Methylphenidate Treatment in Adolescent Rats with an Attention Deficit/Hyperactivity Disorder Phenotype: Cocaine Addiction Vulnerability and Dopamine Transporter Function

Appropriate animal models of attention deficit/hyperactivity disorder (ADHD) and drug reinforcement allow investigation of possible underlying biological bases of ADHD and its comorbidity with cocaine addiction. Toward this end, spontaneously hypertensive rats (SHRs) exhibiting an ADHD phenotype were compared with Wistar-Kyoto (WKY) and Wistar (WIS) rats. Initially, 1.5 mg/kg oral methylphenidate or vehicle was administered between postnatal days 28 and 55, and acquisition of visual discrimination learning was examined. After discontinuing adolescent treatments, adult rats were evaluated for cocaine self-administration and dopamine transporter (DAT) function in the prefrontal cortex (PFC) and striatum. During adolescence, SHRs showed deficits in visual discrimination relative to WKY and WIS rats when non-medicated. Methylphenidate improved visual discrimination only in SHRs. Compared with WKY and WIS rats, SHRs with previous methylphenidate treatment acquired cocaine self-administration faster, identified cocaine as a highly efficacious reinforcer by displaying an upward shift in the cocaine dose–response function, and showed the greatest motivation to self-administer cocaine by exhibiting the highest progressive ratio breakpoints. In the PFC, the maximal dopamine uptake (V_max) at DAT was decreased in SHRs and increased in WKY and WIS rats by previous methylphenidate treatment. The affinity (K_m) for dopamine at DAT in the PFC was not different between strains, nor was V_max or K_m altered in the striatum by previous methylphenidate treatment in any strain. Methylphenidate-induced decreases in dopamine clearance by DAT in the PFC may underlie increased cocaine self-administration in SHRs. These preclinical findings suggest that caution should be exercised when methylphenidate is prescribed for first-time treatment of ADHD in adolescent patients, as cocaine addiction vulnerability may be augmented.     

Chronic Treatment with Extended Release Methylphenidate Does Not Alter Dopamine Systems or Increase Vulnerability for Cocaine Self-Administration: A Study in Nonhuman Primates

Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3–5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹⁸F]fluoroclebopride (DA D2/D3) and [¹⁸F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001–0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.     

Cocaine Self-Administration Produces Pharmacodynamic Tolerance: Differential Effects on the Potency of Dopamine Transporter Blockers,Releasers, and Methylphenidate

The dopamine transporter (DAT) is the primary site of action for psychostimulant drugs such as cocaine, methylphenidate, and amphetamine. Our previous work demonstrated a reduced ability of cocaine to inhibit the DAT following high-dose cocaine self-administration (SA), corresponding to a reduced ability of cocaine to increase extracellular dopamine. However, this effect had only been demonstrated for cocaine. Thus, the current investigations sought to understand the extent to which cocaine SA (1.5 mg/kg/inf × 40 inf/day × 5 days) altered the ability of different dopamine uptake blockers and releasers to inhibit dopamine uptake, measured using fast-scan cyclic voltammetry in rat brain slices. We demonstrated that, similar to cocaine, the DAT blockers nomifensine and bupropion were less effective at inhibiting dopamine uptake following cocaine SA. The potencies of amphetamine-like dopamine releasers such as 3,4-methylenedioxymethamphetamine, methamphetamine, amphetamine, and phentermine, as well as a non-amphetamine releaser, 4-benzylpiperidine, were all unaffected. Finally, methylphenidate, which blocks dopamine uptake like cocaine while being structurally similar to amphetamine, shared characteristics of both, resembling an uptake blocker at low concentrations and a releaser at high concentrations. Combined, these experiments demonstrate that after high-dose cocaine SA, there is cross-tolerance of the DAT to other uptake blockers, but not releasers. The reduced ability of psychostimulants to inhibit dopamine uptake following cocaine SA appears to be contingent upon their functional interaction with the DAT as a pure blocker or releaser rather than their structural similarity to cocaine. Further, methylphenidate''s interaction with the DAT is unique and concentration-dependent.     

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.     

