BACKGROUND & AIMS: BACKGROUND:The catecholamine agonists methylphenidate and atomoxetine effectively treat attention-deficit/hyperactivity disorder (ADHD). Furthermore, dopamine agonists have shown to improve time estimation in ADHD, a core cognitive deficit. However, few have compared the effects of methylphenidate and atomoxetine on brain function in ADHD, and none during time estimation. Using single dose challenges, we investigated shared and drug-specific effects in ADHD adolescents on the neural substrates of time discrimination (TD). METHODS:Twenty ADHD adolescent male subjects were compared in a randomized double-blind cross-over design after single doses of methylphenidate, atomoxetine, and placebo in functional magnetic resonance imaging during TD. Normalization effects were assessed by comparing brain activation under each drug condition with that of 20 healthy age-matched control subjects. RESULTS:Relative to control subjects, patients under placebo showed TD deficits and reduced activation of ventrolateral prefrontal cortex (VLPFC)/insula, inferior frontal cortex, and supplementary motor area. Performance differences were normalized only by methylphenidate, relative to both atomoxetine and placebo. Both medications, however, significantly upregulated right VLPFC/insula activation within patients and normalized its underactivation in ADHD boys under placebo relative to control subjects. The supplementary motor area and inferior frontal cortex activation differences that were observed under placebo were reduced by methylphenidate and atomoxetine, respectively, but neither survived rigorous testing for normalization. CONCLUSIONS:While only methylphenidate had a drug-specific effect of improving TD performance deficits, both drugs significantly upregulated and normalized right VLPFC underactivation in ADHD boys under placebo relative to control subjects, suggesting shared effects of stimulants and nonstimulants on a key prefrontal dysfunction during timing.

背景与目标： 背景：儿茶酚胺激动剂哌醋甲酯和阿莫西汀可有效治疗注意力不足/多动症（ADHD）。此外，多巴胺激动剂已显示可改善ADHD（一种核心的认知缺陷）中的时间估计。然而，几乎没有人比较过哌醋甲酯和托莫西汀对多动症大脑功能的影响，而在时间估计中则没有。使用单剂量挑战，我们调查了多动症青少年在时间歧视（TD）的神经基质上的共享和药物特异性作用。
方法：在TD期间功能性磁共振成像中，单剂量哌醋甲酯，阿托西汀和安慰剂后，在随机双盲交叉设计中对20名ADHD青春期男性受试者进行了比较。通过比较每种药物条件下的大脑激活与20位年龄匹配的健康对照者的大脑激活来评估归一化效果。
结果：与对照组相比，接受安慰剂治疗的患者表现出TD缺陷，并减少了腹侧前额叶皮层（VLPFC）/岛，额叶下皮层和辅助运动区的激活。相对于托莫西汀和安慰剂，仅通过哌醋甲酯将性能差异归一化。然而，相对于对照对象，两种药物均显着上调了患者体内正确的VLPFC /胰岛素岛激活，并使其在安慰剂下的ADHD男孩中的激活不足得以正常化。哌醋甲酯和阿托莫西汀分别减少了在安慰剂下观察到的辅助运动区和额叶下皮质激活差异，但均未通过严格的标准化测试。
结论：虽然只有哌醋甲酯具有改善TD性能缺陷的药物特异性作用，但相对于对照受试者，两种药物均显着上调了安慰剂组ADHD男孩的右VLPFC失活并使其正常化，这表明兴奋剂和非兴奋剂在定时时对关键的前额叶功能障碍具有共同的作用。 。

BACKGROUND & AIMS: :There is growing concern that the psychostimulant Methylphenidate (MPD) is being abused for cognitive enhancement and recreation by healthy adults and adolescents seeking to improve their work or academic performance. This study concomitantly recorded the behavioral and prefrontal cortex (PFC) neuronal activity in freely behaving animals exposed to acute and chronic MPD doses (0.6, 2.5, and 10.0 mg/kg MPD) in order to compare MPD effects on adult and adolescent rats. The PFC is one of the primary brain areas affected by MPD and the drug of choice for treating ADHD. Moreover, the PFC is one of the last brain areas to complete development, suggesting that the behavioral and neurophysiological response to MPD may differ in adolescents and adults. In both adult and adolescent animals, it was observed that the same repetitive (chronic) dose of either 0.6, 2.5, or 10.0 mg/kg MPD elicited behavioral sensitization in some animals and tolerance in others, experimental biomarkers indicating drug of abuse symptoms, and the majority of PFC units recorded in animals expressing behavioral sensitization or tolerance to chronic MPD exposure responded by increasing and decreasing their neuronal firing rate, respectively. Further, it was shown that high doses of 10.0 mg/kg MPD significantly modified adolescent behavioral activity but did not impact adults suggesting that adolescents may be more receptive to chronic MPD exposure. These findings raise concerns regarding the use and abuse of MPD in normal, healthy individuals and support the notion that the adolescent PFC is more susceptible than the adult PFC to neuromodulation from chronic MPD use.

