Biomedical subjects

J D Roache

Publications and source records attributed to J D Roache.

At least 19 recordsLinked to original sources

PubMed2006

Dissociation of physiology and behavior in PTSD.

We have previously reported that subjects with posttraumatic stress disorder (PTSD) differ from trauma controls in their ability to produce and withhold responses in the Stop-Signal Task depending on the motivational context as determined by financial reward. This experiment measured skin conductance and heart rate to assess autonomic changes accompanying these different patterns of behavior. Fowles hypothesized that heart rate would increase with behavioral activation and that increases in skin conductance would accompany behavioral inhibition. Both PTSD and comparison groups showed the expected behavioral changes in response to rewards, but they differed in their physiological responses. The subjects in the traumatized comparison group showed changes in skin conductance and heart rate consistent with Fowles' hypothesis and the observed changes in behavioral inhibition and activation. However, PTSD subjects showed no significant change in either physiological measure. These results demonstrate a dissociation between autonomic reactivity and motivated behavior in PTSD that may represent one aspect of emotional numbing.

Adult↗

PubMed2002

Orally delivered alprazolam, diazepam, and triazolam as reinforcers in rhesus monkeys.

RATIONALE: Benzodiazepines are among the most frequently prescribed drugs and are usually taken by mouth. However, there have been few studies of oral self-administration of these drugs, and the results of IV self-administration studies indicate that benzodiazepines are modest reinforcers. OBJECTIVES: To determine if orally delivered alprazolam, diazepam, and triazolam could serve as reinforcers for rhesus monkeys, and to determine some of the conditions under which benzodiazepine reinforced behavior occurs. METHODS: Diazepam or midazolam was initially established as a reinforcer by a fading procedure whereby increasing concentrations were added to a 1 or 2% ethanol solution, and subsequently the ethanol concentration was decreased in steps to zero. Diazepam- and midazolam-reinforced responding persisted in the absence of ethanol. Triazolam and alprazolam served as reinforcers when substituted for diazepam or midazolam. RESULTS: Alprazolam, diazepam, and triazolam served as effective reinforcers across a wide range of concentrations and under fixed-ratio sizes of 16 and 32. Rates of responding were usually far higher than that for the concurrently available vehicle, water. Drug intake (mg drug/kg body weight) generally increased with increases in drug concentration. When large drug amounts were consumed, signs of intoxication were observed. CONCLUSIONS: In contrast to reports of low response rates and weakly maintained behavior, the present results show that the three benzodiazepines can serve as effective reinforcers.

Administration, Oral↗

PubMed2001

Combining ondansetron and naltrexone treats biological alcoholics: corroboration of self-reported drinking by serum carbohydrate deficient transferrin, a biomarker.

BACKGROUND: Recently, we showed by using self-report that combining ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) was effective at reducing drinking and increasing abstinence among early-onset alcoholics (EOAs), who are characterized by a range of antisocial behaviors and high biological and familial disease predisposition. Here, we investigated whether the self-reported differences in drinking would be corroborated by measurements of serum carbohydrate-deficient transferrin (CDT) level, a sensitive, reliable, and well-validated marker of transient alcohol consumption. METHOD: An 8-week double-blind clinical trial was performed in which 20 EOAs were randomized to receive ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized cognitive behavioral therapy. Serum CDT was assessed at weeks 0 (baseline), 4, and 8. RESULTS: Log serum CDT was significantly lower in the ondansetron and naltrexone group (group mean, 1.44 +/- 0.076) compared with the placebo group (group mean, 1.82 +/- 0.113), as evidenced by a main effect of group [F(1,15) = 7.2, p = 0.017; effect size = 0.32], visit [F(1,16) = 11.2, p = 0.004; effect size = 0.41], and an interaction between group and visit [F(1,16) = 27.54, p < 0.001; effect size = 0.63]. CONCLUSIONS: The combination of ondansetron plus naltrexone was superior to placebo at reducing serum CDT. This corroborated our self-reported drinking data and demonstrated that the medication combination is an effective treatment for EOAs.

Adult↗

PubMed2000

Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population.

