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Introduction: Stimulant drugs are thought to alter processing of rewarding stimuli. However, the mechanisms by which they do this are not fully understood. Method: In this study we used EEG to assess effects of single doses of methamphetamine (MA) on neural responses during anticipation and receipt of reward in healthy volunteers. Healthy young men and women (N = 28) completed three sessions in which they received placebo, a low MA dose (10 mg) or a higher MA dose (20 mg) under double blind conditions. Subjective and cardiovascular measures were obtained, and EEG was used to assess brain activity during an electrophysiological version of the Monetary Incentive Delay (eMID) task. Results: EEG measures showed expected patterns during anticipation and receipt of reward, and MA produced its expected effects on mood and cardiovascular function. However, MA did not affect EEG responses during either anticipation or receipt of rewards. Conclusions: These findings suggest that the effects of MA on EEG signals of reward processing are subtle, and not related to the drug's effects on subjective feelings of well-being. The findings contribute to our understanding of the neural effects of MA during behaviors related to reward. [ABSTRACT FROM AUTHOR]

Rationale: Stimulant drugs like methamphetamine (MA) activate brain reward circuitry, which is linked to the development of problematic drug use. It is not clear how drugs like MA alter neural response to a non-drug reward. Objectives: We examined how acute MA impacts neural response to receipt of a monetary reward relative to a loss in healthy adults. We hypothesized that MA (vs. placebo) would increase mesolimbic neural activation to reward, relative to loss. Methods: In a within-subject, randomized, cross-over, double-blind, placebo-controlled design, 41 healthy adults completed the Doors monetary reward task during fMRI after ingestion of placebo or 20 mg MA. We examined drug effects on neural response to reward receipt (Win vs. Loss) using a priori anatomical striatal regions of interest (nucleus accumbens (NAcc), caudate, putamen). Results: MA decreased NAcc BOLD activation to reward vs loss compared to placebo (p=.007) without altering caudate or putamen BOLD activation. Similar effects for reward vs. loss were obtained using whole brain analysis. Additional exploratory ROI analysis comparing reward and loss activation relative to a neutral "fixation" period indicated that MA increased NAcc BOLD activation during loss trials, without decreasing activation during win trials. Conclusions: This preliminary evidence suggests that MA increases NAcc neural response to the receipt of monetary loss. Additional studies are needed to replicate our findings and clarify the mechanisms contributing to altered mesolimbic neural response to reward and loss receipt during stimulant intoxication. [ABSTRACT FROM AUTHOR]

RationaleOver the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute.MethodsHere, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites.Results2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α2-adrenoceptor subtypes. 2-AI had particularly high affinity for α2C receptors (Ki = 41 nM) and slightly lower affinity for the α2A (Ki = 134 nM) and α2B (Ki = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor.Conclusions2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability.

RATIONALE: Attentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior. OBJECTIVES/METHOD: An attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm. RESULTS: Poor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps  0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training. CONCLUSIONS: ABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

Rationale: Exposure to rewards can alter behavioral reactivity to them. For example, stimulants sensitize locomotor activation, whereas sexual experience sensitizes copulatory behaviors. Moreover, rewards can cross-sensitize one another. Although stimulants are known to cross-sensitize locomotor effects, the evidence for cross-sensitization between stimulants and sex is less clear. Objectives: This study determined the effects of single and repeated pre-exposure to methylphenidate (MPH) or sex on one another in adult male rats. Methods: Cross-sensitization between MPH (5 mg/kg) and sex (30 min with sexually experienced female) was examined. Adult male rats were pre-exposed to 0, 1, or 10 trials of either sex or MPH before being exposed to the other reward. Locomotor chambers were used in MPH trials. Bilevel chambers were used in sexual trials, and sexual behaviors were video scored. Results: The amount of prior sexual experience differentially influenced the ceiling of MPH-dependent sensitization; in the last drug trial, locomotion was highest in males given 1 previous sexual trial compared with 0 or 10. Compared with MPH-naive males, pre-exposure to MPH (1 and 10 trials) reduced the number of ejaculations without impacting sexual performance (intromission/mount latency and frequency). Conclusions: These findings indicate that the degree of pre-exposure to a reward can differentially affect reactivity to novel rewards. The results showed that previous findings of cross-sensitization between amphetamine and sex do not extend to MPH. However, exposure to MPH prior to sexual experience can increase the amount of sexual stimulation needed to achieve ejaculation. [ABSTRACT FROM AUTHOR]

