Acute topiramate differentially affects human aggressive responding at low vs. moderate doses in subjects with histories of substance abuse and antisocial behavior.

Anticonvulsant drugs have demonstrated efficacy in the management of irritability and aggression in a variety of psychiatric populations. We examined the acute effects of topiramate on aggression using a laboratory model of human aggression (PSAP) in individuals at high risk for aggressive and violent behavior.Twelve subjects, on parole/probation and with an Axis-II personality disorder and/or a substance use disorder, received 100, 200, 300, and 400 mg in an ascending sequence, with intervening placebo doses.Subjects participated 2-3 days per week over 4-6 weeks. Due to cognitive side effects at 300 mg, two subjects only completed through the 200 mg dose. Topiramate produced an inverted U-shaped dose response curve, with increases in aggression peaking at 200 mg and a modest decrease at 400 mg. Statistical analysis revealed a polynomial trend for dose (p=0.001). The observed inverted U-shaped function in aggressive responding is consistent with non-human aggression studies of GABA-A modulators. Acute topiramate doses >400 mg may have anti-aggressive effects, but dose levels in the 200-300 mg range may produce increases in aggression and side effects.

Modulation of human risky decision making by flunitrazepam.

RATIONALE: GABA-modulating drugs produce disinhibitory effects that increase the probability of risk-taking behavior. Previous reports suggest that the misuse of the benzodiazepine flunitrazepam is associated with several forms of harmful risky behavior, including theft, violence, and intoxication-related auto accidents. OBJECTIVES: The present study examined the dose-response relationships between acute flunitrazepam administration and human decision making under conditions of risk. The analyses also examined flunitrazepam-mediated changes in decision-making processes using a computational modeling approach, the expectancy valence model (EVM). MATERIALS AND METHODS: Using a laboratory measure of risky decision making designed to address acute drug effects, 12 adults were administered placebo, 0.5, 1.0, and 2.0 mg/70 kg flunitrazepam in a within-subject, repeated measures counterbalanced design. Flunitrazepam was compounded and doses were administered in an 8-oz liquid solution. Primary data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, and personality correlates related to peak drug effects. Individual-subject data were submitted to a computational modeling analysis (EVM) that provided parameter estimates corresponding to components of valence; updating expectancies about alternatives (learning/memory); and consistency between choices and expected outcomes (sensitivity to learned outcomes). RESULTS: Flunitrazepam produced dose-related changes in subjective effects and response rates, and increased selection of the risky response option. High doses significantly changed decision-making processes related to the learning/memory and consistency parameters. CONCLUSIONS: At sufficiently high doses, flunitrazepam can engender increases in risky decision making. Globally, these changes appear similar to previous effects we have observed after acute administration of alcohol and alprazolam. As suggested by the EVM outcomes, the mechanisms underlying the changes in risky decision making are more similar to alprazolam than alcohol.

Effects of acute tiagabine administration on aggressive responses of adult male parolees.

Experimental and clinical studies have supported a relationship between gamma-aminobutyric acid (GABA) and aggressive behavior in non-humans and humans. Tiagabine is a GABA uptake inhibitor that has been shown to produce acute behavioral effects in animals. In addition, tiagabine has been shown to decrease aggression in agitated patients when administered chronically. The present study was designed to investigate the effects of acute administration of tiagabine on aggressive responding on a laboratory task in adult humans. Ten adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape, and monetary-reinforced response options. All subjects received four acute oral doses of Tiagabine (4, 8, 12 and 16 mg) separated by placebo sessions. Tiagabine decreased aggression at doses that either did not affect, or affected to a lesser extent, monetary-reinforced responding. The results are consistent with some prior research using the PSAP showing a possible unique role for GABA in the regulation of human aggression. A possible behavioral mechanism for the rate-decreasing effects on aggressive responding produced in the present study is that tiagabine may modify aggressive responding by suppressing reactions to aversive stimuli.

Human proactive aggression: association with personality disorders and psychopathy.

