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1.  Separate and combined effects of the GABAB agonist baclofen and Δ9-THC in humans discriminating Δ9-THC 
Drug and alcohol dependence  2012;126(1-2):216-223.
Background
Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABAB receptor subtype by assessing the separate and combined effects of the GABAB-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures.
Methods
Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected.
Results
Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone.
Conclusions
These results suggest that the GABAB receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABAB receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABAA) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans.
doi:10.1016/j.drugalcdep.2012.05.023
PMCID: PMC3478434  PMID: 22699093
drug-discrimination; marijuana; subjective effects; repeated acquisition task; digit-symbol-substitution task; cardiovascular
2.  Too little, too late or too much, too early? Differential hemodynamics of response inhibition in high and low sensation seekers 
Brain research  2012;1481:1-12.
High sensation seeking is associated with strong approach behaviors and weak avoidance responses. The present study used functional magnetic resonance imaging (fMRI) to further characterize the neurobiological underpinnings of this behavioral profile using a Go/No-go task. Analysis of brain activation associated with response inhibition (No-go) versus response initiation and execution (Go) revealed the commonly reported right lateral prefrontal, insula, cingulate, and supplementary motor area network. However, right lateral activation was associated with greater No-go than Go responses only in low sensation seekers. High sensation seekers showed no differential activation in these regions but a more pronounced Go compared to No-go response in several other regions that are involved in salience detection (insula), motor initiation (anterior cingulate) and attention (inferior parietal cortex). Temporal analysis of the hemodynamic response for Go and No-go conditions revealed that the stronger response to Go than No-go trials in high sensation seekers occurred in in the earliest time window in the right middle frontal gyrus, right mid-cingulate and right precuneus. In contrast, the greater No-go than Go response in low sensation seekers occurred in the later time window in these same regions. These findings indicate that high sensation seekers more strongly attend to or process Go trials and show delayed or minimal inhibitory responses on No-go trials in regions that low sensation seekers use for response inhibition. Failure to engage such regions for response inhibition may underlie some of the risky and impulsive behaviors observed in high sensation seekers.
doi:10.1016/j.brainres.2012.08.004
PMCID: PMC3637656  PMID: 22902769
Functional magnetic resonance imaging; cognitive control; personality
3.  Expressive talking among caregivers of hematopoietic stem cell transplant survivors: acceptability and concurrent subjective, objective and physiologic indicators of emotion 
Journal of psychosocial oncology  2012;30(3):294-315.
This study sought to examine the effects of an expressive talking intervention for 58 caregiving partners of hematopoietic stem cell transplant survivors, persons known to experience distress. Caregivers were randomly assigned to a 3-session emotional expression (EE) or control condition. Subjective, objective and physiologic indicators of emotion were assessed. Relative to controls, EE participants experienced more negative emotion, uttered more negative emotion words, and perceived the exercises as more helpful and meaningful. The trajectory of skin conductance and the use of cognitive mechanism words increased across EE sessions, suggesting sustained emotional engagement. Future research is warranted to determine the optimal dose and timing of EE for this population.
doi:10.1080/07347332.2012.664255
PMCID: PMC3753090  PMID: 22571245
caregiver; emotional expression; negative affect; skin conductance; oncology
4.  Comparison of the behavioral and cardiovascular effects of intranasal and oral d-amphetamine in healthy human subjects 
Journal of clinical pharmacology  2010;51(6):888-898.
Recent reports indicate an increase in intranasal use of prescription oral stimulant medication. However, there do not appear to be any published clinical studies that have characterized the behavioral and cardiovascular effects of intranasally administered d-amphetamine, which is commonly prescribed for ADHD. In this study, a range of d-amphetamine doses (0, 16, 24 and 32 mg/70 kg) was administered as an intranasal solution delivered using a mucosal atomization device. Equal oral doses were included for comparison. Assessments were conducted before, and at regular intervals for three hours following drug administration, and included self-reported drug-effect questionnaires, cardiovascular indices, a performance task, and two measures of impulsivity. d-Amphetamine produced prototypical stimulant effects (e.g., increased subject ratings of Stimulated and Like Drug, elevated heart rate and blood pressure, and improved rate and accuracy on the DSST) irrespective of dose, but the onset of these effects was generally earlier following intranasal administration, with significant effects emerging at 15–30 minutes after intranasal dosing and 45–60 minutes after oral dosing. These results demonstrate that intranasal administration of d-amphetamine results in a more rapid onset compared to oral dosing, which could be associated with the popularity of intranasal prescription stimulant use and an enhanced potential for abuse.