背景与目标： ：越来越多的人担心，试图改善自己的工作或学习成绩的健康成年人和青少年会滥用精神兴奋剂哌醋甲酯（MPD）来增强认知和娱乐。这项研究同时记录了暴露于急性和慢性MPD剂量（0.6、2.5和10.0μmg/ kg MPD）的自由行为动物的行为和前额叶皮层（PFC）神经元活性，以比较MPD对成年和青春期大鼠的影响。 PFC是受MPD影响的主要大脑区域之一，也是治疗ADHD的首选药物。此外，PFC是完成发育的最后一个大脑区域之一，表明对MPD的行为和神经生理反应在青少年和成年人中可能有所不同。在成年和青春期动物中，观察到相同的重复（长期）剂量0.6、2.5或10.0mg / kg MPD在某些动物中引起行为敏化，而在另一些动物中引起耐受，实验生物标志物表明药物滥用症状，并且动物中表现出对慢性MPD暴露具有行为敏锐性或耐受性的动物中记录的大多数PFC单位分别通过增加和降低其神经元放电速率来响应。此外，研究表明，高剂量10.0mg / kg MPD可以显着改变青少年的行为活动，但不会影响成年人，这表明青少年可能更容易接受慢性MPD暴露。这些发现引起了对在正常，健康个体中使用和滥用MPD的担忧，并支持这样的观念，即青春期PFC比成人PFC更容易受到慢性MPD使用的神经调节作用。

BACKGROUND & AIMS: :An increasing number of healthy people use methylphenidate, a psychostimulant that increases dopamine and noradrenaline transmission in the brain, to help them focus over extended periods of time. While methylphenidate has been shown to facilitate some cognitive functions, like focus and distractor-resistance, the same drug might also contribute to cognitive impairment, for example, in creativity. In this study, we investigated whether acute administration of a low oral dose (20 mg) of methylphenidate affected convergent and divergent creative processes in a sample of young healthy participants. Also, we explored whether such effects depended on individual differences in ADHD symptoms and working memory capacity. Contrary to our expectations, methylphenidate did not affect participants' creative performance on any of the tasks. Also, methylphenidate effects did not depend on individual differences in trait hyperactivity-impulsivity or baseline working memory capacity. Thus, although the effects of methylphenidate on creativity might be underestimated in our study due to several methodological factors, our findings do not suggest that methylphenidate impairs people's ability to be creative.

背景与目标： ：越来越多的健康人使用哌醋甲酯（一种精神兴奋药，可增加大脑中的多巴胺和去甲肾上腺素的传递），以帮助他们长期专注。尽管已显示哌醋甲酯可促进某些认知功能，如专注力和抗干扰能力，但同一药物也可能导致认知障碍，例如创造力下降。在这项研究中，我们调查了低剂量口服哌醋甲酯（20mg）的急性给药是否会影响年轻健康参与者样本中的收敛和发散创意过程。此外，我们探讨了这种影响是否取决于ADHD症状和工作记忆能力的个体差异。与我们的预期相反，哌醋甲酯并不影响参与者在任何任务上的创造力。同样，哌醋甲酯的作用并不取决于性格亢进冲动或基线工作记忆能力的个体差异。因此，尽管由于多种方法学因素，哌醋甲酯对创造力的影响可能在我们的研究中被低估了，但我们的发现并不表明哌醋甲酯会损害人们的创造力。

BACKGROUND & AIMS: :A series of threo-1-aza-3 or 4-substituted-5-phenyl[4.4.0]decanes (quinolizidines), which were envisioned as restricted rotational analogues (RRAs) of methylphenidate (MP), was synthesized and tested for inhibitory potency against [(3)H]WIN35,428, [3H]citalopram, and [3H]nisoxetine binding to the dopamine, serotonin, and norepinephrine transporters, respectively. Two different synthetic schemes were used; a Wittig reaction or acylation (followed by an intramolecular condensation) was a key feature of each scheme. The unsubstituted RRA, threo(trans)-1-aza-5-phenyl[4.4.0]decane (12a), was equipotent to unconstrained threo-MP against [(3)H]WIN35,428 binding. The extra ring in these RRAs (which reduces the conformational freedom) and the orientation and polarity of substituents at the 4-position on this extra ring are of critical importance to the biological activity. Generally, the RRAs paralleled the corresponding unconstrained MP derivatives in binding affinity to the three transporters. The results suggest that the conformation of MP in which the carbonyl group of the methyl ester is H-bonded to the piperidinyl N-H may be the bioactive form of the molecule.