Aggressive behaviors can be divided into two categories: reactive and proactive. Reactive aggressive behaviors occur in response to a stimulus or provocation. Proactive aggressive behaviors occur without provocation and are goal directed. A number of findings have suggested that individuals displaying proactive aggression may be discerned from individuals not displaying proactive aggression on measures of personality, psychopathology and psychopathy as well as in aggressive histories and type and severity of aggressive behaviors committed. In this study, subjects were recruited from a large urban community and classified as proactive (n = 20), reactive-only (n = 20) or nonaggressive (n = 10) based on laboratory behavioral testing. Subjects were administered a battery of questionnaires and structured interviews pertaining to personality disorders and psychopathy. It was hypothesized that proactive aggressive subjects would show greater numbers of personality disorders and have greater psychopathy relative to reactive-only and nonaggressive subjects. These hypotheses were supported. These results suggest that proactive aggression may be identified in a laboratory-based task, and differences between proactive and reactive-only aggressors can be detected.

Response perseveration and adaptation in heavy marijuana-smoking adolescents.

The present study examined two behavioral processes - response perseveration and response adaptation - in adolescents who were heavy marijuana smokers and control adolescents. Testing took place in a controlled laboratory setting, using customized software and either a computer keyboard or a custom built response panel for response input. Adolescents age 14-18 were recruited into a heavy smoking (near daily) group (N=22) or a control group (N=31) with <15 lifetime uses of marijuana and no history of substance abuse or dependence. Marijuana use was verified by daily quantification of urinary cannabinoids and self-reports. Participants completed laboratory tasks designed to measure response perseveration (Wisconsin Card Sort Task, WCST) and response adaptation (concurrent variable-ratio reinforcement schedule with changing contingencies). Data were analyzed via ANOVA, controlling for multiple factors including: gender, age, nicotine use, presence of conduct disorder, and subscales of the Youth Self Report. After controlling for these compared to controls marijuana-using participants made significantly more perseverative and total errors on the WCST and showed significantly impaired (e.g., less adaptive) response allocation to the changing reinforcement contingencies on the concurrent-reinforcement task. Within the constraints of the study's limitations in controlling for alternative sources of between-subject variability, the data suggest that individuals who regularly smoke marijuana during adolescence show measurable perturbations in important basic behavioral processes. The data are also consistent with a previous laboratory study demonstrating reduced motivation in marijuana-smoking adolescents versus controls [Lane, S.D., Cherek, D.R., Pietras, C.J., and Steinberg, J.L. (2005). Performance of heavy marijuana-smoking adolescents on a laboratory measure of motivation. Addictive Behaviors, 30, 815-828].

Effects of marijuana on temporal discriminations in humans.

Marijuana has been reported to alter the discrimination of time. The present study used a psychophysical approach to examine the effects of marijuana on temporal discrimination in humans. Research participants were required to push one of two buttons depending on the duration of a conditional stimulus (a blue square on a computer monitor). Correct choices ('C' button after a 2-s stimulus; 'A' button after a 4-s stimulus) resulted in an increase in session earnings of 0.12 dollars. Intermediate durations (probe stimuli between 2 and 4 s) were also presented. Psychophysical functions relating the probability of judging a duration as 'long' (4 s) as a function of actual stimulus durations were characterized by a logistic function fitted to the data. Administration of both low (1/2 placebo and 1/2 2.2% Delta (9)-tetrahydrocannabinol cigarette) and high (3.89% Delta(9)-tetrahydrocannabinol) potency marijuana cigarettes produced a bias of judging intervals as long, consistent with an interpretation that subjective time passes more quickly when an individual is intoxicated by marijuana. Deliberation time, operationally defined as response latency, peaked on trials with sample durations that corresponded to the measure of central tendency, and shifted in a similar manner after marijuana administration. The data are consistent with other studies on the effects of marijuana on time estimation.

Individual differences in aggressive responding to intravenous flumazenil administration in adult male parolees.