Rationale: ±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that shows substantial promise as a psychotherapeutic agent. Still, there is some concern regarding its behavioral toxicity, and its dose-effect relationship is poorly understood. We previously explored the role of dose in the cognitive effects of MDMA in a systematic review of existing literature and found no evidence in animals that MDMA impairs memory at low doses (< 3 mg/kg) but mixed results at high doses (≥ 3 mg/kg). Since this review comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted. Objectives: The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMA-induced amnesia, and to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression. Methods: We systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice. Results: High doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviors. Conclusions: The present dose-ranging study provides further evidence that 3 mg/kg is the threshold for MDMA-induced amnesia. These findings, in addition to our systematic review, demonstrate that careful selection of MDMA dose is critical. High doses (≥ 3 mg/kg) should likely be avoided due to evidence that they can produce amnesia and addiction. Conversely, there is little evidence to suggest that low doses, which are usually administered in clinical studies (approximately 1–2 mg/kg), will lead to these same adverse effects. Ultra-low doses (< 1 mg/kg) are likely even safer and should be investigated for therapeutic effects in future studies. [ABSTRACT FROM AUTHOR]

Rationale: Misuse of dextroamphetamine occurs in work and recreational contexts. While acute drug effects broadly predict abuse liability, few studies have considered the relationship between acute effects and context. Objectives: This study examined how individual differences in acute effects of dextroamphetamine relate to desire to take dextroamphetamine again in different contexts. Methods: This secondary analysis used data from healthy adults with no history of moderate-to-severe substance use disorder, who received oral doses of placebo and dextroamphetamine (10 and 20 mg) over 3 sessions under double-blind, randomized conditions. Subjects rated subjective effects and completed reward-related behavioral tasks. Subjects rated their desire to take dextroamphetamine again in hypothetical work and recreational contexts. Multilevel models examined within-subjects change scores (10 mg-placebo; 20 mg-placebo) to determine how subjective effects and behavioral outcomes predicted desire to take dextroamphetamine again for work versus recreation. Results: Subjects reported more desire to take 20 mg dextroamphetamine again for work than for recreation. At 20 mg, there was an interaction between context and liking/wanting, such that liking/wanting predicted desire to use dextroamphetamine for work only. There was also an interaction at 20 mg between context and psychomotor speed, such that psychomotor speed predicted interest in using dextroamphetamine for recreation only. Conclusions: We found that positive subjective effects predicted desire to use dextroamphetamine again for work, while increased motor effects predicted desire to use dextroamphetamine recreationally. Hedonic effects may be perceived as advantageous when working, while increased physical energy may be preferred during recreation, suggesting that context of intended use is important when examining abuse liability. [ABSTRACT FROM AUTHOR]

Rationale: Currently there is little research into the role of frustration in substance use disorders despite research showing that frustration tolerance in humans is associated with a lower likelihood of developing substance use problems, better outcomes in recovery, and fewer relapses. Objective: In order to address this need, our studies use a rat model to focus on frustration-related behavior in natural reward and addiction-related behavioral procedures. Frustration is defined as when a subject is unable to achieve a reinforcer, receives less of a reinforcer than anticipated, or has to work harder to achieve a reinforcer. Results: In these studies, bar-press durations increase when rats are in a state of frustration during self-administration of sucrose, fentanyl, or cocaine. Conclusions: These data also show that average bar-press durations do not correlate with the number of bar presses, meaning that press duration is an independent measurement that represents a behavioral construct distinct from craving, which is typically measured with number of bar presses. Essentially, these results support that bar press durations can be used as a real-time measure of frustration as a 4th major facet of addiction-related behavior, adding to craving, impulsivity, and habit. [ABSTRACT FROM AUTHOR]