背景与目标： ：合成了一系列的threo-1-aza-3或4-取代的5-苯基[4.4.0]癸烷（喹quin嗪），它们被设想为哌醋甲酯（MP）的限制性旋转类似物（RRA），并对其进行了测试对[（3）H] WIN35,428，[3H]西酞普兰和[3H] nisoxetine分别结合多巴胺，5-羟色胺和去甲肾上腺素转运蛋白的抑制作用。使用了两种不同的合成方案。 Wittig反应或酰化反应（随后是分子内缩合反应）是每种方案的关键特征。未取代的RRA，苏式（反式）-1-氮杂-5-苯基[4.4.0]癸烷（12a），与不受约束的苏式-MP等效于[（3）H] WIN35,428结合。这些RRA中的额外环（降低构象自由度）以及该额外环上4位取代基的方向和极性对于生物活性至关重要。通常，RRA在与三个转运蛋白的结合亲和力上与相应的不受约束的MP衍生物平行。结果表明，其中甲酯的羰基H键合至哌啶基N-H的MP的构象可能是分子的生物活性形式。

BACKGROUND & AIMS: BACKGROUND:The efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder (ADHD) shows wide between-study variability, which yields heterogeneous results in meta-analysis. The reasons for this variability have not been comprehensively investigated. OBJECTIVES:To determine the influence of treatment-related covariates of methylphenidate for adults with ADHD by means of meta-analysis. Clinical and methodological moderators and clinical trial reporting quality were also collected to control for their potential confounding effect. METHODS:We searched for randomized, placebo-controlled clinical trials investigating the efficacy of methylphenidate for adults with ADHD. The study outcome was the efficacy of methylphenidate for reducing ADHD symptom severity. Treatment-related covariates included dose, type of drug-release formulation (formulations with a continuous drug release vs those with a non-continuous drug release), dose regimen (fixed vs flexible) and treatment length. Clinical (presence of co-morbid substance use disorders [SUD]) and methodological (design and rater) covariates were also collected, in addition to clinical trial reporting quality. The standardized mean difference (SMD) was calculated for each study. The analysis of the influence of methylphenidate effect modifiers was performed by means of random-effects meta-regression. RESULTS:Eighteen studies were included. Dose, type of formulation and SUD appeared to modify the efficacy of methylphenidate in the bivariate analysis. These variables were included in a multivariate meta-regression, which showed that methylphenidate, at an average dose of 57.4 mg/day, delivered by means of non-continuous-release formulations, had a moderate effect on ADHD symptoms compared with placebo (SMD 0.57-0.58). A dose-response relationship was found, indicating that efficacy could be increased by SMD 0.11-0.12 for every 10 mg increment of methylphenidate. Continuous-release formulations and co-morbid SUD appeared to reduce the efficacy of methylphenidate. Nevertheless, the effect of treatment formulation may have been confounded by co-morbid SUD, since all studies using this continuous-release formulation were conducted in dual ADHD-SUD patients. No residual heterogeneity was found. CONCLUSIONS:This study shows that methylphenidate improves ADHD symptoms in adults in a dose-dependent fashion. The efficacy of methylphenidate appears to be reduced in patients with co-morbid SUD. It is unclear whether methylphenidate efficacy is influenced by the type of formulation, because the effect of this covariate is confounded by that of co-morbid SUD.