Nonhuman and human studies have shown that benzodiazepine (BZD) receptor agonists can modify aggressive behaviour. However, it is unknown whether flumazenil, a BZD receptor antagonist, enhances or inhibits aggressive behaviour. The present study was designed to investigate the effects of acute administrations of flumazenil on aggressive responding in adult humans. Six adult males with histories of childhood conduct disorder (DSM IV R) participated in experimental sessions. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP; Cherek 1992), which provided subjects with aggressive and monetary-reinforced response options. Acute doses of flumazenil (2 and 3mg) did not produce statistically significant changes in either monetary-reinforced responding or aggressive responding. The analysis of individual subjects data revealed that aggressive responses varied across subjects. The results are discussed in terms of individual differences based on the previous history of BZD abuse. Additional laboratory research is needed to better clarify the behavioural mechanisms by which BZD receptor antagonists modify human aggressive responding.

Acute effects of alprazolam on risky decision making in humans.

RATIONALE: GABA-A receptor ligands, including benzodiapines, may induce disinhibitory effects that increase the probability of risky decision making. To date, few laboratory studies have examined the acute, dose-related effects of benzodiazepines on human risk-taking behavior. Recent data indicate that in the United States alprazolam is the benzodiazepine most frequently misused for recreational purposes. OBJECTIVES: The present study was designed to demonstrate a dose-response relationship between acute alprazolam administration and human risk taking. Furthermore, this investigation sought to examine: (1) the behavioral mechanisms that may be involved in changes in the probability of risky decision making related to alprazolam administration and (2) risk seeking-related personality variables that may predict drug effects on risk taking. METHODS: Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.5, 1.0, and 2.0 mg alprazolam in a within-subject repeated-measures design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, trial-by-trial response probabilities, and personality correlates related to drug effects at the 2.0-mg dose. RESULTS: Alprazolam administration produced dose-related changes in subjective effects, response rates, and, most importantly, dose-dependently increased selection of the risky response option. The 2.0-mg dose increased the probability of making consecutive risky responses following a gain on the risky response option. Increases at 2.0 mg were related to a combination of personality scales that included high venturesomeness and novelty seeking and low harm avoidance. CONCLUSIONS: Alprazolam administration produced increases in human risk taking under laboratory conditions. In union with previous studies, the observed shift in trial-by-trial response probabilities suggests that sensitivity to consequences (e.g., oversensitivity to recent rewards) may be an important mechanism in the psychopharmacology of risky decision making. Additionally, risk-seeking personality traits may be predictive of acute drug effects on risk-taking behavior.

Performance of heavy marijuana-smoking adolescents on a laboratory measure of motivation.

Marijuana smoking produces effects that may persist for hours or days beyond the period of acute intoxication. Despite evidence that adolescence represents a period of heightened exposure to marijuana, little research exists regarding possible impairment in adolescents who smoke marijuana regularly, and none exists regarding basic behavioral processes. In the present study, adolescents who smoked marijuana on a regular basis (near daily) were compared to a control group of adolescents on a two-option experimental task designed to measure motivation. The contingencies were arranged such that one option (work), which required systematically increasing response output, initially produced greater rates of monetary reinforcement than an alternative option (non-work) that required no response output to earn money. Switching to the non-work option was interpreted as a measure of reduced motivation. Significant differences were found between the groups: the marijuana-smoking participants switched earlier to the non-work option, and derived a greater percentage of their earnings from the non-work option. These differences existed when controlling for differences in cognitive aptitude, gender, and the presence of conduct disorder. A significant correlation between cannabinoid levels and percent of earnings derived from the non-work option suggests that these effects could be associated with the presence of cannabinoids in the marijuana-smoking group.

Marijuana effects on human forgetting functions.

It has long been known that acute marijuana administration impairs working memory (e.g., the discrimination of stimuli separated by a delay). The determination of which of the individual components of memory are altered by marijuana is an unresolved problem. Previous human studies did not use test protocols that allowed for the determination of delay-independent (initial discrimination) from delay-dependent (forgetting or retrieval) components of memory. Using methods developed in the experimental analysis of behavior and signal detection theory, we tested the acute effects of smoked marijuana on forgetting functions in 5 humans. Immediately after smoking placebo, a low dose, or a high dose of marijuana (varying in delta9-THC content), subjects completed delayed match-to-sample testing that included a range of retention intervals within each test session (0.5, 4, 12, and 24 s). Performances (discriminability) at each dose were plotted as forgetting functions, as described and developed by White and colleagues (White, 1985; White & Ruske, 2002). For all 5 subjects, both delta9-THC doses impaired delay-dependent discrimination but not delay-independent discrimination. The outcome is consistent with current nonhuman studies examining the role of the cannabinoid system on delayed matching procedures, and the data help illuminate one behavioral mechanism through which marijuana alters memory performance.