Effect of Atomoxetine on the Cognitive Functions in Treatment of Attention Deficit Hyperactivity Disorder in Children with Congenital Hypothyroidism: A Pilot Study

Background:

With early initiation of thyroxine supplementation, children with congenital hypothyroidism (CH) retain some subtle deficits, such as attention and inhibitory control problems. This study assessed the effects of atomoxetine on cognitive functions in treatment of attention deficit hyperactivity disorder (ADHD) symptoms in children with CH.

Methods:

In a 6-month, open-labeled pilot study, 12 children were recruited and received atomoxetine. The measures of efficacy were scores on the Swanson, Nolan and Pelham Teacher and Parent Rating Scale, version IV (SNAP-IV) and Clinical Global Impression-Severity scale (CGI-S). The cognitive functions were evaluated with the Wechsler Intelligence Scale for Chinese Children, Digit Span, Wisconsin Card Sorting Test, and Stroop test.

Results:

A statistically significant difference was found between the mean CGI-S and SNAP-IV scores before and after treatment (p < 0.01). All the indicators of cognitive functions at the endpoint were improved compared with those at baseline. No serious adverse events were reported.

Conclusion:

Atomoxetine appears to be useful in improving ADHD symptoms, as well as cognitive functions, in children with CH. Larger, randomized, double-blinded, clinical trials are required to replicate these results.     

Effects of Chronic Varenicline Treatment on Nicotine,Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004–0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7–10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.     

A Treatment Algorithm for Attention Deficit Hyperactivity Disorder in Cocaine-Dependent Adults: A One-Year Private Practice Study with Long-Acting Stimulants,Fluoxetine, and Bupropion

A subgroup of adults in private treatment for cocaine dependence in remission reported a therapeutic effect from cocaine during the initial phases of cocaine addiction and, also, met DSM-IV criteria for ADHD. We report evidence that study subjects probably medicated their ADHD symptoms with cocaine and describe a 1-year treatment algorithm featuring long-acting stimulants that was effective in the management of their ADHD and cocaine dependence. Nineteen stable patients in full remission from all substance dependence were entered into an open label, prospective, treatment trial for ADHD. The treatment schedule consisted of the progressive introduction—and discontinuation of ineffective medication—of each of several medications in the following order: fluoxetine, bupropion, pemoline, sustained-release methylphenidate, dextroamphetamine spansules, and methamphetamine gradumets. Treatment of ADHD was successful. Several treatment regimens, especially those including long-acting stimulants, alone or in combination with other agents, were highly effective. All but 1 of the 19 subjects had a fully effective response for at least 1 full year. Mean UTAH scale scores were 7.4 before any medications were administered and 1.6 at the end of the study. Treatment proved successful in suppressing ADHD symptoms, with minimal cocaine slips or side effects.     

Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder

Atomoxetine (Strattera^?, Eli Lilly & Co.) is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.     

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamine-induced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)). Many age-related differences were found, including cortical thinning, white matter development, larger dopamine-mediated activation responses and increased striatal functional connectivity. Methylphenidate reduced anterior cingulate cortical network strength in both adolescents and adults. In contrast to clinical observations from ADHD patient studies, methylphenidate did not increase white matter tissue volume or cortical thickness in rat. Nevertheless, DTI-based fractional anisotropy was higher in the anterior part of the corpus callosum following adolescent treatment. Furthermore, methylphenidate differentially affected adolescents and adults as evidenced by reduced striatal volume and myelination upon adolescent treatment, although we did not observe adverse treatment effects on striatal functional activity. Our findings of small but significant age-dependent effects of psychostimulant treatment in the striatum of healthy rats highlights the importance of further research in children and adolescents that are exposed to methylphenidate.     

Barriers to Implementation of Treatment Guidelines for ADHD in Adults With Substance Use Disorder

Objective: Attention deficit hyperactivity disorder (ADHD) is common among adult patients with a substance use disorder, yet often goes undetected. This is a qualitative study to explore implementation barriers to a guideline developed in Belgium for the recognition and treatment of ADHD in adult patients with substance use disorder and to gain a better understanding of the strategies to overcome these barriers.

Methods: Focus groups were conducted with caregivers and patients to explore experiences with comorbid substance use disorder and ADHD. The barriers reported in these focus groups became the subject of further study in focus groups with addiction professionals (physicians, psychiatrists, and psychologists) who had tried the guideline and with psychiatrists specializing in addiction but without experience with ADHD.