Subtyping alcoholics may provide a more accurate guide as to the course and character of the disease. Classifications of different ages of onset of problem drinking have so far resulted in categorical inconsistencies. In the past, hospital-based alcoholics have over-represented those most severely ill, and comprehensive evaluations of psychopathology for discriminating between alcoholic subtypes have been infrequent. In a heterogeneous treatment-seeking, outpatient, alcoholic population, we tested the hypothesis that age of onset represents a continuum of disease, and that greater severity of psychopathology is associated with lower ages of onset. Using a standard questionnaire, 253 male and female treatment-seeking alcoholics were stratified according to specific ages of onset: a) < 20 years; b) 20-25 years, and c) > 25 years. These age of onset groups were compared on alcohol severity and craving, family history, childhood behavior, personality, hostility, overt aggression, mood, and social functioning. Symptom severity and age of onset were negatively correlated, and the 20-25-year onset group usually had intermediate scores. The < 20 year onset group was characterized by greater severity of alcohol-related problems, family history, childhood behavioral problems, craving, hostility, antisocial traits, mood disturbance, and poor social functioning. Alcoholics with an earlier age of onset have relatively greater psychopathology than those of later onset. While the preponderance of psychopathology among those in the < 20-year onset group could be conceptualized as a clinical "subtype," such a characterization would not define an entirely homogeneous category. Yet, this clinical characterization would be clinically important if specific age of onset levels were found to be differentially sensitive to pharmacological and/or psychological treatments.

Adult↗

PubMed2000

Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.

Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated because of cardiovascular toxicity or medication abuse potential. However, they also suggest that the subjective effects of methylphenidate may not be positive enough for an adequate replacement approach.

Adult↗

PubMed1999

Isradipine, a dihydropyridine-class calcium channel antagonist, attenuates some of d-methamphetamine's positive subjective effects: a preliminary study.

RATIONALE: Dopamine (DA) pathways in the midbrain mediate d-methamphetamine's rewarding effects associated with its abuse liability. Isradipine, a dihydropyridine-class calcium channel antagonist, reduces the rewarding effects of psychostimulants such as cocaine and d-amphetamine, presumably by antagonizing these central DA pathways. This is the first experiment to test the hypothesis that the rewarding effects of d-methamphetamine, like other psychostimulants, can be reduced by isradipine. OBJECTIVE: We studied the effects of high dose isradipine (0.21 mg/kg orally), on the positive subjective effects associated with the abuse liability of low and high dose d-methamphetamine (0.21 mg/kg and 0.42 mg/kg orally, respectively). METHODS: Using a double-blind, double-dummy, placebo-controlled, Latin-Square, cross-over design, 18 healthy male and female volunteers received each of the following six treatments separated by a rest period of 2-7 days: a) placebo+placebo; b) low-dose d-methamphetamine+placebo); c) high-dose d-methamphetamine+placebo; d) high dose isradipine+placebo); e) low-dose d-methamphetamine+high dose isradipine, and f) high-dose d-methamphetamine+high dose isradipine. RESULTS: d-Methamphetamine produced orderly increases in positive subjective measures of both stimulation and mood. Pre-treatment with isradipine significantly reduced some of these positive subjective effects and craving for d-methamphetamine. CONCLUSION: Isradipine as an anti-reward or craving reducing medication is a promising therapeutic agent for the treatment of d-methamphetamine dependence.

Adrenergic Agents↗

PubMed1999

Predictors of individual differences in alprazolam self-medication.

Twenty-seven patients with generalized anxiety or panic disorder participated in a 6-week outpatient study. Participants received capsules containing either alprazolam or placebo and were free to choose between them for anxiety treatment. Measures of drug use included alprazolam preference, amount, and frequency of use. Alprazolam clearly was preferred over placebo; however, there were large between-subjects differences in the amount of medication used. A variety of demographic, drug history, personality, mood, and expectational variables were examined for correlation with medication use. Findings indicated that a substantial amount of variance in medication use could be explained by patients' intake characteristics. Findings also suggested that the tendency to consume capsules frequently may signal a greater risk factor for dependence than does drug preference in and of itself.

Adult↗

PubMed1997

Alprazolam-reinforced medication use in outpatients with anxiety.