doi:10.1177/0091270010375956
PMCID: PMC3684273  PMID: 20671295
d-Amphetamine; Intranasal; Subjective; Digit Symbol Substitution Task; Balloon Analog Risk Task; Delay Discounting
5.  Sensation Seeking Predicts Brain Responses in the Old-New Task: Converging Multimodal Neuroimaging Evidence 
Novel images and message content enhance visual attention and memory for high sensation seekers, but the neural mechanisms associated with this effect are unclear. To investigate the individual differences in brain responses to new and old (studied) visual stimuli, we utilized Event-related Potentials (ERP) and functional Magnetic Resonance Imaging (fMRI) measures to examine brain reactivity among high and low sensation seekers during a classic old-new memory recognition task. Twenty low and 20 high sensation seekers completed separate, but parallel, ERP and fMRI sessions. For each session, participants initially studied drawings of common images, and then performed an old-new recognition task during scanning. High sensation seekers showed greater ERP responses to new objects at the frontal N2 ERP component, compared to low sensation seekers. The ERP Novelty-N2 responses were correlated with fMRI responses in the orbitofrontal gyrus. Sensation seeking status also modulated the FN400 ERP component indexing familiarity and conceptual learning, along with fMRI responses in the caudate nucleus, which correlated with FN400 activity. No group differences were found in the late ERP positive components indexing classic old-new amplitude effects. Our combined ERP & fMRI results suggest that sensation-seeking personality affects the early brain responses to visual processing, but not the later stage of memory recognition.
doi:10.1016/j.ijpsycho.2012.03.003
PMCID: PMC3367102  PMID: 22484516
novelty seeking personality; old-new effect; recognition memory; evoked potentials; brain imaging; ERP; fMRI
6.  Performance and subjective effects of diazepam and d-amphetamine in high and low sensation seekers 
Behavioural pharmacology  2009;20(5-6):505-517.
Although sensation-seeking status is associated with age of initiation and amount of drug use among adolescents, and sensitivity to the behavioral and reinforcing effects of drugs among young adults, it is unclear whether sensation-seeking status among adolescents is predictive of sensitivity to the pharmacological effects of drugs (i.e. abuse potential) as adults. This study examined the acute behavioral effects of oral diazepam and d-amphetamine in young adults, ages 18–21 years, who had consistently scored in the highest or lowest third of their grade-based cohort on a modified Sensation Seeking Scale that was completed annually between ages 10 and 14 years. Healthy participants completed 16 7.5-h test days, with test days separated by a minimum of 48 h. Each day, assessments consisting of computer task performance, verbal report of drug effects, and cardiovascular measures were completed 0, 50, 110, 170, 230, and 290 min after drug administration. Placebo and three active doses of diazepam and d-amphetamine (2.5, 5.0 and 10.0 mg/70 kg) were tested under double-blind conditions according to a randomized-block design. Typical stimulant and sedative effects were obtained with d-amphetamine and diazepam, respectively. Drug effects varied as a function of sensation-seeking status, with magnitude of effects on cardiovascular function, task performance, and report of positive drug effects being greater among high sensation seekers, and report of negative drug effects being greater among low sensation seekers. Adolescents who report high levels of sensation seeking on a consistent basis are more sensitive to pharmacological effects of stimulant and sedative drugs that are associated with abuse potential as young adults.
doi:10.1097/FBP.0b013e3283305e8d
PMCID: PMC3148198  PMID: 19654505
abuse potential; d-amphetamine; diazepam; human; performance; personality; sensation seeking; substance abuse; verbal report of drug effect
7.  A translational behavioral model of mood-based impulsivity: implications for substance abuse 
Drug and Alcohol Dependence  2011;122(1-2):93-99.
Background
Laboratory tasks that measure various facets of impulsivity derived from self-report questionnaires are important for elucidating the behavioral consequences of impulsivity in humans and for back-translating these facets to non-human species. Negative urgency, or mood-based rash action, is a self-report facet of impulsivity linked to problem substance use; however, a valid behavioral task is lacking.
Method
The current studies were designed to bridge self-report questionnaire and behavioral measures of negative urgency in humans and to determine if this could be back-translated to rats.
Results
Humans scoring high in negative urgency showed greater behavioral responding and increased frustration following unexpected reward omission on a monetary-based task compared to subjects low in negative urgency. Rats also showed elevated responding for either sucrose pellets or intravenous amphetamine following unexpected reward omission.
Conclusion
These results suggest that impulsive behavior engendered by unexpected reward omission may represent a valid behavioral model of negative urgency linked to substance abuse.
doi:10.1016/j.drugalcdep.2011.09.014
PMCID: PMC3270200  PMID: 21975194
Impulsivity; Negative Urgency; Translational Research; Substance Abuse; Amphetamine; Self-Administration
8.  Separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC 
Drug and Alcohol Dependence  2011;122(1-2):61-69.