Rationale: Systemic administration of the tobacco smoke constituent nicotine stimulates brain reward function in rats. However, it is unknown if the inhalation of tobacco smoke affects brain reward function. Objectives: These experiments investigated if exposure to smoke from high-nicotine SPECTRUM research cigarettes increases reward function and affects the rewarding effects of nicotine in adult male and female Wistar rats. Methods: Reward function after smoke or nicotine exposure was investigated using the intracranial self-stimulation (ICSS) procedure. A decrease in reward thresholds reflects an increase in reward function. In the first experiment, the rats were exposed to tobacco smoke for 40 min/day for 9 days, and the rewarding effects of nicotine (0.03–0.6 mg/kg) were investigated 3 weeks later. In the second experiment, the dose effects of tobacco smoke exposure (40-min sessions, 1–4 cigarettes burnt simultaneously) on reward function were investigated. Results: Tobacco smoke exposure did not affect the nicotine-induced decrease in reward thresholds or response latencies in male and female rats. Smoke exposure lowered the brain reward thresholds to a similar degree in males and females and caused a greater decrease in latencies in females. There was a positive relationship between plasma nicotine and cotinine levels and the nicotine content of the SPECTRUM research cigarettes. Similar smoke exposure conditions led to higher plasma nicotine and cotinine levels in female than male rats. Conclusion: These findings indicate that tobacco smoke exposure enhances brain reward function but does not potentiate the rewarding effects of nicotine in male and female rats. [ABSTRACT FROM AUTHOR]

Rationale: Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute. Methods: Here, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites. Results: 2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α2-adrenoceptor subtypes. 2-AI had particularly high affinity for α2C receptors (Ki = 41 nM) and slightly lower affinity for the α2A (Ki = 134 nM) and α2B (Ki = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor. Conclusions: 2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability. [ABSTRACT FROM AUTHOR]

Rationale: Research documents a reciprocal impact of anxiety on working memory (WM), although its strength and direction depend on factors like task difficulty. A better understanding of these factors may generate insights into cognitive mechanisms of action involved in anxiety, culminating into treatment implications. By blocking the physiological effects of anxiety, propranolol might also block anxiety interference on WM. Conversely, by improving task-directed attention, methylphenidate might reduce anxiety, or, alternatively, by improving cognitive efficiency and free up processing resources to compute anxiety. Objectives: To investigate the interplay between induced anxiety and WM, we pharmacologically manipulated either anxiety or cognition, using single doses of 40 mg propranolol (PRO), 20 mg methylphenidate (MPH), or placebo (PLA). In this double-blind parallel-group design study, 60 healthy volunteers (20/drug group) performed a verbal WM task under three loads, 1-, 2- and 3-back, and in two conditions, threat of shock and safety. Startle electromyography (EMG) was used to measure anxiety. Results: Findings were twofold: (1) MPH blocked anxiety interference only on the 3-back WM performance, while PRO or PLA had no effects on anxiety-WM interference, and (2) drugs had no effects on anxiety, but, after controlling for baseline anxiety, MPH enhanced anxiety-potentiated startle during the 3-back task. Conclusions: These findings support that MPH-related improvement of cognitive efficiency permits anxiety to be processed and expressed. In conclusion, MPH may be a useful tool to investigate the mechanisms of interaction between anxiety and WM, particularly those under catecholaminergic control. [ABSTRACT FROM AUTHOR]

Rationale: Stimulant use is a significant and prevalent problem, particularly in criminal populations. Previous studies found that cocaine and methamphetamine use is related to impairment in identifying emotions and empathy. Stimulant users also have abnormal neural structure and function of the ventromedial prefrontal cortex (vmPFC), amygdala, and anterior (ACC) and posterior cingulate (PCC), regions implicated in moral decision-making. However, no research has studied the neural correlates of stimulant use and explicit moral processing in an incarcerated population. Objectives: Here, we examine how stimulant use affects sociomoral processing that might contribute to antisocial behavior. We predicted that vmPFC, amygdala, PCC, and ACC would show abnormal neural response during a moral processing task in incarcerated methamphetamine and cocaine users. Methods: Incarcerated adult males ( N = 211) were scanned with a mobile MRI system while completing a moral decision-making task. Lifetime drug use was assessed. Neural responses during moral processing were compared between users and non-users. The relationship between duration of use and neural function was also examined. Results: Incarcerated stimulant users showed less amygdala engagement than non-users during moral processing. Duration of stimulant use was negatively associated with activity in ACC and positively associated with vmPFC response during moral processing. Conclusions: These results suggest a dynamic pattern of fronto-limbic moral processing related to stimulant use with deficits in both central motive and cognitive integration elements of biological moral processes theory. This increases our understanding of how drug use relates to moral processing in the brain in an ultra-high-risk population. [ABSTRACT FROM AUTHOR]

Rationale: Addiction is a disease of learning and memory, as learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play central roles in addiction. Early developmental stress enhances risk for drug problems in adulthood. Environmental factors influencing learning and memory processes relevant to addiction remain incompletely characterized. Objectives: To determine effects of prenatal immune activation and developmental stress on conditioned place preference to amphetamine, and reversal learning. Methods: Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or vehicle on gestational day 14. Half of the male offspring received 2 h of restraint stress at post-natal day 35. Behavioral testing was performed in adulthood. Results: Restraint stress inhibited acquisition of place preference to low-dose amphetamine (0.5 mg/kg), while poly I:C treatment had no measurable effect on place preference acquisition. In contrast, drug-induced reinstatement of preference for drug-paired chamber was enhanced in offspring of poly I:C-treated dams [ F(1,25) = 5.31, p = 0.03]. Performance on a Morris water maze reversal learning task was impaired in poly I:C offspring. Reversal learning performance was correlated with place preference reinstatement in non-stressed ( r = 0.42, p = 0.0095), but not stressed rats ( r =0.04, p = 0.49). Conclusions: Prenatal immune activation enhances drug-induced reinstatement of conditioned place preference. These data demonstrate longstanding impact on behaviors with potential influence on risk for drug relapse as a consequence of prenatal immune activation. Further study is needed to determine clinical and epidemiological consequences of similar exposures in human populations. [ABSTRACT FROM AUTHOR]

Rationale: Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups. Objectives: The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias. Methods: Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N = 56,013). Results: From the total comparisons identified, a small magnitude effect was evident ( d = .15; p < .00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons ( n = 3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect ( d = .58; p < .00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples ( d = .61) compared with studies using nonclinical samples ( d = .45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate. Conclusions: These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed. [ABSTRACT FROM AUTHOR]

Caffeine typically produces positive effects on mood and performance. However, tolerance may develop following habitual use, and abrupt cessation can result in withdrawal symptoms, such as fatigue. This study investigated whether caffeine has a greater stimulant effect in a withdrawn state compared to a normal caffeinated state, among moderate daily caffeine consumers. Using a within-subjects design, 17 caffeine consumers (mean ± sd = 375 ± 101 mg/day) ingested placebo or caffeine (250 mg) following 30-h of caffeine abstention or normal dietary caffeine use on four separate days. Self-reported mood and performance on choice reaction time, selective attention, and memory tasks were measured. Caffeine had a greater effect on mood and choice reaction time in the abstained state than in the normal caffeinated state, but caffeine improved selective attention and memory in both states. Although improvements in mood and reaction time may best explained as relief from withdrawal symptoms, other performance measures showed no evidence of withdrawal and were equally sensitive to an acute dose of caffeine in the normal caffeinated state. [ABSTRACT FROM AUTHOR]

Recommended medication prescribing hierarchies for adult attention-deficit hyperactivity disorder (ADHD) vary between different guideline committees. Few trials directly compare competing ADHD medications in adults and provide little insight for clinicians making treatment choices. The objective of this study was to assess comparative benefits and harms of competing medications for adult ADHD using indirect comparison meta-analysis. Eligible studies were English-language publications of randomized controlled trials comparing ADHD drugs to placebo. Data sources were electronic bibliographic databases, Drugs@FDA, manufacturer data, and reference lists. Two reviewers independently abstracted data on design, internal validity, population, and results. Benefits and harms were compared between drug types using indirect comparison meta-regression (ratio of relative risks). Twenty-two placebo-controlled trials were included ( n = 2,203). Relative benefit of clinical response for shorter-acting stimulants, primarily immediate release methylphenidate, was 3.26 times greater than for patients taking longer-acting stimulants (95% CI 2.03, 5.22) and 2.24 times greater than for patients taking longer-acting forms of bupropion (95% CI 1.23, 4.08). Immediate release methylphenidate is also the only drug shown to reduce ADHD symptoms in adults with substance abuse disorders. Neither non-stimulants nor longer-acting stimulants reduced adverse effects compared to shorter-acting stimulants. Key gaps in evidence were academic, occupational, social functioning, cardiovascular toxicity, and longer-term outcomes, influences of ADHD subtype and/or comorbidities, and misuse/diversion of the drugs. Current best evidence supports using immediate release methylphenidate as first-line treatment for most adults with ADHD. [ABSTRACT FROM AUTHOR]