The reinforcing effects of alprazolam were investigated in 14 patients who had generalized anxiety or panic disorder, but were not current users/abusers of other psychoactive substances. Using a double-blind outpatient choice procedure, color-coded alprazolam (0.5 mg) and placebo capsules were provided to patients for use 'as needed' in the treatment of anxiety symptoms. Comparisons of alprazolam and placebo during a 2 week sampling period in which placebo and alprazolam were available sequentially revealed no significant differences on measures of medication usage or anxiety levels, although alprazolam did increase subjective ratings of drug effects side effects. During a 4 week choice period, alprazolam was strongly preferred over placebo in 11 out of 14 patients indicating that alprazolam functioned as a reinforcer. Medication usage ranged from zero to 4.0 mg alprazolam in a day. Variations in daily medication-use were positively correlated with anxiety level fluctuations for a majority of patients. For a majority of patients, the results indicate that alprazolam functioned as a reinforcer without accompanying signs of abuse or addiction.

Adult↗

PubMed1997

Ethanol and pentobarbital: comparison of behavioral and subjective effects in sedative drug abusers.

The behavioral and subjective effects of acute oral doses of placebo, ethanol (0.5, 1.0, and 2.0 g/kg), and pentobarbital (150, 300, 600, and 750 mg/70 kg) were compared in 8 male volunteers with histories of sedative drug abuse using a double-blind, double-dummy, cross-over design. Ethanol and pentobarbital produced similar dose-related decrements in psychomotor and cognitive performance and exhibited a similar profile of effects on staff- and participant-rated measures. There was some evidence indicating that, at the highest dose, pentobarbital was perceived by participants as being more sedating than ethanol and that pentobarbital has a greater abuse liability than ethanol. In conjunction with the results of previous human laboratory studies comparing the effects of different types of sedative-hypnotic drugs, these results support a mostly barbiturate-like rather than benzodiazepine-like profile of effects for ethanol.

Adult↗

PubMed1997

Replacement medication for cocaine dependence: methylphenidate.

Agonists, or "replacement medications," are useful adjuncts in treatment of opiate and nicotine dependence. They have not been systematically examined in cocaine dependence. Results of early open trials with methylphenidate for treatment of cocaine dependence were equivocal. Twenty-four cocaine-dependent subjects were enrolled in an 11-week double-blind, placebo-controlled study of methylphenidate. Assignment was random. Intake included a 2-day human laboratory procedure in which subjects received initial doses of methylphenidate or placebo. Subjects attended the clinic Monday through Friday and received oral doses of methylphenidate (5 mg plus 20-mg sustained release) or placebo at 8:00 a.m., with afternoon and weekend take-home doses (20 mg sustained-release or placebo) provided in Medication Events Monitoring System bottles to monitor compliance. Clinic visits included therapy sessions, electrocardiograms, self-report measures, and twice-weekly urine screens. The two groups were equivalent in terms of retention (methylphenidate 48% and placebo 42%) and had similar cocaine use outcomes (40% benzoylecgonine-positive urine screens). There were no significant adverse effects. The doses were sufficient to permit detection of psychoactive effects ("stimulant," "more energy") and side effects ("jitteriness," "eating less") without increased "craving." Additional medications with different effects profiles are being studied to further evaluate the replacement model in cocaine dependence.

Adult↗

PubMed1997

Human ethanol self-administration. I: The interaction between response requirement and ethanol dose.

The effects of work requirement on human ethanol self-administration were systematically examined. Healthy volunteers with a history of moderate alcohol consumption (12 to 16 drinks per week) were recruited as subjects. Four subjects self-administered 4, 8 or 16% w/v ethanol solution contingent upon completion of a fixed-ratio (FR) response requirement. The ratio requirements were FR 32, FR 64 and FR 128 responses. Ethanol consumption at lower doses decreased with increases in FR. Ethanol consumption at the high dose was greatest across all ratio requirements and was unchanged by increases in the ratio requirement, indicating greater relative reinforcing effects of the high dose of ethanol. Ethanol consumption was sensitive to unit price with 53-82% of the variance explained by the unit price analysis.

Adult↗

PubMed1995

Effects of caffeine deprivation on complex human functioning.