Background
The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC using more pharmacologically specific drug-discrimination procedures.
Methods
Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received tiagabine (6 and 12 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected.
Results
Δ9-THC produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on psychomotor performance tasks. The higher tiagabine dose substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. In combination, tiagabine shifted the discriminative-stimulus effects of Δ9-THC leftward/upward and enhanced Δ9-THC effects on other outcomes.
Conclusions
These results indicate that GABA is involved in the clinical effects of Δ9-THC, and by extension, cannabis. Future studies should test selective GABAergic compounds to determine which receptor subtype(s) are responsible for the effects observed when combined with cannabinoids.
doi:10.1016/j.drugalcdep.2011.09.010
PMCID: PMC3307819  PMID: 21975195
drug-discrimination; marijuana; subjective effects; repeated acquisition task; digit-symbol-substitution task; cardiovascular
9.  Influence of estradiol on functional brain organization for working memory 
Neuroimage  2011;59(3):2923-2931.
Working memory is a cognitive function that is affected by aging and disease. To better understand the neural substrates for working memory, the present study examined the influence of estradiol on working memory using functional magnetic resonance imaging. Pre-menopausal women were tested on a verbal n-back task during the early (EF) and late follicular (LF) phases of the menstrual cycle. Although brain activation patterns were similar across the two phases, the most striking pattern that emerged was that estradiol had different associations with the two hemispheres. Increased activation in left frontal circuitry in the LF phase was associated with increased estradiol levels and decrements in working memory performance. In contrast, increased activation in right hemisphere regions in the LF phase was associated with improved task performance. The present study showed that better performance in the LF than the EF phase was associated with a pattern of reduced recruitment of the left-hemisphere and increased recruitment of the right-hemisphere in the LF compared to EF phase. We speculate that estradiol interferes with left-hemisphere working-memory processing in the LF phase, but that recruitment of the right hemisphere can compensate for left-hemisphere interference. This may be related to the proposal that estradiol can reduce cerebral asymmetries by modulating transcallosal communication (Hausmann, 2005).
doi:10.1016/j.neuroimage.2011.09.067
PMCID: PMC3392124  PMID: 21985908
functional magnetic resonance imaging; n-back; menstrual cycle; performance; hemispheric lateralization
10.  Effects of 24 Hours of Tobacco Withdrawal and Subsequent Tobacco Smoking Among Low and High Sensation Seekers 
Nicotine & Tobacco Research  2011;13(10):943-954.
Introduction:
Previous studies have indicated that high sensation seekers are more sensitive to the reinforcing effects of nicotine, initiate smoking at an earlier age, and smoke greater amounts of cigarettes. This study examined the influence of sensation-seeking status on tobacco smoking following deprivation in regular tobacco users.
Methods:
Twenty healthy tobacco-smoking volunteers with low or high impulsive sensation-seeking subscale scores completed 2 consecutive test days per week for 3 consecutive weeks. Each week, a range of self-report, performance, and cardiovascular assessments were completed during ad libitum smoking on Day 1 and before and after the paced smoking of a tobacco cigarette containing 0.05, 0.6, or 0.9 mg of nicotine following 24 hr of tobacco deprivation on Day 2. In addition, self-administration behavior was analyzed during a 2-hr free access period after the initial tobacco administration.
Results:
In high sensation seekers, tobacco smoking independent of nicotine yield ameliorated deprivation effects, whereas amelioration of deprivation effects was dependent on nicotine yield among low sensation seekers. However, this effect was limited to a small subset of measures. Subsequent cigarette self-administration increased in a nicotine-dependent manner for high sensation seekers only.
Conclusions:
Compared with low sensation seekers, high sensation seekers were more sensitive to the withdrawal relieving effects of nonnicotine components of smoking following 24 hr of deprivation on selective measures and more sensitive to nicotine yield during subsequent tobacco self-administration. These results are consistent with studies suggesting that factors driving tobacco dependence may vary as a function of sensation-seeking status.
doi:10.1093/ntr/ntr102
PMCID: PMC3179670  PMID: 21690318
11.  Progesterone effects on the discriminative stimulus, subjective and performance effects of triazolam in healthy, premenopausal women 
Behavioural pharmacology  2011;22(5-6):441-449.
There is accumulating evidence that sex plays a critical role in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, GABAA receptor function is positively modulated by progesterone metabolites. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines, which also serve as positive modulators of GABAA receptors. The purpose of this experiment was to determine the independent and combined discriminative stimulus, subjective and psychomotor effects of progesterone and triazolam in healthy adult premenopausal women. Oral micronized progesterone (100 mg), triazolam (0.06, 0.12 and 0.25 mg/70 kg) and placebo were administered to healthy, premenopausal women (n =9) under conditions of low circulating sex hormones. Triazolam alone functioned as a discriminative stimulus and produced prototypical sedative-like effects (e.g., performance impairment, enhanced reports of sedative effects). Progesterone alone produced sedative-like effects on several subjective and performance measures and the dose combination effects of progesterone and triazolam on several subjective measures of drug effect were similar to the summation of the two drug effects in isolation. Progesterone did not substitute for or modify the discriminative stimulus effects of triazolam. These results suggest that the parent hormone, progesterone, and triazolam have discordant neuropharmacological mechanisms of action. Additional research is necessary to determine the degree to which neurosteroids influence sex differences in benzodiazepine use and abuse.
doi:10.1097/FBP.0b013e328349fc02
PMCID: PMC3172674  PMID: 21808190
Progesterone; Neurosteroid; Benzodiazepine; Triazolam; Women’s health
12.  Separate and combined effects of the cannabinoid agonists nabilone and Δ9-THC in humans discriminating Δ9-THC 
Drug and alcohol dependence  2011;116(1-3):86-92.
Background
Agonist replacement treatment is a promising strategy to manage cannabis-use disorders. The aim of this study was to assess the combined effects of the synthetic cannabinoid agonist nabilone and Δ9-tetrahydrocannabinol (Δ9-THC) using drug-discrimination procedures, which are sensitive to drug interactions. Testing the concurrent administration of nabilone and Δ9-THC was also conducted to provide initial safety and tolerability data, which is important because cannabis users will likely lapse during treatment.
Methods
Six cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received nabilone (0, 1 and 3 mg) and Δ9-THC (0, 5, 15 and 30 mg), alone and in combination. Subjects completed the Multiple-Choice Procedure to assess drug reinforcement, and self-report, task performance and physiological measures were collected.
Results
Δ9-THC and nabilone alone shared discriminative-stimulus effects with the training dose of Δ9-THC, increased crossover point on the Multiple-Choice Procedure, produced overlapping subject ratings and decreased skin temperature. Nabilone alone also elevated heart rate. In combination, nabilone shifted the discriminative-stimulus effects of Δ9-THC leftward/upward and enhanced Δ9-THC effects on the other outcome measures.
Conclusions
These results replicate a previous study demonstrating that nabilone shares agonist effects with the active constituent of cannabis in cannabis users, and contribute further by indicating that nabilone would likely be safe and well tolerated when combined with cannabis. These data support the conduct of future studies to determine if nabilone treatment would produce cross-tolerance to the abuse-related effects of cannabis and reduce cannabis use.
doi:10.1016/j.drugalcdep.2010.11.019
PMCID: PMC3089804  PMID: 21227600
agonist replacement; drug-discrimination; marijuana; multiple-choice procedure; subjective effects; time reproduction; repeated acquisition task; digit-symbol-substitution task; cardiovascular; temperature
13.  Physiological doses of progesterone potentiate the effects of triazolam in healthy, premenopausal women 
Psychopharmacology  2011;215(3):429-439.
Rationale
Gender plays a critical role in the effects of drugs and drug abuse liability. Biological factors, including ovarian hormones, may contribute to gender differences in drug abuse. Preclinical and some clinical research suggests that progesterone and its metabolites have activity at the GABAA receptor and may enhance the effect of GABAergic compounds (e.g., benzodiazepines). Because women are exposed to varying levels of progesterone from puberty until menopause, and appear more sensitive to the negative consequences of benzodiazepine use, it is important to understand the impact of progesterone on GABAergic drug effects.
Objectives
The purpose of this experiment was to characterize the behavioral effects of progesterone, alone and in combination with the short-acting benzodiazepine, triazolam, to determine if progesterone potentiates the behavioral effects of triazolam.
Methods
Oral micronized progesterone (0, 100, and 200 mg) and oral triazolam (0.00, 0.12, and 0.25 mg/70 kg) were administered to healthy, premenopausal women (n=11) under conditions of low circulating sex hormones. The subjective, performance and physiological effects of progesterone, alone and in combination with triazolam, were assessed.
Results
Triazolam alone produced prototypical sedative-like effects. Progesterone alone also engendered some sedative effects, although the time course of the effects was more limited than that of triazolam. Progesterone increased and extended the duration of triazolam effects and delayed the onset of triazolam peak effects, most notably at the 0.12 mg/70 kg dose.