Acute marijuana effects on human risk taking.

Previous studies have established a relationship between marijuana use and risky behavior in natural settings. A limited number of laboratory investigations of marijuana effects on human risk taking have been conducted. The present study was designed to examine the acute effects of smoked marijuana on human risk taking, and to identify behavioral mechanisms that may be involved in drug-induced changes in the probability of risky behavior. Using a laboratory measure of risk taking designed to address acute drug effects, 10 adults were administered placebo cigarettes and three doses of active marijuana cigarettes (half placebo and half 1.77%; 1.77%; and 3.58% Delta9-THC) in a within-subject repeated-measures experimental design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined cardiovascular and subjective effects, response rates, distribution of choices between the risky and nonrisky option, and first-order transition probabilities of trial-by-trial data. The 3.58% THC dose increased selection of the risky response option, and uniquely shifted response probabilities following both winning and losing outcomes following selection of the risky option. Acute marijuana administration thereby produced measurable changes in risky decision making under laboratory conditions. Consistent with previous risk-taking studies, shifts in trial-by-trial response probabilities at the highest dose suggested a change in sensitivity to both reinforced and losing risky outcomes. Altered sensitivity to consequences may be a mechanism in drug-induced changes in risk taking. Possible neurobiological sites of action related to THC are discussed.

Psychopharmacology of conduct disorder: current progress and future directions.

Behavioural manifestations of conduct disorder (CD) among children and adolescents are one of the most common referrals to community psychiatrists. Patients with CD are difficult to treat. The patterns of maladaptive behaviours they exhibit are diverse and can vary as a function of age and gender. Although different pharmacological interventions have been reported as potentially promising options in the treatment of CD, no medication has yet received a formal approval from the licensure authorities, either in the US or Europe. This article reviews efficacy results and associated adverse effects from selected clinical trials that have the strongest outcome evidence for the treatment of CD in children and adolescents. Critical issues in the effectiveness of the evidence-based pharmacotherapy for CD are raised and future directions of the psychopharmacology of CD are examined.

Alcohol effects on human risk taking.

RATIONALE: Despite a well-established relationship between alcohol and risky behavior in the natural environment, laboratory investigations have not reliably shown acute alcohol effects on human risk-taking. OBJECTIVES: The present study was designed to demonstrate a dose-response relationship between acute alcohol administration and human risk taking. Further, this investigation sought to delineate behavioral mechanisms that may be involved in alcohol-induced changes in the probability of risky behavior. METHODS: Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.2, 0.4, and 0.8 g/kg alcohol in a within-subject repeated measures experimental design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and non-risky. Data analyses examined: breath alcohol level (BAL), subjective effects, response rates, distribution of choices between the risky and non-risky option, and trial-by-trial probabilities of making losing and winning risky responses. RESULTS: The alcohol administration produced the expected changes in BAL, subjective effects, and response rate. Alcohol dose-dependently increased selection of the risky response option, and at the 0.8 g/kg dose, increased the probability of making consecutive losing risky responses following a gain on the risky response option. CONCLUSIONS: Acute alcohol administration can produce measurable changes in human risk-taking under laboratory conditions. Shifts in trial-by-trial response probabilities suggest insensitivity to past rewards and more recent losses when intoxicated, an outcome consistent with previous studies. This shift in sensitivity to consequences is a possible mechanism in alcohol-induced changes in risk taking.

Acute effects of gabapentin on laboratory measures of aggressive and escape responses of adult parolees with and without a history of conduct disorder.