Twenty-five managers who reported an average daily caffeine consumption of 575 mg participated in two complex simulations. A double-blind cross-over design was employed to assess the effects of normal caffeine consumption versus caffeine deprivation upon seven validated measures of managerial effectiveness. Data from a Caffeine Withdrawal Questionnaire indicated discomfort upon deprivation. Systolic blood pressure increased during "normal" caffeine consumption levels but fell quickly and remained lower during deprivation. Several measures of managerial performance indicated decreased effectiveness upon caffeine deprivation. In contrast to prior research from simpler task settings, cognitive effectiveness (during complex task performance) was diminished. However, a measure of strategic performance which requires a relatively high level of cognitive effort showed no impact of caffeine deprivation.

Adult↗

PubMed1995

Reinforcing effects of triazolam in sedative abusers: correlation of drug liking and self-administration measures.

Six male subjects with histories of sedative abuse were allowed to orally self-administer a maximum of 18 color-coded triazolam and placebo capsules during daily 3-h sessions. The schedule of reinforcement was a signaled fixed-interval 10-min schedule in which triazolam and placebo were concurrently available as mutually exclusive choices. Triazolam was shown to be a reinforcer in four of the six subjects. The two subjects who did not self-administer triazolam in preference to placebo also had lesser histories of drug dependence. Self-administration of triazolam (0.125 or 0.25 mg per capsule) was generally stable over 7-10 days. Manipulations of triazolam dose (0.0312-0.25 mg) per capsule in two subjects showed that the number of capsules self-administered was inversely related to capsule dose. Subject ratings of drug liking obtained from experimenter-administered doses of triazolam were correlated with self-administration behavior occurring 1-7 days later. Of the subject ratings, next day ratings obtained on the day after dosing resulted in significant correlations whereas same day ratings obtained while subjects were under the influence of triazolam did not. These results have important implications for abuse liability prediction and suggest that next day ratings have greater predictive validity than measures collected while subjects are under the influence of benzodiazepines.

Adult↗

PubMed1994

The effects of smoked marijuana on progressive-interval schedule performance in humans.

In three experiments, 8 human subjects participated in a study of the effects of smoked marijuana on progressive-interval schedule performance. A two-component chained progressive-interval fixed-interval schedule of point delivery was used. In the progressive-interval component, the interval length began at 20 s and increased either geometrically or arithmetically (by either 20 s, 40 s, 80 s, 100 s, or 160 s) on each subsequent interval. After this interval elapsed, a single button press produced the fixed-interval component, with a total of five reinforcers of varying magnitude ($0.05, $0.20, or $0.40) available on a fixed-interval 20-s schedule. After the five reinforcer deliveries, the schedule returned to the initial progressive-interval component. Several relationships were found among rates of responding, postreinforcement pauses and drug administration in the progressive-interval component: (a) Postreinforcement pauses increased as the temporal requirements of the progressive-interval schedule increased; (b) rates of responding during successive progressive-interval components rapidly decreased to low rates of responding after the first few progressions; (c) postreinforcement pauses decreased systematically as dose of smoked marijuana increased; and (d) rates of responding increased after smoking active marijuana but not after smoking placebo cigarettes. Results are discussed in the context of behavioral control and relevance to other studies that have investigated the effects of smoked marijuana on schedule performance.

Adult↗

PubMed1994

Establishing benzodiazepines as oral reinforcers: midazolam and diazepam self-administration in rhesus monkeys.

Oral benzodiazepine self-administration was examined in four adult male rhesus monkeys with histories of ethanol- and pentobarbital-reinforced behavior. Drug solutions and vehicle were concurrently available for 3-hr each day under fixed-ratio (FR) reinforcement schedules. Initially, the monkeys rejected a midazolam solution (0.1 mg/ml) after direct substitution of the drug for an 8% ethanol solution. However, midazolam self-administration was subsequently established by using a fading procedure in which increasing amounts of drug (0.0125-0.2 mg/ml) were gradually added to an 8% ethanol solution, followed by gradual reduction of the ethanol concentration to zero. Midazolam was an effective reinforcer for three of four monkeys tested, i.e., responding that was maintained by the drug solution exceeded that maintained by the drug vehicle. The fourth monkey also self-administered midazolam but drug-maintained responding was not consistently greater than vehicle-maintained responding. The responding maintained by the drug was an inverted-U-shaped or bitonic function of midazolam concentration. The midazolam intake (in milligrams per kilogram) increased as a function of increases in the drug concentration. At the higher concentrations, marked sedative intoxication was observed. There was an inverse relationship between FR size (varied from FR 8 to FR 32) and the amount of drug self-administered. The three monkeys in which midazolam functioned as a reinforcer were then tested with diazepam (0.2 mg/ml), which maintained drug self-administration behavior on direct substitution for 0.2-mg/ml midazolam. Diazepam-maintained responding usually exceeded water responding as the diazepam concentration was increased to 0.8 mg/ml. These data demonstrate robust reinforcing effects of both "short-" and "long-acting" benzodiazepines delivered by the oral route.

Administration, Oral↗

PubMed1993

Acute effects of marijuana smoking on aggressive, escape and point-maintained responding of male drug users.

Aggressive, escape and point-maintained operant responding of male marijuana smokers were measured during six 25-min sessions conducted over an 8-h experimental day. Aggressive responding ostensibly subtracted points exchangeable for money from another subject. Escape responding protected the subject's counter from point subtractions initiated by the other subject for some period of time. Aggressive and escape responding were engendered by subtracting points from the subjects and maintained by initiation of intervals free of point subtractions. Point subtractions presented to the subjects were attributed to other persons. Subjects earned points exchangeable for money on a third response option. Subjects participated in one session prior to smoking and five sessions after smoking. Subjects smoked placebo or three different potencies of active marijuana cigarettes. Marijuana smoking effects on escape responding were not significant and depended upon the frequency of provocation. Point-maintained responding was decreased after marijuana smoking. Aggressive responding was increased for the first hour after smoking and returned to placebo levels later in the day. These effects of marijuana smoking on aggressive responding are discussed in terms of subject characteristics, particularly drug use history.

Adult↗

PubMed1993

Triazolam and ethanol effects on human matching-to-sample performance vary as a function of pattern size and discriminability.

The effects of placebo, triazolam (2.0, 4.0 and 8.0 micrograms/kg) and ethanol (0.25, 0.5, 1.0 g/kg) on perceptual-motor performance were examined using a visual pattern matching-to-sample procedure in which pattern size and comparison stimulus discriminability were systematically varied. Baseline response rates and accuracy increased as the discriminability of the comparison stimuli increased. At the highest dose, both drugs decreased response accuracy. This disruption of accuracy was attenuated by increasing the discriminability of non-matching stimuli. Triazolam produced dose-related decreases in response rate while ethanol produced only slight decreases at the highest baseline rates of responding. Thus, triazolam produced response rate slowing at relatively lower doses than ethanol.

Adult↗

PubMed1993

Differential effects of triazolam and ethanol on awareness, memory, and psychomotor performance.

Eight normal, healthy, male volunteers each received four triazolam doses (0, 2, 4, and 8 micrograms/kg) and four ethanol doses (0, 0.25, 0.5 and 1.0 g/kg) in a double-blind, double-dummy experiment in which within-subject dose sequence was determined by a balanced Latin square design. Triazolam and ethanol produced dose-related and time-related effects on subject ratings of mood and perceived drug effects and objective measures of memory and psychomotor performance. Dose-response curves for the two drugs were not parallel, and therefore, comparisons of the two drugs were based upon comparisons of the high dose of each drug. Although the two high-dose conditions generally were not different from one another, there were differences in their relative effect sizes, which were important. The high dose of each drug produced comparable degrees of impairment on two different psychomotor tasks. Triazolam, but not ethanol, produced significant impairment on two different memory tasks. The relative effects of each drug on subject ratings of mood and perceived drug effects varied across different subject-rated measures. Only ethanol significantly increased subject ratings of alcohol strength and feeling drunk. In comparison to ethanol, triazolam tended to produce less-pronounced subject ratings of drug effect magnitude, drug liking, and estimated performance impairment. However, less-pronounced subjective effects of triazolam were not universally observed on all subject ratings. Triazolam produced greater effects on several sedative symptoms and produced comparable effects on several mood factor scales.

Adult↗