Conclusions
Progesterone potentiates the behavioral effects of benzodiazepines and may contribute to benzodiazepine use and abuse among women.
doi:10.1007/s00213-011-2206-7
PMCID: PMC3137367  PMID: 21350928
Progesterone; Prometrium; Neurosteroid; Benzodiazepine; Triazolam; Subjective effects; Performance effects; Women’s health
14.  Crewmember Performance Before, During, And After Spaceflight 
The development of technologies for monitoring the welfare of crewmembers is a critical requirement for extended spaceflight. Behavior analytic methodologies provide a framework for studying the performance of individuals and groups, and brief computerized tests have been used successfully to examine the impairing effects of sleep, drug, and nutrition manipulations on human behavior. The purpose of the present study was to evaluate the feasibility and sensitivity of repeated performance testing during spaceflight. Four National Aeronautics and Space Administration crewmembers were trained to complete computerized questionnaires and performance tasks at repeated regular intervals before and after a 10-day shuttle mission and at times that interfered minimally with other mission activities during spaceflight. Two types of performance, Digit-Symbol Substitution trial completion rates and response times during the most complex Number Recognition trials, were altered slightly during spaceflight. All other dimensions of the performance tasks remained essentially unchanged over the course of the study. Verbal ratings of Fatigue increased slightly during spaceflight and decreased during the postflight test sessions. Arousal ratings increased during spaceflight and decreased postflight. No other consistent changes in rating-scale measures were observed over the course of the study. Crewmembers completed all mission requirements in an efficient manner with no indication of clinically significant behavioral impairment during the 10-day spaceflight. These results support the feasibility and utility of computerized task performances and questionnaire rating scales for repeated measurement of behavior during spaceflight.
doi:10.1901/jeab.2005.77-04
PMCID: PMC1243980  PMID: 16262187
NASA; spaceflight; operant behaviour; performance measures; self-report measures; humans
15.  Prefrontal Cortex and Drug Abuse Vulnerability: Translation to Prevention and Treatment Interventions 
Brain research reviews  2010;65(2):124-149.
Vulnerability to drug abuse is related to both reward seeking and impulsivity, two constructs thought to have a biological basis in the prefrontal cortex (PFC). This review addresses similarities and differences in neuroanatomy, neurochemistry and behavior associated with PFC function in rodents and primates. Emphasis is placed on monoamine and amino acid neurotransmitter systems located in anatomically distinct subregions: medial prefrontal cortex (mPFC); lateral prefrontal cortex (lPFC); anterior cingulate cortex (ACC); and orbitofrontal cortex (OFC). While there are complex interconnections and overlapping functions among these regions, each is thought to be involved in various functions related to health-related risk behaviors and drug abuse vulnerability. Among the various functions implicated, evidence suggests that mPFC is involved in reward processing, attention and drug reinstatement; lPFC is involved in decision-making, behavioral inhibition and attentional gating; ACC is involved in attention, emotional processing and self-monitoring; and OFC is involved in behavioral inhibition, signaling of expected outcomes and reward/punishment sensitivity. Individual differences factors (e.g., age and sex) influence functioning of these regions, which, in turn, impacts drug abuse vulnerability. Implications for the development of drug abuse prevention and treatment strategies aimed at engaging PFC inhibitory processes that may reduce risk-related behaviors are discussed, including the design of effective public service announcements, cognitive exercises, physical activity, direct current stimulation, feedback control training and pharmacotherapies. A major challenge in drug abuse prevention and treatment rests with improving intervention strategies aimed at strengthening PFC inhibitory systems among at-risk individuals.
doi:10.1016/j.brainresrev.2010.09.001
PMCID: PMC3005953  PMID: 20837060
Anterior cingulate cortex; Dopamine; Drug abuse; GABA; Glutamate; Impulsivity; Lateral prefrontal cortex; Medial prefrontal cortex; Norepinephrine; Orbitofrontal cortex; Serotonin
16.  Effects of d-amphetamine in human models of information processing and inhibitory control 
Drug and alcohol dependence  2005;77(2):151-159.
Although stimulants are generally associated with enhanced information processing, reports of stimulant effects on behavioral functions that rely on inhibitory processes have been inconsistent. The present research tested the joint effects of d-amphetamine on information processing and inhibitory control in healthy adults (N = 22) with no reported history of illicit stimulant use or drug dependence. Information processing was measured by a rapid information processing (RIP) task and inhibitory control was measured using a stop-signal task. Performance was measured in response to 15 mg/70 kg, 7.5 mg/70 kg, and 0 mg/70 mg (placebo) doses of d-amphetamine, administered double-blind in a randomized, within-subjects design. Results showed that d-amphetamine improved information processing in a dose-dependent manner. By contrast, no enhancement of response inhibition was observed. Stimulant effects were also observed in physiological and subjective effects measures. The findings indicate that a stimulant drug can enhance aspects of cognitive functioning without producing a concomitant improvement in inhibitory control of behavior. The findings highlight the complex nature of stimulant effects on human behavior and the utility of performance tasks as models of complex behavioral and cognitive functions.
doi:10.1016/j.drugalcdep.2004.07.013
PMCID: PMC3201830  PMID: 15664716
d-Amphetamine; Response inhibition; Information processing; ADHD; Human
17.  The reinforcing, subject-rated, performance, and cardiovascular effects of d-amphetamine: Influence of sensation-seeking status 
Addictive behaviors  2006;32(6):1177-1188.
Individual differences that may contribute to vulnerability to abuse drugs have been identified. Sensation-seeking status has been shown to influence both vulnerability to drug use and response to acute drug administration. The purpose of the present experiment was to examine the reinforcing effects of d-amphetamine in high and low sensation-seeking subjects using a modified progressive-ratio procedure. A battery of subject-rated, performance, and cardiovascular measures was also included to better characterize the effects of d-amphetamine in these groups. Ten high sensation seekers and ten low sensation seekers that were matched for education, age, drug use, height, and weight, first sampled doses of d-amphetamine (0, 8, and 16 mg). In subsequent sessions, subjects were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. d-Amphetamine functioned as a reinforcer and produced prototypical stimulant-like effects (e.g., increased subject-ratings of Like Drug, enhanced performance, and increased heart rate). High sensation seekers were more sensitive than low sensation seekers to the reinforcing and some of the subject-rated effects of d-amphetamine. The results of the present experiment extend those of previous findings by demonstrating that the reinforcing effects of d-amphetamine vary as a function of the biologically based sensation-seeking personality trait. These results suggest that increased stimulant drug use and abuse among high sensation seekers may be related, in part, to increased sensitivity to the reinforcing effects of stimulants among these individuals.
doi:10.1016/j.addbeh.2006.08.006
PMCID: PMC3191905  PMID: 17011712
d-Amphetamine; Sensation-seeking status; Subject-rated effects; Performance effects; Drug reinforcement
18.  Individual differences in drug abuse vulnerability: d-Amphetamine and sensation-seeking status 
Psychopharmacology  2006;189(1):17-25.
Rationale
While the personality dimensions of novelty seeking and sensation seeking are associated with drug abuse vulnerability, the mechanisms associated with this vulnerability remain obscure.
Objective
This study examined the behavioral effects of d-amphetamine in healthy volunteers scoring in the upper and lower quartiles based on age- and gender-adjusted population norms on the impulsive Sensation-Seeking Scale (SSS) of the Zuckerman–Kuhlman personality questionnaire (ZKPQ).
Method
Participants completed 7-day outpatient studies examining the subjective, performance, and cardiovascular effects of d-amphetamine (0, 7.5, and 15 mg/70 kg, p.o.) under double-blind conditions according to a randomized block design. Performance tasks included behavioral measures of impulsivity, including attention, inhibition, and risk-taking behavior.
Results
No differences in baseline performance or d-amphetamine effects on measures of attention, inhibition, and risk-taking behavior were observed. High impulsive sensation seekers reported greater increases on several subjective report measures associated with drug abuse potential, including visual analog scales feel drug, like drug, and high.
Conclusions
Healthy adults scoring in the top quartile on the population of the impulsive SSS of the ZKPQ may be vulnerable to the abuse potential of d-amphetamine.
doi:10.1007/s00213-006-0487-z
PMCID: PMC3188427  PMID: 16972106
d-amphetamine; Sensation-seeking status; Vulnerability; Subjective effects; Performance effects; Abuse potential
19.  Measurement of the Subjective Effects of Methylphenidate in 11- to 15-Year-Old Children with Attention-Deficit/Hyperactivity Disorder 
Objective
This study examined subjective and other behavioral effects of methylphenidate (MPH) among adolescents.
Methods
Standard abuse liability assessment methods that have been used in adult populations were modified for attention-deficit/hyperactivity disorder (ADHD) adolescents. MPH effects (0, 0.25 mg/kg) were evaluated under randomized, double-blind conditions in two 5-hour laboratory sessions in 24 (13 female) 11–15 year olds diagnosed with ADHD.
