John D. Roache

Emerging Biomarkers : New directions and clinical applications

This article summarizes content proceedings of a symposium held at the 2004 Research Society on Alcoholism Scientific Annual Meeting in Vancouver, Canada. The chairs were Friedrich M. Wurst and Raye Litten. The presentations were (1) Introduction, by Raye Litten; (2) Direct Ethanol Metabolites--On the Threshold From Science to Routine Use, by Friedrich M. Wurst; (3) Sialic Acid Index of Plasma Apolipoprotein J (SIJ) as a Viable Marker for Chronic Alcohol Consumption, by Philippe Marmillot; (4) The Emergence of Ethyl Glucuronide (EtG) Testing as a Tool in Monitoring Healthcare Professionals, by Gregory E. Skipper; (5) Application of Biomarkers for Alcohol Use Disorders in Clinical Practice, by Tim Neumann; (6) Utility of Biomarkers in Assessing the Efficacy of Medications for Treating Alcoholism, by Marty Javors; and (7) Discussion, by Raye Litten.

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 subjects 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.

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.

Excess coffee consumption in simulated complex work settings : Detriment or facilitation of performance ?

Twenty-four managers who normally consume between 400 and 1,000 mg of caffeine per day participated in all-day quasi-experimental simulations. In a crossover, doubleblind design, they made complex managerial decisions either on treatment with their typical daily dose of caffeine or on treatment with 400 mg of caffeine in excess of daily consumption. The effect of caffeine treatment on various validated performance indicators was investigated. The impact of excess caffeine consumption was mild. Increased caffeine facilitated speed of response to incoming information but decreased utilization of opportunity. No significance was obtained for other measures of managerial effectiveness (such as activity, breadth, strategy, and emergency response).

Effects of Alcohol Intoxication on Risk Taking, Strategy, and Error Rate in Visuomotor Performance

Adult men (N = 44) participated for 2 days (alcohol vs. placebo treatment) in a double-blind, crossover experiment. Performance on the Digit Symbol Substitution Task (DSST) and a visuomotor (VM) task was measured 4 times each day. On the alcohol-treatment day, data were obtained once during ascending breath alcohol levels (BALs), once during maximal BALs (0.05 or 0.10), and twice during descending BALs. Data were collected at the same time points on the placebo-treatment day. Limited evidence for acute tolerance was obtained with the DSST, but error rates on the VM task were higher during maximal and descending BALs. Error rates remained near placebo values, and participants displayed slightly greater caution, while BALs were ascending. Strategy scores on the VM task exceeded placebo scores during maximal intoxication. Data interpretation is focused on individuals in higher level (e.g., professional) positions.

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

Abstract.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.

Benzodiazepine-induced impairment of matching-to-sample performance in humans

The effects of benzodiazepines on a visual pattern matching-to-sample (MTS) task were examined in nine healthy male volunteers. The MTS task employed randomly generated checkerboard-like stimuli presented on a video display. The sample and two comparison stimuli were simultaneously presented. Nonmatching comparison stimuli were randomly generated to be 3.125, 6.25, 12.5, 25.0, 37.5, or 50.0 percent different from the sample. Subjects responded on left or right button manipulanda to identify the matching comparison stimulus. The nonmatching stimulus condition was maintained constant for a 60-sec component and the percentage difference of the nonmatching stimuli was systematically varied across multiple components. The effects of triazolam (2.25-9.0 micrograms/kg) and lorazepam (7.5-45 micrograms/kg) were examined in a within-subjects, double-blind, placebo-controlled study. Under placebo conditions, response rates and accuracy were a positive function of the nonmatching stimulus discriminability. Triazolam produced dose-related decreases in response rate at nonmatching stimulus conditions greater than or equal to 25%. Only the 9.0 micrograms/kg dose of triazolam decreased accuracy and this occurred across all nonmatching stimulus conditions. Lorazepam effects were qualitatively similar but less robust than those of triazolam.

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.

Relative reinforcing effects of different benzodiazepine doses for rhesus monkeys

The relative reinforcing effects of different doses of benzodiazepines were determined by giving rhesus monkeys concurrent access to different diazepam and midazolam concentrations. For each monkey a dose response function was obtained using three drug concentrations: low (L), intermediate (I), and high (H). The benzodiazepine and the water vehicle were concurrently available under independent fixed-ratio (FR) schedules. After establishing that each concentration was a reinforcer in comparison to vehicle, relative preference for the different concentrations was examined by making pairs of concentrations concurrently available under independent FR schedules. Three pairs were studied (H vs. L, H vs. I, and I vs. L). With both drugs, higher concentrations maintained greater response rates than lower concentrations. Thus, relative reinforcing effects increased with dose. These findings are similar to those obtained with other reinforcing drugs and provide further evidence that benzodiazepines share significant characteristics with other drug reinforcers. Importantly, absolute response rates (responses per session) obtained when only one drug dose was present were not reliably predictive of subsequent preferences for the dose. Both benzodiazepines served as effective reinforcers in that consistent levels of responding were maintained across doses and above vehicle levels under concurrent FR 32 schedules. As with other reinforcing drugs, the reinforcing effects of benzodiazepines increase with increases in dose over a broad range of values.

Effects of methylphenidate on behavioral adjustment in children with mental retardation and ADHD: Preliminary findings from a study in progress

In this preliminary report from a study in progress, the effects of methylphenidate on behavioral adjustment in children (N=13) with mental retardation (MR) and Attention Deficit Hyperactivity Disorder (ADHD) were investigated using a placebo-controlled, double blind, crossover design. Parent and teacher behavioral ratings, and reports of side effects, were obtained with placebo, 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg BID dosages of methylphenidate. Results revealed significant declines in ADHD symptomatology (e.g., inattention, hyperactivity) with medication treatment, with the most significant declines appearing at the 0.60 mg/kg dose of the medication. No significant behavioral improvements (relative to placebo) were noted below the 0.60 mg/kg threshold, i.e., at the 0.15 mg/kg or 0.30 mg/kg dosages. These preliminary results strongly suggest that teachers may be more sensitive raters of symptoms of ADHD, or else may simply have more opportunity to observe the core symptoms of ADHD in a setting in which such symptoms are most likely to be problematic. Although teachers appeared to be more sensitive raters of ADHD symptomatology, parents may have been more sensitive raters of symptoms of side effects than were teachers. Results suggest that both parents and teachers provide important information in titrating stimulant medication in children with MR and ADHD.