Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.

Lisdexamfetamine Dimesylate: A Review in Paediatric ADHD.

Lisdexamfetamine dimesylate (lisdexamfetamine; Elvanse®; Tyvense®), an orally-active dexamfetamine prodrug, is indicated in the EU for the treatment of attention-deficit hyperactivity disorder (ADHD) in children aged ≥ 6 years (including adolescents) when the response to previous methylphenidate (MPH) treatment is clinically inadequate. The original approval of the drug was based on the results of phase III trials in children and adolescents with ADHD who had an inadequate response to previous pharmacotherapy (e.g. MPH) or were treatment naïve. In these studies, short-term treatment with flexibly-dosed lisdexamfetamine demonstrated greater efficacy than atomoxetine, based on a prospective comparison, and osmotic-release oral system (OROS)-MPH, based on a post hoc comparison. Improvements in ADHD symptoms were accompanied by improvements in health-related quality of life and functioning that were maintained as long as treatment with lisdexamfetamine was continued in a long-term extension of one of these trials. In subsequent phase IV head-to-head studies in adolescents with ADHD and an inadequate response to previous pharmacotherapy, lisdexamfetamine demonstrated greater efficacy than OROS-MPH when both medications were force-titrated, but not when they were flexibly-titrated. Lisdexamfetamine was generally well tolerated, with an adverse event profile (e.g. decreased appetite, headache, weight reduction, insomnia and irritability) typical of that reported for other stimulants. Thus, lisdexamfetamine provides an alternative option for the treatment of children and/or adolescents with ADHD who have not responded adequately to previous ADHD pharmacotherapies.

A Case of Narcolepsy Type 2 and Postural Tachycardia Syndrome Secondary to Lesions of the Thalamus and Amygdala.

ABSTRACT: Although there are reports of narcolepsy type 1 caused by lesions of the central nervous system, there are far fewer reports of narcolepsy type 2 (NT2) caused by discrete brain lesions. We report a case of a patient in whom NT2 was diagnosed after a viral illness, and inflammatory lesions in the right thalamus and amygdala were found. In addition, symptoms of autonomic impairment developed and postural tachycardia syndrome was subsequently diagnosed in this patient. To our knowledge this is the first reported case of NT2 resulting from central nervous system lesions in these discrete locations, as well as the first reported case of postural tachycardia syndrome associated with narcolepsy.

The "induced hyperactivity" test for the de-risking of potential off-target activity of antihypertensive drugs.

INTRODUCTION: Compound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the "induced hyperactivity" test for CNS de-risking of Compound X. METHODS: Male Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine). RESULTS: Induced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/kg) to show its PDE-10a activity, its low brain penetration (~10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca(2+) channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses. CONCLUSION: The relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.

Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.

A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.

Use of prescription stimulant for Attention Deficit Hyperactivity Disorder in Aboriginal children and adolescents: a linked data cohort study.

BACKGROUND: Increasing recognition of Attention Deficit Hyperactivity Disorder (ADHD) among Aboriginal children, adolescents and young adults is a public health challenge. We investigated the pattern of prescription stimulants for ADHD among Aboriginal individuals in Western Australia (WA). METHODS: Using a whole-population-based linked data we followed a cohort of individuals born in WA from 1980-2005, and their parents were born in Australia, to identify stimulant prescription for ADHD derived from statutory WA stimulant prescription dispensing between 2003 and 2007. Parental link was ascertained through WA Family Connections Genealogical Linkage System. Cox proportional hazards regression (HR) models were performed to determine the association between stimulant use and Aboriginal and non-Aboriginal status. RESULTS: Of the total cohort of 186,468, around 2% (n = 3677) had prescription stimulants for ADHD. Individuals with both Aboriginal parents were two-thirds (HR 0.33, 95 % CI 0.26-0.42), and with only Aboriginal mother were one-third (HR 0.69, 95% CI 0.53-0.90) less likely to have stimulants, compared to individuals with non-Aboriginal parents. HR in Aboriginals was 62% lower (HR 0.35, 95% CI 0.25-0.49) in metropolitan areas, and 72% lower (HR 0.28, 95% CI 0.20-0.38) in non-metropolitan areas, than non-Aboriginals. The risk for simulant use was four times higher among Aboriginal boys than Aboriginal girls (HR 4.08, 95% CI, 2.92-5.69). CONCLUSION: Aboriginal cultural understanding of ADHD and attitude towards stimulant medication serve as a determinant of their access to health services. Any ADHD intervention and policy framework must take into account a holistic approach to Aboriginal culture, beliefs and individual experience to provide optimal care they need.