背景与目标： 背景：哌醋甲酯对成人注意力缺陷多动障碍（ADHD）的疗效显示出广泛的研究间变异性，在荟萃分析中产生了异类结果。尚未对此原因进行全面调查。
目的：通过荟萃分析确定治疗相关的哌醋甲酯对ADHD成人的影响。还收集了临床和方法主持人以及临床试验报告质量，以控制其潜在的混淆效果。
方法：我们搜寻了随机，安慰剂对照的临床试验，以研究哌醋甲酯对成人多动症的疗效。研究结果是哌醋甲酯降低多动症症状严重程度的功效。与治疗有关的协变量包括剂量，药物释放制剂的类型（连续释放药物与非连续释放药物的配方），剂量方案（固定与灵活）和治疗时间。除临床试验报告质量外，还收集了临床（共病物质使用障碍[SUD]的存在）和方法学（设计和评定者）的协变量。为每项研究计算标准化均值差（SMD）。通过随机效应的元回归对哌醋甲酯效果修饰剂的影响进行了分析。
结果：纳入十八项研究。在双变量分析中，剂量，制剂类型和SUD似乎改变了哌醋甲酯的功效。这些变量包括在多元荟萃回归中，这表明通过非连续释放制剂给药的哌醋甲酯平均剂量为57.4 mg /天，与安慰剂相比对ADHD症状有中等程度的影响（SMD 0.57 -0.58）。发现剂量-反应关系，表明每增加10 mg哌醋甲酯，SMD 0.11-0.12可以提高疗效。连续释放制剂和合并病态的SUD似乎降低了哌醋甲酯的功效。然而，由于所有使用这种持续释放制剂的研究都是在双重ADHD-SUD患者中进行的，因此，合并病态的SUD可能混淆了治疗制剂的效果。没有发现残留异质性。
结论：这项研究表明哌醋甲酯以剂量依赖的方式改善了成年人的ADHD症状。在患有合并症的SUD患者中，哌醋甲酯的疗效似乎降低了。尚不清楚哌醋甲酯的功效是否受制剂类型的影响，因为该协变量的作用与共病SUD的作用混淆。

BACKGROUND & AIMS: :Methylphenidate is a psychostimulant used to treat attention deficit hyperactivity disorder. Neurogenesis occurs throughout adulthood within the dentate gyrus of the hippocampus and can be altered by psychoactive medications; however, the impact of methylphenidate on neurogenesis is not fully understood. We investigated the effects of chronic low (1 mg/kg) and high (10 mg/kg) intraperitoneal doses of methylphenidate on neurogenesis in mouse hippocampus following 28 days and 56 days of treatment. Interestingly, methylphenidate, at both doses, increased neurogenesis. However, if methylphenidate treatment was not continued, the newly generated cells did not survive after 28 days. If treatment was continued, the newly generated neurons survived only in the mice receiving low-dose methylphenidate. To investigate the mechanism for this effect, we examined levels of proteins linked to cell proliferation in the hippocampus, including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB), and beta-catenin. BDNF or GDNF levels were not significantly different between groups. However, hippocampal VEGF, TrkB, and beta-catenin were significantly increased in mice receiving low-dose methylphenidate for 28 days compared to controls. Interestingly, high-dose methylphenidate significantly decreased beta-catenin after 28 days and decreased VEGF, beta-catenin, and TrkB after 56 days compared to controls. Thus, low-dose methylphenidate appears to increase cell proliferation and cell survival in the hippocampus, and these effects may be mediated by increase in VEGF, TrkB, and beta-catenin. While high dose methylphenidate may initially increase neuronal proliferation, newly generated neurons are unable to survive long-term, possibly due to decrease in VEGF, TrkB and beta-catenin.

背景与目标： ：哌醋甲酯是一种精神刺激药，用于治疗注意力缺陷多动障碍。神经发生发生在整个成年期的海马齿状回内，可以通过精神药物来改变。然而，哌醋甲酯对神经发生的影响尚不完全清楚。我们研究了28天和56天治疗后慢性低剂量（1 mg / kg）和高剂量（10 mg / kg）的哌醋甲酯腹膜内剂量对小鼠海马神经发生的影响。有趣的是，两种剂量的哌醋甲酯均可增加神经发生。但是，如果不继续使用哌醋甲酯处理，则新生成的细胞将在28天后无法存活。如果继续治疗，新产生的神经元仅在接受低剂量哌醋甲酯的小鼠中存活。为了研究这种效应的机制，我们研究了与海马细胞增殖相关的蛋白质水平，包括脑源性神经营养因子（BDNF），神经胶质细胞系源性神经营养因子（GDNF），血管内皮生长因子（VEGF），原肌球蛋白受体激酶B（TrkB）和β-连环蛋白。两组之间的BDNF或GDNF水平没有显着差异。但是，与对照组相比，在接受低剂量哌醋甲酯治疗28天的小鼠中，海马VEGF，TrkB和β-连环蛋白显着增加。有趣的是，与对照组相比，大剂量哌醋甲酯在28天后显着降低了β-catenin，在56天后显着降低了VEGF，β-catenin和TrkB。因此，低剂量的哌醋甲酯似乎会增加海马中的细胞增殖和细胞存活，并且这些作用可能是由VEGF，TrkB和β-catenin的增加介导的。虽然高剂量哌醋甲酯最初可能会增加神经元增殖，但新生成的神经元无法长期存活，这可能是由于VEGF，TrkB和β-连环蛋白的减少所致。