Results: Our analysis revealed a number of barriers to the implementation of this guideline, including lack of information from the family, pressure from patients and caregivers to make an ADHD diagnosis, and the potential for abuse of ADHD medication. Furthermore, diagnostic instruments for ADHD have not been validated in people with substance use disorder. Although patients with ADHD are usually treated in an outpatient setting, patients with ADHD comorbid with substance use disorder are difficult to identify in an outpatient setting for various reasons. Finally, there is a lack of specific ADHD expertise in substance use treatment organizations.

Conclusions: Despite the availability of an approved guideline for recognizing and treating adult ADHD in patients with a substance use disorder, underdiagnosis and inadequate treatment still persist. As in general substance use treatment, medication only plays a supportive role in the treatment of substance use disorder with comorbid ADHD. An integrated approach and further improvements in the competence of practitioners may help to reduce the resistance to diagnosing ADHD in substance use treatment centers. Practitioners who specialize in addiction medicine and therapists without medical education view the problem from different perspectives and therefore each group needs specific information and training. Targeted interventions need to be developed to keep these patients in treatment.     

A treatment algorithm for attention deficit hyperactivity disorder in cocaine‐dependent adults: A one‐year private practice study with long‐acting stimulants,fluoxetine, and bupropion

A subgroup of adults in private treatment for cocaine dependence in remission reported a therapeutic effect from cocaine during the initial phases of cocaine addiction and, also, met DSM‐IV criteria for ADHD. We report evidence that study subjects probably medicated their ADHD symptoms with cocaine and describe a 1‐year treatment algorithm featuring long‐acting stimulants that was effective in the management of their ADHD and cocaine dependence. Nineteen stable patients in full remission from all substance dependence were entered into an open label, prospective, treatment trial for ADHD. The treatment schedule consisted of the progressive introduction—and discontinuation of ineffective medication—of each of several medications in the following order: fluoxetine, bupropion, pemoline, sustained‐release methylphenidate, dextroamphetamine spansules, and methamphetamine gradumets. Treatment of ADHD was successful. Several treatment regimens, especially those including long‐acting stimulants, alone or in combination with other agents, were highly effective. All but 1 of the 19 subjects had a fully effective response for at least 1 full year. Mean UTAH scale scores were 7.4 before any medications were administered and 1.6 at the end of the study. Treatment proved successful in suppressing ADHD symptoms, with minimal cocaine slips or side effects.     

Pediatric pharmacoepidemiology - safety and effectiveness of medicines for ADHD

Introduction: Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children and adolescents that comprises core symptoms of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. Stimulant (methylphenidate, amphetamines) and non stimulant (atomoxetine, clonidine and guanfacine) are the treatment usually prescribed for ADHD.

Area covered: This review covers the safety of ADHD medications in children and adolescents.

MEDLINE, EMBASE and PsycINFO databases were searched with the aim to retrieve prospective studies that monitored the incidence of adverse events (AEs) in children receiving drug therapy for ADHD. Many of the studies investigated the risk of specific AEs. In particular, the cardiovascular safety, the impact on growth and on sleep pattern, the risk of substance use disorders and of suicidal ideation are among the topics more studied.

Expert opinion: Effective drugs for ADHD appears to be safe and well tolerated. Most of the adverse events reported in the randomised controlled trials are mild and transient. Decreased appetite, growth decrease and the impact on sleep (insomnia for stimulants and somnolence for alpha2-agonists) are among the most common events. Concerns exist about cardiovascular and psychiatric AEs, even if the available evidence does not support an association with medications.     

Adult ADHD and Substance Abuse: Diagnostic and Treatment Issues

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral, developmental disorder most often diagnosed during childhood, marked by the core symptoms of inattention, hyperactivity, and impulsivity that results in social, academic, and occupational underachievement. Although the disorder has a prevalence of 3–9% in the general childhood population and 1–5% in the general adult population, it affects between 11 and 35% of “substance-abusing” adults, oftentimes complicating treatment response. The present review discusses diagnostic assessment issues, prevalence, comorbidity, pharmacotherapy, and psychological interventions in substance-abusing adults with ADHD.     