The confounding effect of the development of idiopathic orthostatic edema and thyrotoxcosis on weight fluctuation related to effects on free water clearance in a woman with long-standing surgically induced panhypopituitarism and diabetes insipidus.

PURPOSE: To evaluate the effect of idiopathic orthostatic edema and the effect of thyrotoxicosis on weight fluctuation and fluid retention in the presence of surgically induced panhypopituitarism and diabetes insipidus controlled with hormone replacement. MATERIALS AND METHODS: Dextroamphetamine sulfate was used for weight gain when no other etiologic factor was found. Methimazole was used when weight loss occurred when serum T4 and free T4 indicated thyrotoxicosis. RESULTS: Sympathomimetic amine therapy very effectively controlled the weight gain and methimazole controlled the weight loss. CONCLUSIONS: Hypopituitarism and diabetes insipidus controlled with hormone replacement do not protect against fluid retention from idiopathic edema.

Distinct pro-vigilant profile induced in rats by the mGluR5 potentiator LSN2814617.

While treatment options are available, excessive daytime sleepiness (EDS) remains a significant unmet medical need for many patients. Relatively little rodent behavioural pharmacology has been conducted in this context to assess potential pro-vigilant compounds for their ability to restore functional capacity following experimentally induced sleep loss. Male Wistar rats were prepared for electroencephalographic (EEG) recording and subject to 11 h of sleep restriction using a biofeedback-induced cage rotation protocol. A simple response latency task (SRLT) was used to behaviourally index sleep restriction and the effects of pro-vigilant compounds: modafinil, D-amphetamine, caffeine, and the mGlu5-positive allosteric modulator LSN2814617. Sleep restriction resulted in a consistent, quantified loss of non-rapid eye movement (NREM) and REM sleep that impaired SRLT performance in a manner suggestive of progressive task disengagement. In terms of EEG parameters, all compounds induced wakefulness. Amphetamine treatment further decreased SRLT performance capacity, whereas the other three compounds decreased omissions and allowed animals to re-engage in the task. Caffeine and modafinil also significantly increased premature responses during this period, an effect not observed for LSN2814617. While all compounds caused compensatory sleep responses, the magnitude of compensation observed for LSN2814617 was much smaller than would be predicted to result from the prolongation of wakefulness exhibited. Using simple response latencies to index performance, an mGlu5 PAM dramatically increased wakefulness and improved functional capacity of sleep-restricted animals, without eliciting a proportionate compensatory sleep response. This effect was qualitatively distinct from that of amphetamine, caffeine and modafinil.

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure.

BACKGROUND: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown. METHODS: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. RESULTS: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. CONCLUSIONS: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.

Interpreting the results of a retrospective comparison of test and reference treatments in a randomized clinical trial setting.

BACKGROUND AND OBJECTIVES: The retrospective comparison of test and reference treatment arms in a randomized prospective clinical trial is potentially useful in economic modeling seeking to assess the cost effectiveness of alternative therapies. METHODS: To enhance the credibility of such retrospective comparisons, we propose the application of the following adjustments to significance levels obtained from standard statistical methodology: (1) a significance test for the lower bound of the 95 % confidence interval for the observed difference, (2) a conservative Bonferroni method of adjustment for multiple comparisons, (3) an adjusted p-value calculated using Scheffe's single-step method, and (4) Bayesian 95 % credibility intervals with a prior centered at zero. RESULTS: These adjustments were applied to data from a randomized double-blind concurrent trial (SPD489-325) that established the efficacy and safety of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Prospectively planned analyses demonstrated that the reduction in the symptoms of ADHD was significantly greater than placebo in patients treated with either LDX or the reference treatment, osmotic-release oral system methylphenidate (OROS-MPH). Retrospective analyses showed that the improvement in the symptoms of ADHD was greater in patients treated with LDX than OROS-MPH. We now show that this observation remained significant after the application of the four statistical penalties. CONCLUSIONS: By adjusting the significance level, it is possible to compare quantitatively such retrospective results with prospectively defined comparisons. However, the qualitative level of such retrospective evidence should remain secondary to that obtained from prospectively specified comparisons in a randomized clinical trial.