Rationale: Studies with laboratory animals demonstrating different effects of self- vs experimenter-administered drug suggest that the ability to control or predict drug delivery may be an important determinant of drug action. Objective: This study assessed whether self-administered and yoked cocaine injections produce different effects in humans. Methods: Ten inpatient volunteers with experience in using cocaine participated in a double-blind, yoked design during which four experimental test sessions were conducted. During two sessions, participants controlled if and when up to six 40 mg/70 kg i.v. cocaine injections were given. During two sessions, participants received noncontingent exposure to the same pattern of injections given during the preceding session (i.e., yoked) under blind conditions. Sessions followed a fixed-order, ABAB design. Measures of subjective and physiological response to cocaine were taken throughout each session. Results: Cardiovascular safety parameters were exceeded in some individuals after yoked, but not self-administered, cocaine resulting in some scheduled injections being delayed or withheld. Mean systolic and diastolic blood pressures were higher following yoked compared to self-administered cocaine. In contrast, analysis of the subjective effects revealed only small and generally nonsignificant differences in the effects of self-administered vs yoked cocaine. Conclusions: These results suggest that under the laboratory methods employed, control over the schedule of drug delivery may not alter the subjective effects of cocaine in humans. In contrast, the cardiovascular effects of cocaine appear to be greater when the drug is administered noncontingently. [ABSTRACT FROM AUTHOR]

Rationale: Stimulant addicts exhibit increased behavioural disinhibition under the influence of the drug. In laboratory animals, however, the effects of amphetamine on behavioural disinhibition are equivocal, and the effects of cocaine have not been investigated. Objectives: The current set of experiments was designed to test the effects of cocaine on behavioural disinhibition and to assess whether the possible impairments are due to deficits in conditional discrimination or attention. Methods: Separate groups of rats were trained to respond in an asymmetrically reinforced Go/No-go task, a Conditional discrimination task or a Vigilance task. Upon reaching criterion performance, animals were treated with cocaine (0-20 mg/kg) immediately prior to testing. Results: Cocaine (15 mg/kg) increased No-go interval responses, indicating an increase in behavioural disinhibition. Conditional discrimination was also impaired by cocaine (15 and 20 mg/kg); animals made more incorrect trials per completed trial. Cocaine-treated animals also made more premature responses in this task, indicating increased behavioural disinhibition independent of a conditional discrimination deficit. Finally, cocaine (0-20 mg/kg) had no effect on vigilance. Conclusions: Administration of moderate to high doses of cocaine increases behavioural disinhibition, and this increase may be independent of an impairment in conditional discrimination. [ABSTRACT FROM AUTHOR]

Aims. Not every tablet sold as "ecstasy" contains MDMA (3,4-methylenedioxymethamphetamine). The historical origins and evolution of this mismatch will be reviewed, in order to estimate the proportions of ecstasy tablets containing MDMA at different periods over the past 30 years. Methods. Surveys into the pharmacological constituents of ecstasy tablets, dosage levels, and empirical reports of their perceived purity, provide the main data for this review. Results. During the 1980s and early 1990s there were few problems with the purity of ecstasy tablets, and the biochemical evidence shows that they nearly always contained MDMA. During the mid-1990s, the majority of ecstasy tablets continued to contain MDMA, while many others comprised MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxyethylamphetamine), or amphetamine drug mixtures. However, a small proportion (4-20% according to survey, time and place), comprised non-amphetamine drugs such as caffeine, ephedrine, ketamine, paracetamol, or placebo. During the late 1990s, the proportion of ecstasy tablets containing MDMA increased to around 80-90%. The latest reports suggest that non-MDMA tablets are now very infrequent, with purity levels between 90% and 100%. Dosage levels of tablets are also highly variable, with low dose tablet often encountered during the mid-1990s, and high dose tablets now seen more frequently. The theoretical and practical implications of these findings will be debated. Conclusions. The ecstasy purity problem was predominantly a phenomenon of the mid to late 1990s, when many tablets contained substances other than MDMA. Before and since then, the proportion of ecstasy tablets containing MDMA has been very high. [ABSTRACT FROM AUTHOR]