Results
Repeated measures analysis of covariance indicated significant dose and dose by time interactions on subjective ratings on the modified amphetamine (A) [F (1, 20) = 5.98; p < 0.05; η2 = 0.36], morphine–benzedrine group (MBG) [F (1, 21) = 8.93 p < 0.01; η2 = 0.38] and benzedrine group scale (BG) [F (1, 21) + 13.10 p < 0.01; η2 = 0.37] scales of the Addiction Research Center Inventory; “Hungry” and “How sure are you that you got the medication today?” from the Visual Analogue Scale, the Profile of Mood States Depression scale, performance on the Continuous Performance Task, heart rate and blood pressure, and level of activity.
Conclusions
This is the first study to document subjective effects of stimulants in adolescents with ADHD that have been associated with drug abuse potential in adults. There are increasing concerns about nontherapeutic stimulant use in adolescents and young adults. Assessing subjective effects of pharmacotherapies for ADHD along with other measures of abuse potential such as drug self-administration may aid in assessing the therapeutic effects and/or risk of medications used in the treatment of ADHD.
doi:10.1089/cap.2006.0020
PMCID: PMC3184246  PMID: 17343554
20.  Caffeine Use: Association with Nicotine Use, Aggression, and Other Psychopathology in Psychiatric and Pediatric Outpatient Adolescents 
TheScientificWorldJournal  2008;8:512-516.
The objective of this study was to evaluate the relationship between caffeine use, other drug use, and psychopathology in adolescents, using self-report measures. The study group consisted of 132 adolescents (average age 14.01 ± 2.06 years, 52% female, 19% African American, 5% other categories, 76% Caucasian). Most (47%) were recruited from a child psychiatry clinic with emphasis on youth with disruptive disorders, with 35% from an adolescent pediatric clinic with emphasis on prevention of risk-taking behavior and 18% from a pediatric clinic for families with limited resources. Subjects were consecutively recruited before or after regular clinic visits. Consent was obtained from parents and assent from the youth. High caffeine consumption was associated with daily cigarette use; aggressive behavior; conduct, attention deficit/hyperactivity, and social problems; and increased somatic complaints in adolescents.
doi:10.1100/tsw.2008.82
PMCID: PMC3176831  PMID: 18516472
adolescence; risk behavior; caffeine; child health; human development; psychopathology
21.  Neural Correlates of Emotional Reactivity in Sensation Seeking 
Psychological science  2009;20(2):215-223.
High sensation seeking has been linked to increased risk for drug abuse and other negative behavioral outcomes. This study explored the neurobiological basis of this personality trait using functional magnetic resonance imaging (fMRI). High sensation seekers (HSSs) and low sensation seekers (LSSs) viewed high- and low-arousal pictures. Comparison of the groups revealed that HSSs showed stronger fMRI responses to high-arousal stimuli in brain regions associated with arousal and reinforcement (right insula, posterior medial orbitofrontal cortex), whereas LSSs showed greater activation and earlier onset of fMRI responses to high-arousal stimuli in regions involved in emotional regulation (anterior medial orbitofrontal cortex, anterior cingulate). Furthermore, fMRI response in anterior medial orbitofrontal cortex and anterior cingulate was negatively correlated with urgency. Finally, LSSs showed greater sensitivity to the valence of the stimuli than did HSSs. These distinct neurobiological profiles suggest that HSSs exhibit neural responses consistent with an overactive approach system, whereas LSSs exhibit responses consistent with a stronger inhibitory system.
doi:10.1111/j.1467-9280.2009.02283.x
PMCID: PMC3150539  PMID: 19222814
22.  A COMPARISON OF THE ASSOCIATIONS OF CAFFEINE AND CIGARETTE USE WITH DEPRESSIVE AND ADHD SYMPTOMS IN A SAMPLE OF YOUNG ADULT SMOKERS 
Journal of addiction medicine  2010;4(1):52-54.
Objectives
This study examined the relationship between psychiatric symptoms and nicotine, caffeine, alcohol, and marijuana use in young adult smokers
Methods
Young adult smokers completed self-report measures of nicotine, caffeine, alcohol and marijuana use, Conner's Adult ADHD (Attention-Deficit/Hyperactivity Disorder) Rating Scale-Short Version (CAARS-SS), Beck Depression and Anxiety Inventories (BDI and BAI), and provided a breath carbon monoxide (CO) sample.
Results
Self-reported cigarette use was positively correlated with carbon monoxide, CAARS-SS and the BDI levels. Caffeine intake was correlated with CAARS-SS, BAI and BDI levels and emerged as the more significant predictor of BDI, BAI and CAARS-SS scores when regressed with cigarette use.