The use of stimulants and atomoxetine in adults with comorbid ADHD and bipolar disorder

Introduction: Attention deficit/hyperactivity disorder (ADHD) persists into adulthood in about 50% of the affected children, with high rates of comorbidity with bipolar disorder (BD). Stimulants and atomoxetine (ATX) are effective treatments for ADHD, but their use in adults with comorbid BD (ADHD-BD) has not been extensively studied and may be problematic.

Areas covered: The aim of the paper is to summarize the available literature regarding the use of these medications in ADHD-BD adult patients. Results of randomized-controlled and open-label trials, case reports, and case series are reviewed. We also reviewed data relative to some specific issues of this comorbidity in adults, especially substance use disorder, malingering, and stimulants misuse.

Expert opinion: ADHD-BD may be associated with more severe symptoms, course, and worst outcome of both conditions. The frequent coexistence with alcohol and substance abuse may further complicate treatment management. Stimulants are the most effective medications for ADHD, but their use may be contraindicated in the presence of a comorbid drug abuse or in patients that simulate or exaggerate ADHD symptoms in order to obtain stimulants for diversion or abuse. ATX may be effective in the treatment of ADHD symptoms in BD patients, with a modestly increased risk of (hypo)manic switches and destabilization of the mood disorder when utilized in association with mood stabilizers. In the majority of the cases, a hierarchical approach is desirable, with mood stabilization preceding the treatment of ADHD symptoms. Although systematic trials on the use of stimulants and ATX in ADHD-BD comorbidity in adulthood are necessary, both treatments should be considered possible options to be carefully evaluated once the patient has been stabilized.     

Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence

Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [¹²³I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients.This trial is registered at the Dutch Trial Register, www.trialregister.nl, under Trial ID number NTR3127.     

Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.     

Effects of MDMA on Extracellular Dopamine and Serotonin Levels in Mice Lacking Dopamine and/or Serotonin Transporters

3,4-Methylendioxymethamphetamine (MDMA) has both stimulatory and hallucinogenic properties which make its psychoactive effects unique and different from those of typical psychostimulant and hallucinogenic agents. The present study investigated the effects of MDMA on extracellular dopamine (DA(ex)) and serotonin (5-HT(ex)) levels in the striatum and prefrontal cortex (PFC) using in vivo microdialysis techniques in mice lacking DA transporters (DAT) and/or 5-HT transporters (SERT). subcutaneous injection of MDMA (3, 10 mg/kg) significantly increased striatal DA(ex) in wild-type mice, SERT knockout mice, and DAT knockout mice, but not in DAT/SERT double-knockout mice. The MDMA-induced increase in striatal DA(ex) in SERT knockout mice was significantly less than in wildtype mice. In the PFC, MDMA dose-dependently increased DA(ex) levels in wildtype, DAT knockout, SERT knockout and DAT/SERT double-knockout mice to a similar extent. In contrast, MDMA markedly increased 5-HT(ex) in wildtype and DAT knockout mice and slightly increased 5-HT(ex) in SERT-KO and DAT/SERT double-knockout mice. The results confirm that MDMA acts at both DAT and SERT and increases DA(ex) and 5-HT(ex).     

托莫西汀与哌甲酯治疗注意缺陷多动障碍患儿的疗效和安全性比较

目的:比较托莫西汀与哌甲酯治疗注意缺陷多动障碍患儿的疗效和安全性。方法:选择我院收治的注意缺陷多动障碍患儿共52例,随机分为托莫西汀组与哌甲酯组各26例,治疗结束后观察两组患儿的治疗有效率、ADHDRS-IV-Parent:Inv评分以及CPRS-R:S评分。结果:托莫西汀组与哌甲酯组的治疗有效率相近。治疗后托莫西汀组与哌甲酯组的ADHDRS-IV-Parent:Inv各项评分均明显下降,与治疗前比较差异均有统计学意义(P<0.05)。治疗后托莫西汀组与哌甲酯组CPRS-R:S评分的分数均明显下降,与治疗前比较差异均有统计学意义(P<0.05)。托莫西汀组的多动分变化值大于哌甲酯组,差异有统计学意义(P<0.05),两组患儿在治疗过程中均未发现严重的药物不良反应。结论:托莫西汀的疗效与哌甲酯相近,都具有良好的安全性,值得临床推广。