Rationale. Impaired ability to refrain from initiating cocaine-taking is a central feature of cocaine dependence and an important target for behavioral and pharmacological interventions. One potential trigger of cocaine-taking is exposure to cocaine (i.e. priming). Objective. Here, we report a model of human cocaine self-administration that quantifies the ability to refrain from initiating cocaine self-administration during abstinence and after cocaine administration. Methods. In a double-blind, within-subject, residential laboratory study, we assessed cocaine-taking as a function of the choice dose, priming dose, and the magnitude of alternative reinforcement. During each of 3 weeks, cocaine-dependent volunteers participated in one sample and three choice sessions. During sample sessions, participants were administered the dose of cocaine (0, 15 or 30 mg/70 kg IV) available during subsequent choice sessions that week. During choice sessions, participants chose between cocaine and decreasing amounts of money ($19, $16, $13, $10, $7, $4, $1). A priming dose of cocaine (0, 15 or 30 mg/70 kg) was administered 30 min prior to the first choice trial during each of three choice sessions each week. Results. Cocaine-taking was moderate, dose-dependent, and negatively related to the monetary alternative. An active priming injection of cocaine compared to placebo shifted choice to cocaine over money earlier in the session. Conclusions. A descending schedule of alternative reinforcement provided a measure of cocaine-taking during abstinence that was sensitive to cocaine choice dose, magnitude of alternative reinforcement, and priming. This procedure may be a useful tool for assessing potential therapies for cocaine dependence. [ABSTRACT FROM AUTHOR]

Rationale. Low doses of ethanol stimulate locomotion in mice, but in rats the typical response to peripheral ethanol administration is a dose-dependent suppression of locomotion. Moreover, chronic ethanol administration fails to produce signs of locomotor sensitization in rats. Objective. The present study was undertaken to determine whether intraventricular (i.c.v.) infusions of low doses of ethanol (as determined by comparisons with systemic doses, and by analyses of brain extract ethanol levels) could increase locomotor activity in rats after acute or repeated administration. Methods. Male rats received acute doses of ethanol i.p. (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) or i.c.v. (0.0, 0.7, 1.4, or 2.8 μmol) and were tested for motor activity. In a third experiment, repeated i.c.v. vehicle or ethanol (2.8 μmol) was administered for 15 sessions over a 30-day period, and motor activity was recorded. This phase was followed by a single challenge session, in which a low dose of ethanol (0.7 μmol) was injected i.c.v. to both groups of rats. Results. Rats injected with i.p. ethanol showed no increase in activity at low doses, with higher doses suppressing activity. In contrast, i.c.v. injections of low doses of ethanol increased motor activity. After repeated administration, ethanol-treated rats were more sensitive than control-treated rats to the locomotor stimulant effect of ethanol. Conclusions. These results demonstrate that central administration of low doses of ethanol can increase locomotor activity in rats and suggest that i.c.v. ethanol can produce some signs of motor sensitization, a characteristic that has been related to the potential addictive properties of many drugs. [ABSTRACT FROM AUTHOR]

Rationale. Increased sleepiness while working and sleep disruptions are common complaints among shift workers. Consequently, shift workers may be more susceptible to diminished performance and work-related accidents. Objective. To examine the effects of the central nervous system stimulant methamphetamine on psychomotor task performance, subjective effects, and food intake during shift work under laboratory conditions. Methods. Seven participants completed this 23-day, within-participant design, residential laboratory study. They received a single oral methamphetamine dose (0, 5, 10 mg) 1 h after waking for three consecutive days under two shift conditions: (1) during the day shift, participants performed computerized psychomotor tasks from 0830 hours to 1730 hours and went to bed at 2400 hours and (2) during the night shift, participants performed tasks from 0030 hours to 0930 hours and went to bed at 1600 hours. Shifts alternated three times during the study; shift conditions were separated by an "off" day during which participants were not on a schedule and data were not collected. Results. When participants received placebo, psychomotor task performance and subjective effects were disrupted during the night shift, relative to the day shift. Changing shift conditions did not alter food intake significantly. Methamphetamine reversed performance and subjective-effects disruptions, and decreased food intake during the night shift. Conclusion. These data indicate that shift changes produce performance impairments and mood alterations, and that a single low to moderate dose of methamphetamine attenuates many shift change-related disruptions in performance and mood. [ABSTRACT FROM AUTHOR]

This study assessed the ability of high doses of caffeine to reverse changes in alertness and mood produced by prolonged sleep deprivation. Fifty healthy, nonsmoking males between the ages of 18 and 32 served as volunteers. Following 49 h without sleep, caffeine (0, 150, 300, or 600 mg/70 kg, PO) was administered in a double-blind fashion. Measures of alertness were obtained with sleep onset tests, the Stanford Sleepiness Scale (SSS), and Visual Analog Scales (VAS). Sleep deprivation decreased onset to sleep from a rested average of 19.9 min to 7 min. Following the highest dose of caffeine tested, sleep onset averaged just over 10 min; sleep onset for the placebo group averaged 5 min. Scores on the SSS increased from a rested mean of 1.6-4.8 after sleep deprivation. Caffeine reduced this score to near rested values. Caffeine reversed sleep deprivation-induced changes in three subscales of the POMS (vigor, fatigue, and confusion) and produced values close to fully rested conditions on several VAS. Serum caffeine concentrations peaked 90 min after ingestion and remained elevated for 12 h. This study showed that caffeine was able to produce significant alerting and long-lasting beneficial mood effects in individuals deprived of sleep for 48 h. [ABSTRACT FROM AUTHOR]