Sympathomimetic amine therapy found effective for treatment of refractory chronic complex regional pain syndrome (reflex sympathetic dystrophy).

PURPOSE: To determine if treatment with sympathomimetic amines could improve the pain from complex regional pain disorder (CRPD) which was keeping a woman from trying to conceive her second child. MATERIALS AND METHODS: Dextroamphetamine sulfate was prescribed. RESULTS: Within a short length of time the woman's wrist pain considerably improved to the point that she is ready to try in vitro fertilization once again to have a second baby. CONCLUSIONS: Though sympathomimetic amines are used by some reproductive endocrinologists for unexplained infertility and unexplained recurrent miscarriages, the most common use by the gynecologist is for pelvic pain. Despite the thought by some clinicians and researchers that the etiology for CRPD may be related to sympathetic nervous system hyperactivity (and thus sympathomimetic amines could theoretically exacerbate the symptoms), in fact, the treatment with dextroamphetamine sulfate may turn out to be a new and possibly the most effective, least risky, and least expensive treatment to date for CRPD.

Neurocognitive effects of neurofeedback in adolescents with ADHD: a randomized controlled trial.

OBJECTIVE: Neurofeedback aims to reduce symptoms of attention-deficit/hyperactivity disorder (ADHD), mainly attention problems. However, the additional influence of neurofeedback over treatment as usual (TAU) on neurocognitive functioning for adolescents with ADHD remains unclear. METHOD: By using a multicenter parallel randomized controlled trial (RCT) design, male adolescents with a DSM-IV-TR diagnosis of ADHD (mean age = 16.1 years; range, 12-24) were randomized to receive either a combination of TAU and neurofeedback (n = 45) or TAU (n = 26). Randomization was computer generated and stratified by age group (ages 12 through 15, 16 through 20, and 21 through 24 years). The neurofeedback intervention consisted of approximately 37 sessions over a period of 25 weeks of theta/sensorimotor rhythm training on the vertex (Cz). Primary neurocognitive outcomes included performance parameters derived from the D2 Test of Attention, the Digit Span backward, the Stroop Color-Word Test and the Tower of London, all assessed preintervention and postintervention. Data were collected between December 2009 and July 2012. RESULTS: At postintervention, outcomes of attention and/or motor speed were improved, with faster processing times for both intervention conditions and with medium to large effect sizes (range, ηp2 = .08-.54; P values < .023). In both groups, no improvements for higher executive functions were observed. Results might partly resemble practice effects. CONCLUSIONS: Although neurocognitive outcomes improved in all adolescents receiving treatment for ADHD, no additional value for neurofeedback over TAU was observed. Hence, this study does not provide evidence for using theta/sensorimotor rhythm neurofeedback to enhance neurocognitive performance as additional intervention to TAU for adolescents with ADHD symptoms. TRIAL REGISTRATION: Trialregister.nl identifier: 1759.

Effects of aberrant gamma frequency oscillations on prepulse inhibition.

Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

OBJECTIVES: Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. METHODS: Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. RESULTS: Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). DISCUSSION: The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure.

Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers.

RATIONALE: Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects. OBJECTIVES: The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli. METHODS: A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES50) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity. RESULTS: Dexamphetamine increased the threshold and ES50 of the response to pulse-alone trials in both sexes and reduced R MAX exclusively in females. Dexamphetamine modestly increased PPI of the R MAX across both attention conditions. PPI of R MAX was reduced during the ATTEND condition compared to the IGNORE condition. CONCLUSIONS: Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia.

Combination effects of amphetamines under hyperthermia - the role played by oxidative stress.