RATIONALE: The possible role of GABA in human aggression was evaluated by administering gabapentin to subjects with and without a history of conduct disorder and comparing the effects on laboratory measures of aggression and escape. METHODS: Eighteen male and two female subjects with a history of criminal behavior participated in experimental sessions, which measured aggressive and escape responses. Ten subjects had a history of childhood conduct disorder (CD+) and ten subjects with no history (non-CD controls). Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP), which provided subjects aggressive, escape and monetary reinforced response options. RESULTS: Acute doses (200, 400 and 800 mg) of gabapentin had similar effects on aggressive responses among CD+ subjects compared to non-CD control subjects. Aggressive responses of CD+ and non-CD control subjects increased at lower gabapentin doses, and decreased at the highest 800 mg gabapentin dose. Gabapentin increased escape responses for both CD+ and non-CD controls CD- subjects at the lowest dose, but then produced dose-related decreases at the two higher doses in both groups. No changes in monetary reinforced responses were observed, indicative of no CNS stimulation or sedation. CONCLUSIONS: Gabapentin produced similar bitonic effects upon aggressive and escape responses in subjects with and without a history of childhood conduct disorder. This is in marked contrast to prior differential effects of baclofen on aggressive responses between CD+ and non-CD control subjects in a previous study.

Measurement of delay discounting using trial-by-trial consequences.

DELAY DISCOUNTING IN HUMANS WAS INVESTIGATED USING THREE DIFFERENT PROCEDURES: a frequently used discounting procedure with hypothetical rewards and delays; a procedure with hypothetical rewards and delays compressed down to much smaller values; and a contingent procedure in which each choice had a direct consequence. In the contingent procedure, on every trial, participants actually experienced the delay and obtained the reward amount associated with their choice. Each participant was exposed to all three procedures. Orderly temporal discounting patterns were obtained in all three procedures and described well by a hyperbolic model. Comparisons of the data revealed patterns unique to each procedure. The distributions of the discounting measures differed across the three procedures. In the contingent procedure, several subjects showed no discounting, e.g. complete self-control. Procedural factors in studies of impulsivity are discussed, and suggestions are offered for experiments in which the contingent-discounting procedure may prove useful.

Effects of methylphenidate on impulsive choice in adult humans.

RATIONALE: Several studies with nonhumans and humans have shown that stimulants decrease impulsive choices on delay-to-reinforcement (self-control) procedures. Little is known, however, about the effects of the stimulant methylphenidate on choice for delayed reinforcers in humans. OBJECTIVES: The present study was designed to investigate the effects of acute methylphenidate administrations on impulsive responding in adult humans on a delay-to-reinforcement task. METHODS: Eleven adult males with a history of criminal behavior but no history of attention-deficit hyperactivity disorder (ADHD) participated. Impulsive responding was measured using an adjusting-delay procedure in which subjects were presented with repeated choices between a small amount of money delivered after a short delay and a larger amount of money delivered after a delay that adjusted as a function of previous choices. Subjects were exposed to four experimental sessions each day of participation and 60 min prior to the first daily session received placebo or 0.15, 0.30, or 0.60 mg/kg methylphenidate. Stable choice patterns were re-established between each methylphenidate dose. RESULTS: Individuals differed in their sensitivity to methylphenidate, but in over half of the subjects methylphenidate decreased impulsive (i.e., increased the number of self-control choices) and increased the delay to the large reinforcer. The largest increases in self-control choices tended to occur at the 0.30-mg/kg and 0.60-mg/kg doses, and the effects often persisted across multiple daily sessions. In six subjects, under at least one methylphenidate dose, the number of impulsive choices decreased to zero. CONCLUSIONS: Acute methylphenidate administrations tended to decrease the number of impulsive choices in adult humans on an adjusting-delay procedure, although there were substantial individual differences in the sensitivity of choice to methylphenidate. In no case, however, did methylphenidate increase impulsive choices. These results are consistent with several recent laboratory studies with nonhumans and humans showing that stimulants increase preference for large, delayed reinforcers.

Acute effects of baclofen, a gamma-aminobutyric acid-B agonist, on laboratory measures of aggressive and escape responses of adult male parolees with and without a history of conduct disorder.

RATIONALE: The possible role of gamma-aminobutyric acid (GABA) in human aggression was evaluated by administering baclofen, a GABA-B agonist and comparing the effects on laboratory measures of aggression and escape among subjects with and without a history of conduct disorder. METHODS: Twenty male subjects with a history of criminal behavior participated in experimental sessions, which measured aggressive and escape responses. Ten subjects had a history of childhood conduct disorder (CD+) and ten control subjects had no history of CD. Aggression was measured using the point subtraction aggression paradigm (PSAP), which provides subjects with aggressive, escape, and monetary-reinforced response options. RESULTS: Acute doses (0.07, 0.14 and 0.28 mg/kg) of baclofen had remarkably different effects on aggressive responses among CD+ subjects relative to control subjects. Aggressive responses of CD+ subjects decreased, while aggressive responses of control subjects increased following baclofen administration. Baclofen decreased escape responses for both CD+ and control subjects. No changes in monetary-reinforced responses were observed, indicative of no central nervous system stimulation or sedation. CONCLUSIONS: The GABA-B agonist baclofen suppressed aggressive responses in subjects with a history of childhood CD, while producing the opposite effect in control subjects. These suggest a possible unique role for GABA in the regulation of aggression in CD+ population.

Marijuana effects on sensitivity to reinforcement in humans.

Under controlled laboratory conditions, eight adult subjects smoked placebo and three different potencies of marijuana cigarettes ranging in Delta(9) THC content. Immediately following smoking, subjects were exposed to a laboratory task that provided concurrently available response options. One option systematically decreased in reinforcement frequency throughout the session, and thus required a reallocation of behavior to the non-decreasing option to maximize monetary earnings. After smoking the two highest doses (1.77% and 3.58% Delta(9) THC) subjects earned fewer reinforcers and allocated a higher proportion of responding to the decreasing option, compared with placebo and the lowest dose. The difference in reinforcers earned could not be accounted for by a change in response rates. Quantitative and graphical analyses revealed that the higher doses produced considerable periods of time spent on the decreasing option despite earning few reinforcers. The data are discussed with regard to marijuana effects on dopamine/cannabinoid systems and adaptive behavior change.

Possible amotivational effects following marijuana smoking under laboratory conditions.

Human participants earned money by responding on a progressive-ratio (PR) schedule (initial value $50) or received money without responding on a fixed-time (FT) schedule. During the session, participants could terminate the PR schedule and initiate an FT 200-s schedule. In Experiment 1, increases in monetary value produced increased number of responses, time spent, and money earned in the PR component. In Experiment 2, marijuana smoking produced potency-related reductions in the number of responses, time spent, and money earned in the PR component, effects that can be interpreted as amotivational. Increasing the monetary value of the reinforcer diminished the acute marijuana effects on PR responding, suggesting that marijuana exerted an effect primarily on reinforcers of a smaller magnitude.

Effects of chronic paroxetine administration on measures of aggressive and impulsive responses of adult males with a history of conduct disorder.

RATIONALE: The role of serotonin in human aggression and impulsivity was evaluated by administering paroxetine or placebo for 3 weeks and comparing the effects on laboratory measures of aggression and impulsivity among male subjects with a history of conduct disorder. METHODS: Twelve male subjects with a history of criminal behavior participated in experimental sessions, which measured aggressive and impulsive responses. Six subjects were assigned to placebo treatment and six subjects to placebo and paroxetine treatment. Aggression was measured using the point subtraction aggression paradigm (PSAP), which provides subjects with an aggressive and monetary reinforced response options. Impulsive responses were measured using a paradigm that gives subjects choices between small rewards after short delays versus larger rewards after longer delays. RESULTS: Chronic administration of paroxetine (20 mg/day) for 21 days produced significant decreases in impulsive responses. Decreases in aggressive responses were evident only at the end of paroxetine treatment. Decreases in impulsive and aggressive responses could not be attributed to a non-specific sedative action because monetary reinforced responses were not decreased as has been observed following CNS sedation. CONCLUSIONS: Inhibition of serotonin reuptake by paroxetine is the possible mechanism for reductions in aggressive and impulsive responses. These results support other data linking serotonin function and aggression and impulsivity.