Caffeine is thought to have stimulant-like behavioral effects on mood and performance. However few behavioral studies have examined this substance's acute effects when administered in a range of doses that include the low doses typically found in foods and over-the-counter drugs. We therefore gave single doses of caffeine (32, 64, 128 and 256 mg) to 20 healthy male subjects and assessed various aspects of performance and self-reported mood states, as well as plasma caffeine concentration. As little as 32 mg (which elevated plasma caffeine concentration to less than 1 μg/ml), typical of the dose found in a single serving of a cola beverage, and less than that found in a single cup of coffee or a single dose of over-the-counter drugs, significantly improved auditory vigilance and visual reaction time. All other caffeine doses administered also significantly improved performance on these tests. No adverse behavioral effects, such as increased anxiety or impaired motor performance, were noted even at the highest dose administered. [ABSTRACT FROM AUTHOR]

An hypothesis is presented about the nature of behavioural tolerance in animals to stimulant drugs. It is suggested that, in many behavioural procedures, tolerance is due to behavioural adaptation to those drug effects which cause disruption of ongoing rewarded behaviour. This unitary hypothesis accounts for the available data on tolerance and cross-tolerance to stimulants more effectively than all of the other more conventional explanations which are based upon dispositional or functional concepts, the most common of which are described, evaluated, and found to be inadequate. Furthermore, it is suggested that attempts to explain tolerance in terms of changes in synaptic functioning are subject to very considerable problems of interpretation and that an analysis of behavioural mechanisms may be of greater value in understanding the process of behavioural tolerance. Evidence for the basic behavioural hypothesis is outlined in some detail, and a theoretical justification presented for its major assumptions. Operant studies of chronic stimulant effects on behaviour have often produced very complex patterns of data, considerable differences being reported both between subjects and between studies. A speculative model is presented which attempts to account for this pattern of data in tolerance studies. [ABSTRACT FROM AUTHOR]

In general, the effects of 8-OH-DPAT on the body temperature of rats or in inducing the 5-HT syndrome show rapid tolerance. However, in contrast, the 8-OH-DPAT-induced increase in the activity of rats in a two-way active avoidance task only occurs after repeated administration, i.e. there is sensitisation. The present study was conducted to examine whether this developing hyperactivity may also be expressed as increased rates of lever press responding, and if so, under which conditions it occurs. Rats were trained to press levers under fixed interval 60-s (FI 60) or differential reinforcement of low rates 20-s or 72-s (DRL20, DRL72) schedules of food reinforcement. Groups of trained rats were then treated daily 5 min before testing with doses of 0.01, 0.1 and 1.0 mg/kg 8-OH-DPAT SC for 10-21 days. In all three procedures, in the first couple of days of drug treatment, 8-OH-DPAT generally suppressed lever pressing in a dose-dependent manner. Thereafter, tolerance to this effect was seen to a greater (DRL20, DRL72) or lesser (FI60) extent. Some evidence for stimulation of low rates of lever press responding was seen after 10 days treatment under FI60, but not in DRL20 or DRL72 during short 30 to 60 min long daytime tests although in the latter case, the rats responded to the stimulating effects of 0.8 mg/kg SC amphetamine administered once at the end of the experiment. However, when rats were allowed to respond under DRL72 testing for 12 h during the night, after 10 days treatment a clear stimulation of lever pressing was observed. This stimulation was not specific to lever pressing, however, since a stimulation of entries into the food tray and licking were also seen. From these results, it may be concluded that the stimulating effect of 8-OH-DPAT after repeated administration may be expressed as increased rates of lever pressing, but not under all conditions in which psychomotor stimulation by amphetamine is seen. The potential for 8-OH-DPAT and related compounds to stimulate motor responding in this way should be taken into account when interpreting the effects of these drugs in animal models of psychiatric disorders. [ABSTRACT FROM AUTHOR]