Conclusions
Caffeine use is associated with psychiatric symptoms in young adult cigarette smokers and should be considered in future research.
doi:10.1097/ADM.0b013e3181b508ec
PMCID: PMC3043357  PMID: 21359163
nicotine; caffeine; alcohol; marijuana
23.  The reinforcing, self-reported, performance and physiological effects of Δ9-tetrahydrocannabinol, triazolam, hydromorphone and methylphenidate in cannabis users 
Behavioural pharmacology  2010;21(1):29-38.
The use of illicit prescription drugs is common in cannabis users; however, the effects of few psychoactive drugs have been characterized in this population. In the present study, Δ9-tetrahydrocannabinol (i.e., Δ9-THC), triazolam, hydromorphone and methylphenidate were administered to cannabis users (N=8). Subjects completed the Multiple-Choice Procedure to assess drug reinforcement, as well as self-report questionnaires and performance tasks; physiological assessments were also conducted. Only Δ9-THC increased the crossover point on the Multiple-Choice Procedure, but all of the drugs increased ratings on one or more “positive” drug-effect questionnaire items, as well as items specific for each drug. Triazolam produced the most robust performance impairment, except on a time reproduction task, which was impacted to a greater degree by Δ9-THC. Δ9-THC elevated heart rate and decreased temperature, triazolam increased heart rate, methylphenidate elevated all cardiovascular indices, and hydromorphone reduced respiration. The effects of the drugs tested in the present study were generally consistent with their known pharmacology, although minimal responses to hydromorphone were observed. Future research to directly compare the effects of different psychoactive drugs in cannabis users and non-users would be useful for identifying potential differences in drug effects as a function of use history.
doi:10.1097/FBP.0b013e32833470d7
PMCID: PMC2903043  PMID: 19949319
marijuana; multiple-choice procedure; subjective effects; time reproduction; repeated acquisition task; digit-symbol-substitution task; cardiovascular; respiration; temperature; human
24.  Human experience seeking correlates with hippocampus volume: convergent evidence from manual tracing and voxel-based morphometry 
Neuropsychologia  2007;45(12):2874-2881.
Experience-seekers continuously pursue novel environmental stimuli, a tendency linked to genetic variation in mesolimbic dopamine transmission. However, the neuroantomical basis accompanying these genetic and neurochemical associations is unknown. Animal and human experimental results suggest a central role for the hippocampus in processing novel stimuli. Here, we explored whether differences in human experience seeking are related to variations in hippocampal volume. High resolution anatomic MR images were analyzed in 40 individuals who ranged from low through high on a validated experience seeking personality scale. Manual tracing analysis demonstrated positive correlation between right hippocampal volumes and scores on the experience seeking scale. A separate voxel-based morphometric analysis confirmed these results and localized the significant increase to the anterior portion of right hippocampal grey matter. We tested and were able to reject the possibility that results were mediated by a personality trait related to, but distinct from, experience seeking. The present data provide the first direct evidence for a relationship between human experience seeking and brain structure. In addition, these results provide new ecologically relevant evidence for a link between right anterior hippocampus and novelty processing.
doi:10.1016/j.neuropsychologia.2007.05.009
PMCID: PMC2971547  PMID: 17603086
25.  Brain responses to repeated visual experience among low and high sensation seekers: role of boredom susceptibility 
Psychiatry research  2009;173(2):100-106.
To better understand individual differences in sensation seeking and its components, including boredom susceptibility and experience seeking, we examined brain responses of high and low sensation seekers during repeated visual experience. Individuals scoring in the top and bottom quartiles from a college-aged population on the Brief Sensation-Seeking Scale (BSSS) participated in an event-related potentials (ERPs) experiment. Line drawings of common objects were randomly intermixed and presented 1–3 times. Sixty-four channel ERP responses were recorded while participants classified items as “man-made” or “not man-made” in a repetition priming task. The two groups showed different ERP responses at frontal electrode sites after seeing a visual stimulus for 400–800 ms. The frontal late positive components (LPC) showed different habituation of ERP responses to new and studied repeated objects between high and low sensation seekers. Source localization analysis (LORETA) indicated that during visual stimulus adaptation the left ventral pre-frontal cortex showed lack of frontal involvement among high sensation seekers. Furthermore, frontal LPC latencies during repeated visual exposure correlated with boredom susceptibility and experience seeking subscales. The distinct profiles of brain responses to repeated visual experience in high and low sensation seekers provide evidence that individual differences in neural adaptation can be linked to personality dimensions.
doi:10.1016/j.pscychresns.2008.09.012
PMCID: PMC2774088  PMID: 19560906
sensation seeking; repetition effect; EEG/ERP; priming; LORETA; LPC

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