they preferred. Subjective effects of the drugs were monitored using the Profile of Mood States (POMS) and a shortened version of the Addiction Research Center Inventory (ARCI). Subjects in all three groups chose 5 mg diazepam as often as placebo but preferred placebo to 10 mg diazepam. In contrast, they chose amphetamine either as often as or more often than placebo. The subjective effects of diazepam (i.e. sedation) were similar across all three groups, but after amphetamine the AGE group showed greater stimulant effects. In addition, the AFT group showed fewer positive mood effects after amphetamine than the CTL group. The AFT and AGE groups also differed from the CTL group on several measures of mood, independently of drug administration. Despite the modest group differences in subjective effects, it was concluded that neither time of day nor age of subjects substantially affected the reinforcing properties of either drug.