Rise in body temperature is a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. We evaluated the impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines, often co-ingested. For this, Hep G2 cells were exposed to MDMA, d-amphetamine, methamphetamine and 4-methylthioamphetamine, individually or combined, at 40.5 °C. The results were compared with normothermia data (37.0 °C). Mixture additivity expectations were calculated by independent action and concentration addition (CA) models. To delineate the mechanism(s) underlying the elicited effects, a range of stress endpoints was evaluated, including quantification of reactive oxygen/nitrogen species (ROS/RNS), lipid peroxidation, reduced/oxidized glutathione (GSH/GSSG), ATP and mitochondrial membrane potential (Δψm) changes. Our data show that, in hyperthermia, amphetamines acted additively and mixture effects were accurately predicted by CA. At 40.5 °C, even slight increases in the concentrations of each drug/mixture promoted significant rises in cytotoxicity, which quickly shifted from roughly undetectable to maximal mortality. Additionally, the increase of RNS/ROS production, decrease of GSH, ATP depletion and mitochondrial impairment were exacerbated under hyperthermia. Importantly, when equieffective cytotoxic concentrations of the mixture and individual amphetamines were compared for all tested stress endpoints, mixture effects did not deviate from those elicited by individual treatments, suggesting that these amphetamines have a similar mode of action, which is not altered in combination. Concluding, our data indicate that amphetamine mixtures produce deleterious effects, even when individual drugs are combined at negligible concentrations. These effects are strongly exacerbated in hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse.

Effects of white noise on off-task behavior and academic responding for children with ADHD.

We evaluated the effects of white noise played through headphones on off-task behavior, percentage of items completed, and percentage of items completed correctly for 3 students with attention deficit hyperactivity disorder (ADHD). Headphones plus white noise were associated with decreases in off-task behavior relative to baseline and headphones-only (no white noise) control conditions. Little change in academic responding occurred across conditions for all participants.

CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents.

RATIONALE: As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF1 receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating. OBJECTIVES: To determine the effects of CRF1 receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs. METHODS: CP154,526 (10-40 mg/kg), SSR125543 (3-30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by D-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of D-amphetamine (2.5-5 mg/kg) and MK801 (0.3-1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on D-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis. RESULTS: No CRF1-antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not D-amphetamine. Further, D-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526. CONCLUSION: The inability of CRF1 receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF1 receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.

Effects of neurofeedback versus stimulant medication in attention-deficit/hyperactivity disorder: a randomized pilot study.

OBJECTIVE: The purpose of this pilot study was to compare the effects of 30 sessions of neurofeedback (NF) with stimulant medication on attention-deficit/hyperactivity disorder (ADHD) patients. METHODS: Thirty-two medication-naïve ADHD patients, ages 7-16, from a neuropsychiatric clinic, were randomized to NF (n=16) or drug treatment (n=16). Other actions, such as parent management training, information, or support in school were given as needed, with no differences between the groups. All participants were assessed before treatment on two rating scales, each with parent and teacher forms. In addition, quantitative electroencephalogram (QEEG) and event-related potentials (ERPs), which included behavioral data from a go/no go test were administered. NF training took place in the clinic over a period of 7-11 months, and was followed by a repeat of the same assessment tools. The mean time interval between pre- and postassesment was not significantly different in the two groups. The 18 symptoms of ADHD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)) were used as the primary outcome measure. RESULTS: Analysis of covariance revealed a significant difference between the groups at evaluation in favor of medication, with a large effect size. This picture was confirmed by other outcome measures. The QEEG spectral power in the theta and beta bands did not change in either group. In ERP, the P3 no go component increased significantly in 8 of 12 patients who had a clinically relevant medication effect, but did not increase in the medication nonresponders or the NF group. CONCLUSIONS: Our study supports effects for stimulants, but not for NF. Effects of NF may require thorough patient selection, frequent training sessions, a system for excluding nonresponders, and active transfer training. The P3 no go ERP component may be a marker for treatment response.

A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil.

Lisdexamfetamine dimesylate, which consists of L-lysine covalently bound to D-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield D-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include D-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, D-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5-1.5 mg/kg [D-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its D-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0-10 mg/kg, p.o.) and D-amfetamine (0.1-1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal D-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as D-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and D-amfetamine by 3.4× and 2.2×, respectively. Modafinil (50-200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self-administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [D-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to D-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics.