Comparison of the subjective,physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users

This study compared the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate with placebo in healthy volunteers. Sixteen non-dependent light drug users participated in six experimental sessions, receiving placebo, atomoxetine (20, 45 and 90 mg) and methylphenidate (20 and 40 mg) using a double-blind, Latin square design. Subjective drug effects were assessed using Visual Analog Scales (VAS), the Addiction Research Center Inventory (ARCI) and Adjective Rating Scales (ARS). Psychomotor performance was evaluated using the Digit Symbol Substitution Test (DSST). Physiological measures were also collected throughout the sessions. Assessments were conducted before drug administration and 30, 60, 90, 120, 150, 180 and 240 min following dosing. Forty milligrams methylphenidate produced significant increases on the stimulant portions of the VAS and ARS and the benzedrine, amphetamine, morphine-benzedrine and lysergic acid diethylamine (LSD) subscales of the ARCI relative to placebo. Ninety mg atomoxetine was reported to be unpleasurable relative to placebo as indicated by significant increases on the 'bad' and 'sick' portions of the VAS, and on the LSD subscale of the ARCI. Compared with placebo, both methylphenidate doses significantly increased systolic blood pressure (BP) and heart rate (HR). For atomoxetine, 90 mg increased diastolic BP, 45 and 90 mg increased systolic BP, and all three doses increased HR relative to placebo. Neither compound produced significant differences from placebo on DSST performance. These results suggest that atomoxetine does not induce subjective effects similar to methylphenidate and suggest that it is unlikely that atomoxetine will have abuse liability.     

Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine

Atomoxetine is a selective norepinephrine (NE) reuptake blocker that has recently been marketed for the treatment of attention deficit hyperactivity disorder. The purpose of the present study was to evaluate the self-administration of atomoxetine in an animal model predictive of abuse liability in humans. Rhesus monkeys (N = 5) were prepared with chronic intravenous catheters and allowed to self-administer cocaine or saline during alternating baseline sessions. When behavior was stable, atomoxetine (0.03-3.0 mg/kg per injection), desipramine (0.1-3.0 mg/kg per injection), methylphenidate (0.001-0.1 mg/kg per injection), or their vehicles were substituted for baseline conditions. Methylphenidate consistently maintained responding above the levels maintained by its vehicle. Atomoxetine and desipramine failed to reliably maintain self-administration above vehicle levels in four of five individual monkeys. These results predict that atomoxetine, in contrast to methylphenidate but like desipramine, will lack reinforcing effects and abuse potential in humans.     

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.     

Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys.

Most medications prescribed for attention-deficit-hyperactivity disorder are psychomotor stimulants with reinforcing effects in laboratory animals (eg methylphenidate). The present studies were conducted to evaluate the reinforcing effects of the recently approved medication atomoxetine in monkeys trained to 'choose' between automated deliveries of either an i.v. injection or food. Rhesus monkeys were trained to lever-press under concurrent schedules of reinforcement; responses on one lever resulted in an injection of either saline or drug, and responses on the alternative lever resulted in food delivery. Data were collected on four measures: response rates, percentage of total responses occurring on the injection-lever (% ILR), number of injections earned, and number of food pellets earned. Dose-effect functions were determined for cocaine (0.003-0.3 mg/kg/inj), methylphenidate (0.003-0.1 mg/kg/inj), amphetamine (0.003-0.1 mg/kg/inj), atomoxetine (0.01-0.3 mg/kg/inj), and desipramine (0.03-1.0 mg/kg/inj) using a double alternation schedule of saline and drug availability. Results indicate that the distribution of behavior changed according to the drug and dose available for self-injection. Saline availability was typically associated with high rates of food-maintained responding. The % ILR increased from 3+/-1% when saline was available to >90% when >0.03 mg/kg/inj of cocaine, methylphenidate or d-amphetamine was available. However, no dose of atomoxetine or desipramine maintained self-administration behavior on the injection-lever. The number of food pellets earned per session decreased as the dose of each drug increased, indicative of behavioral activity with all five drugs. The reinforcing effects of cocaine, methylphenidate, and d-amphetamine in these studies are consistent with previous findings in nonhuman primates and with their documented abuse liability. The absence of reinforcing effects of atomoxetine support the view that, like desipramine, it has no evident abuse potential.     

Atomoxetine, a novel treatment for attention-deficit-hyperactivity disorder

Atomoxetine is the first nonstimulant drug approved by the United States Food and Drug Administration (FDA) for the treatment of attention-deficit-hyperactivity disorder (ADHD), and the only agent approved by the FDA for the treatment of ADHD in adults. Atomoxetine is a norepinephrine transport inhibitor that acts almost exclusively on the noradrenergic pathway. Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine. Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects. A comparative trial of atomoxetine with methylphenidate in school-aged children indicated similar safety and efficacy without the abuse liability associated with some psychostimulants. The most commonly reported adverse effects in children and adolescents are dyspepsia, nausea, vomiting, decreased appetite, and weight loss. The rates of adverse events in the trials were similar for both the once- and twice-daily dosing regimens. The discontinuation rate was 3.5% in patients treated with atomoxetine versus 1.4% for placebo and appeared to be dose dependent, wit a higher percentage of discontinuation at dosages greater than 1.5 mg/kg/day. In clinical trials involving adults, the emergence of clinically significant or intolerable adverse events was low. The most common adverse events in adults were dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention or difficulties with micturition, erectile disturbance, dysmenorrhea, dizziness, and decreased libido. Sexual dysfunction occurred in approximately 2% of patients treated with atomoxetine. Atomoxetine should be used with caution in patients who have hypertension or any significant cardiovascular disorder. Overall, atomoxetine therapy in patient with ADHD appears to be effective in controlling symptoms and maintaining remission, with the advantages being comparable efficacy with that of methylphenidate, a favorable safety profile, and non-controlled substance status. Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment, and comparative trials against other stimulant and nonstimulant agents.     

Abuse liability assessment of sibutramine, a novel weight control agent

Rationale: Sibutramine (Meridia) is a serotonin and norepinephrine reuptake inhibitor marketed for weight control. Previous studies demonstrated low abuse potential for 20 and 30 mg sibutramine (doses near the therapeutic range); however, no data existed on supratherapeutic doses. This study, therefore, examined 25 and 75 mg sibutramine in humans compared to d-amphetamine (20 mg) as a positive control and placebo as a negative control. Objectives: The study examined the acute subjective, reinforcing, and physiological effects of sibutramine to assess its abuse liability. Methods: Twelve polydrug abusers with no history of drug dependence participated in this double-blind, inpatient/outpatient study. Volunteers participated in four drug sessions, in which they completed subjective effects scales including the Profile of Mood States (POMS), Visual Analog Scales (VAS), and the Addiction Research Center Inventory (ARCI). The Multiple Choice Procedure (MCP) was used to evaluate reinforcing efficacy. Results: Sibutramine 25 mg produced subjective effects that were indistinguishable from placebo. Sibutramine 75 mg produced significant unpleasant effects, such as Anxiety, Confusion, and decreased Vigor. On the MCP, volunteers chose to give up an average of $4.04 from their study pay rather than receive the higher dose of sibutramine again. In contrast, d-amphetamine 20 mg produced positive mood changes and was well liked. Conclusions: These data indicate sibutramine lacks amphetamine-type abuse liability when administered acutely. Received: 12 January 1999 / Final version: 21 July 1999     

Evaluation of the abuse potential of the novel analgesic flupirtine maleate

To evaluate the psychopharmacological effects and potential abuse liability of the novel analgesic flupirtine maleate the subjective and behavioral effects of orally administered flupirtine, lorazepam and placebo were studied in polydrug abusers. Effects were measured before and for 6 h after drug administration under double-blind conditions. At therapeutic doses flupirtine was not differentiated from placebo. Lorazepam and higher doses of flupirtine produced increases in subject-rated liking, ARCI MBG scale scores, and sedative-like effects including impaired psychomotor performance. Flupirtine, but not lorazepam, increased ratings on measures indicating dysphoric effects. The results indicate that flupirtine has some sedative-like effects but that its abuse potential is probably modest.     

Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence

This review provides practical information on and clinical reasons for switching children and young people with attention-deficit hyperactivity disorder (ADHD) from neurostimulants to atomoxetine, detailing currently available evidence, and switching options. The issue is of particular relevance following recent guidance from the National Institute for Health and Clinical Excellence and European ADHD guidelines endorsing the use of atomoxetine, along with the stimulants methylphenidate and dexamphetamine, in the management of ADHD in children and adolescents in the UK. The selective norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine, is a non-stimulant drug licensed for the treatment of ADHD in children and adolescents, and in adults who have shown a response in childhood. Following the once-daily morning dose, its therapeutic effects extend through the waking hours, into late evening, and in some patients, through to early the next morning. Atomoxetine may be considered for patients who are unresponsive or incompletely responsive to stimulant treatment, have co-morbid conditions (e.g. tics, anxiety, depression), and have sleep disturbances or eating problems, for patients in whom stimulants are poorly tolerated, and for situations where there is potential for drug abuse or diversion. Atomoxetine has been shown to be effective in relapse prevention and there is suggestion that atomoxetine may have a positive effect on global functioning; specifically health-related quality of life, self-esteem, and social and family functioning. According to one study, approximately 50% of non-responders to methylphenidate will respond to atomoxetine therapy and approximately 75% of responders to methylphenidate will also respond to atomoxetine. Atomoxetine may be initiated by a schedule of dose increases and cross-tapering with methylphenidate. A slow titration schedule with divided doses minimizes the impact of adverse events within the first several weeks of treatment. Atomoxetine may be co-administered with methylphenidate during the switching period without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is necessary). Atomoxetine may be discontinued abruptly and patients may miss the occasional dose without rebound effects or discontinuation syndrome. A trial period of at least 6-8 weeks, perhaps longer, is recommended before evaluation of the overall tolerability and efficacy of atomoxetine. We conclude that patients with ADHD can be switched from neurostimulants, specifically methylphenidate, to atomoxetine, and may benefit from symptom improvement.     

Atomoxetine

Atomoxetine, formerly tomoxetine, is a selective norepinephrine reuptake inhibitor and a new, nonstimulant treatment for attention deficit hyperactivity disorder (ADHD). In vitro, ex vivo and in vivo studies have shown that atomoxetine is a highly selective antagonist of the presynaptic norepinephrine transporter with little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. In four randomized, placebo-controlled clinical trials conducted over 6-9 weeks in children and adolescents with ADHD, atomoxetine (total daily dose 1-1.8 mg/kg administered in one or two doses daily) reduced symptoms (hyperactivity, impulsiveness and inattention) as determined by the reduction in ADHD total score (34-38% with atomoxetine versus 13-15.7% with placebo [p < 0.05]). Atomoxetine also significantly improved ADHD subscale rating scores (p < 0.05 and p < 0.001), psychosocial well-being (p < 0.05) and ADHD-related problem behavior according to parent and teacher ratings (p < 0.05). Atomoxetine was well tolerated in clinical trials and discontinuation rates due to adverse events were low (<5%). The most common treatment-related adverse event was decreased appetite. Atomoxetine shows no abuse potential and is not a controlled substance in the US.     

Nicotine as a conditioned stimulus: impact of attention-deficit/hyperactivity disorder medications

People diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk to start smoking and have greater difficulty quitting. Nicotine, one of the principal addictive components of tobacco smoke, functioned as a conditioned stimulus (CS) for intermittent sucrose delivery in a Pavlovian drug discrimination task with rats. This study compared the ability of commonly prescribed ADHD medications (i.e., methylphenidate, atomoxetine, and bupropion) and additional dopamine reuptake inhibitors (i.e., cocaine and GBR 12909) to substitute for the CS effects of nicotine. Atomoxetine was also used to antagonize these CS effects. Rats acquired the discrimination as evidenced by increased dipper entries in nicotine (0.2 mg base/kg) sessions as compared with saline sessions. Nicotine generalization was dose dependent. Bupropion (10 and 20 mg/kg), methylphenidate (10 mg/kg), and cocaine (5 and 10 mg/kg) partially substituted for the 0.2 mg/kg nicotine CS. Atomoxetine did not substitute for the nicotine CS; however, atomoxetine (1 to 10 mg/kg) partially blocked nicotine's CS effects. These results suggest that atomoxetine, bupropion, and/or methylphenidate may be effective treatments for people diagnosed with ADHD and addicted to nicotine.     

Do formulation differences alter abuse liability of methylphenidate? A placebo-controlled, randomized, double-blind, crossover study in recreational drug users

The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value).The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects.Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.     

An evaluation of the abuse potential of modafinil using methylphenidate as a reference

Modafinil is a unique wake-promoting agent. Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in humans, a double-blind Latin square crossover study was conducted in 24 male volunteers with a history of polysubstance abuse that included the stimulant cocaine. Each subject was given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and placebo. Measures of subjective, behavioural, and physiological responses were evaluated at fixed intervals during 72 h after each dosing occasion. Subjects discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects of both drugs. However, modafinil differed from methylphenidate in its lack of a significant response on the Amphetamine Scale of the Addiction Research Center Inventory. The profile of physiological effects for modafinil differed from methylphenidate in that it showed greater inhibition of observed and reported sleep, less facilitation of orthostatic tachycardia and less reduction of caloric intake. These findings are consistent with preclinical pharmacological data suggesting that modafinil is not an amphetamine-like agent.     

Atomoxetine blocks motor hyperactivity in neonatal 6-hydroxydopamine-lesioned rats: implications for treatment of attention-deficit hyperactivity disorder

We recently reported that selective inhibitors of neuronal transport of norepinephrine (NE), desipramine and nisoxetine, reversed motor hyperactivity in an animal model of attention-deficit hyperactivity disorder (ADHD). In this study, we examined behavioural effects of atomoxetine, a potent new NE reuptake blocker, in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of dopamine projections to the forebrain. 6-OHDA (100 microg) was administered intracisternally on postnatal day (PD) 5 following desipramine (25 mg/kg s.c.) pretreatment to protect noradrenergic neurons. Atomoxetine (1 mg/kg) was given intraperitoneally before recording motor activity for 90 min at PD 23-26 in a novel environment. Atomoxetine greatly reduced motor hyperactivity in 6-OHDA-lesioned rats while exhibiting transient sedative effects in sham controls. The observed effects in this animal model for ADHD are consistent with the emerging clinical use of atomoxetine as a novel, non-stimulant treatment for ADHD.     

A pharmacological analysis of stimulant-induced increases in smoking

Rationale Stimulants increase tobacco smoking in healthy adults under controlled laboratory conditions. The mechanisms that mediate stimulant-induced increases in smoking are not known. Objective The purpose of the present experiment was to characterize the pharmacological specificity of stimulant-induced increases in smoking. We tested the effects of methylphenidate and atomoxetine on smoking behavior. Atomoxetine is a norepinephrine transport inhibitor that does not increase dopamine levels in the nucleus accumbens or striatum. If stimulant-induced increases in smoking result from an additive or synergistic effect of these drugs and nicotine on dopamine levels in the nucleus accumbens or striatum, methylphenidate but not atomoxetine should increase smoking. Materials and methods Doses of methylphenidate (10, 20, and 40 mg) and atomoxetine (20, 40, and 80 mg) were tested once while placebo was tested twice in 12 cigarette smokers. One hour after ingesting drug, participants smoked ad libitum for 4 h. Measures of smoking included total cigarettes, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and food intake was calculated. Results Methylphenidate but not atomoxetine dose-dependently increased the number of cigarettes, puffs, and carbon monoxide levels. Methylphenidate and atomoxetine decreased food intake. Conclusions The results of this experiment are consistent with the notion that stimulant-induced increases in smoking may result from an additive or synergistic effect of these drugs and nicotine on dopamine levels in the nucleus accumbens or striatum. Additional research is needed to more fully understand the pharmacological mechanisms that mediate the relationship between stimulant use and smoking.     

Lack of Amphetamine-Like Effects After Administration of Mefenorex in Normal Young Subjects

Mefenorex is an indirect sympathomimetic amine which acts as an anorectic drug and is used in combination with low diet to treat excess weight. The central nervous system (CNS) effects of mefenorex were assessed in a randomized, double-blind, three-way cross-over, placebo-controlled study involving nine healthy young male volunteers. They received either a single oral dose of mefenorex 80 mg (twice the recommended dose) or d-amphetamine sulfate 18 mg or a placebo at 1-week intervals. CNS pharmacodynamic measurements consisted of subjective evaluation (visual analogue scales and the Addiction Research Centre inventory (ARCI)), EEG, psychomotor performance and attention (tracking, simple and choice reaction times, tapping, continuous performance task, DSST, body sway) and memory (working memory and recall of a word list). d-Amphetamine produced a typical psychostimulant EEG profile (significant decrease in slow delta waves and increase in fast beta activities), significantly increased amphetamine, benzedrine and morphine–benzedrine scores of ARCI and significantly decreased body sway compared to placebo and mefenorex. A trend in favour of a stimulant effect occurred for all other parameters (particularly speed of reaction) and no changes of memory were noticed. In contrast, mefenorex did not produce an amphetamine-like EEG profile, neither significantly changed ARCI scores nor significantly modified psychomotor and memory performance compared to the placebo, although it induced a decrease in body sway. In conclusion, the present results indicate that a single oral dose of mefenorex, at twice the recommended daily dose, does not possess amphetamine-like subjective and EEG stimulant effects or sensations of well-being, often encountered with drugs of abuse liability potential, in a healthy young population.     

A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder

Rationale

Treatment of attention-deficit/hyperactivity disorder (ADHD) has for many years relied on psychostimulants, particularly various formulations of amphetamines and methylphenidate. These are central nervous system stimulants and are scheduled because of their abuse potential. Atomoxetine (atomoxetine hydrochloride; Strattera®) was approved in 2002 for treatment of ADHD, and was the first nonstimulant medication approved for this disorder. It was classified as an unscheduled medication indicating a low potential for abuse. However, the abuse potential of atomoxetine has not been reviewed.

Objectives

In this article, we review the evidence regarding abuse potential of atomoxetine, a selective inhibitor of the presynaptic norepinephrine transporter, which is unscheduled/unrestricted in all countries where it is approved.

Methods

Results from receptor binding, in vitro electrophysiology, in vivo microdialysis, preclinical behavioral, and human laboratory studies have been reviewed.

Results

Atomoxetine has no appreciable affinity for, or action at, central receptors through which drugs of abuse typically act, i.e., dopamine transporters, GABA_A receptors, and opioid μ receptors. In behavioral experiments in rodents, atomoxetine does not increase locomotor activity, and in drug discrimination studies, its profile is similar to that of drugs without abuse potential. Atomoxetine does not serve as a reinforcer in monkey self-administration studies, and human laboratory studies suggest that atomoxetine does not induce subjective effects indicative of abuse.

Conclusion

Neurochemical, preclinical, and early clinical studies predicted and supported a lack of abuse potential of atomoxetine, which is consistent with the clinical trial and postmarketing spontaneous event data in the past 10 years.     

Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.

The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.     

An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers

The present double-blind, placebo-controlled study compared the acute effects of oral administration of the benzodiazepine hypnotics flunitrazepam (6 mg/70 kg) and triazolam (1 and 2 mg/70 kg) on measures relevant to abuse liability as well as on psychomotor performance and observer- and participant-rated measures of drug effects in nine sedative drug abusers. Analysis of participant-rated measures collected 24 h after drug administration (next-day; assessing the overall effects of the drug received 24 h earlier) indicated that flunitrazepam, but neither triazolam dose, produced significant increases relative to placebo in next-day ratings of drug liking, the amount of money the drug would be worth on the street, and the amount of money the participant would be willing to pay for the drug on the street. Importantly, these abuse liability differences between flunitrazepam and triazolam were present at a dose of flunitrazepam (6 mg/70 kg) that produced overall drug effects that were comparable to, or significantly less than, those of a high triazolam dose (2 mg/70 kg). Consistent with results of a previous study in our laboratory, these results suggest that flunitrazepam may have a greater abuse liability than triazolam, and that this abuse liability difference emerges on measures taken 24 h after drug administration but not on same-day measures.