Methylphenidate Research Articles

Increased sperm deoxyribonucleic acid damage leads to poor embryo quality and subfertility of male rats treated with methylphenidate hydrochloride in adolescence.

Methylphenidate hydrochloride (MPH) is a psychostimulant widely used in the treatment of attention-deficit hyperactive disorder (ADHD), as well as a performance enhancer, for at least 60 years. Despite the notable effectiveness as a psychostimulant, ADHD is a chronic disorder and has a two-third chance of accompanying the individual throughout life. Long-term use of MPH has been associated not only with an increase in the development of neurodegenerative diseases, but it also causes side effects on male fertility in experimental animals. To investigate whether methylphenidate poses a risk to sperm DNA structure and to the quality of embryos conceived after treatment during adolescence in rats. Wistar rats at 38 days of age were treated either with 5mg/kg body weight of MPH, in a single daily dose for 30 days, via gavage or with distilled water-only protocol. Levels of oxidative stress in testicular and epididymal tissues were evaluated. Sperm chromatin quality and acrosome integrity was assessed under flow cytometry. From 107 days of age, animals were mated with untreated females. The effects of the paternal contribution at two different embryo development moments-cleavage stage (2.5 days post coitum) and late gestation (20 days post coitum) -were analyzed. MPH caused high levels of sperm DNA damage, which was reflected in 40% of decrease in early embryo quality and a lower number of live pups at 20 dpc. The high level of fragmentation seen in the embryos sired from the MPH group is consistent with the poor chromatin structure of the sperm and does not seem to be a result of oxidative stress in the reproductive tissues. The results presented here suggest that the subchronic use of MPH during male prepubertal phase may cause long-term subfertility and compromise embryo survival.

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Methylphenidate extended‐release (generic) – Ritalin LA (brand)

Systemic inflammation enhances stimulant-induced striatal dopamine elevation in tobacco smokers

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [11C]raclopride positron emission tomography three times—at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [11C]raclopride binding potential (ΔBPND) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.

Investigating the effects of age, IQ, dosing, and anthropometric measures on the treatment persistence in long-term methylphenidate use

Objectives This study aimed to determine anthropometric and clinical correlates of persistence to methylphenidate (MPH) treatment in Turkish youth with attention-deficit hyperactivity disorder (ADHD). Methods Data from medical records of 518 children and adolescents with ADHD were recorded between March 2012 and January 2022. Clinical variables of patients persistent to MPH ≥ 2 years were compared with those of the non-persistent group. Children and adolescent age groups were compared using Kaplan–Meier estimates for treatment drop-outs. Cox regression analysis until the treatment drop-out was implemented to calculate hazard ratios (HRs) for gender, age, full-scale IQ, and anthropometric measures. Weight, height, and body mass index (BMI) z-scores were calculated per national guidelines. Results Persistent and non-persistent study groups had similar full-scale IQ, weight, height, and BMI z-scores at treatment onset. The mean MPH dose was significantly higher in the persistent group compared to the non-persistent counterparts (31.43 ± 10.70 vs. 24.28 ± 9.60 mg/d, p < 0.001, d = 0.70). Compared to children, the adolescents showed earlier treatment drop-outs in males (p < 0.001) but not in females (p = 0.110). Younger age showed a positive effect on treatment persistence. Conversely, baseline BMI and IQ scores were not associated with long-term persistence. Discussion Our study demonstrated lower daily doses and older age-onset were associated with early drop-outs in MPH treatment. These findings supported the notion that effective dosing strategies at younger ages could increase the sustainability of the treatment with MPH in the Turkish population.

Rosmarinus officinalis and Methylphenidate Exposure Improves Cognition and Depression and Regulates Anxiety-Like Behavior in AlCl3-Induced Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurological illness that causes severe cognitive impairment. AD patients also experience at least one of the neuropsychiatric symptoms including apathy, depression, and anxiety during the course of their life. Acetylcholine esterase inhibitors are the available treatment options to alleviate cognitive deficits, whereas methylphenidate (MPH), a psychostimulant, is considered for the treatment of apathy in AD patients. Rosmarinus officinalis, a perennial herb, has been potentially known to have antioxidant and anti-inflammatory properties. The present study investigated the potential effects of MPH and R. officinalis in comparison with the standard drug, Donepezil, on cognition, anxiety, and depression in the AlCl3-induced mouse model of AD. The animals were divided into eight groups (n = 8, each). The results revealed that the MPH- and R. officinalis-treated groups significantly improved memory impairment, whereas R. officinalis substantially reduced depression and anxiety as compared with other treatment groups. MPH treatment induced an antidepressant effect and increased anxiety-like behavior. Moreover, the AlCl3 exposure led to the formation of amyloid beta (Aβ) plaques in mice hippocampus; however, none of the tested drugs caused a significant reduction in amyloid burden at the selected doses. The present study suggested the potential of R. officinalis to improve memory as well as neuropsychiatric symptoms in AD. Although R. officinalis improved cognitive abilities, it did not reduce the amyloid plaque burden, which indicates that the memory-enhancing effects of R. officinalis are due to some alternate mechanism that needs to be explored further.

Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by persistent inattention, hyperactivity and impulsivity. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.). The ADHD symptomatology interferes with subject function and development. The treatment of ADHD requires a multidisciplinary approach based on a combination of non-pharmacological and pharmacological treatments with the aim of ameliorating the symptomatology; among first-line pharmacological treatments are stimulants [such as methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX)]. In this review we explored recent ADHD- and stimulants-related literature, with the aim of compiling available descriptions of molecular pathways altered in ADHD, and molecular mechanisms of current first-line stimulants MPH and LDX. While conducting the narrative review, we applied structured search strategies covering PubMed/MEDLINE database and performed handsearching of reference lists on the results of those searches. The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications. The lack of comprehensive understanding of the underlying molecular pathology makes both the diagnosis and treatment difficult. Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of MPH and LDX differentially modulate ADHD pathophysiology and control ADHD symptomatology.

Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats.

Methylphenidate (MPH) is among the main drugs prescribed to treat patients with attention-deficit and hyperactivity disease (ADHD). MPH blocks both the norepinephrine and dopamine reuptake transporters (NET and DAT, respectively). Our study was aimed at further understanding the mechanisms by which MPH could modulate neurotransmitter efflux, using ex vivo radiolabelled neurotransmitter assays isolated from rats. Here, we observed significant dopamine and norepinephrine efflux from the prefrontal cortex (PFC) after MPH (100 µM) exposure. Efflux was mediated by both dopamine and norepinephrine terminals. In the striatum, MPH (100 µM) triggered dopamine efflux through both sodium- and vesicular-dependent mechanisms. Chronic MPH exposure (4 mg/kg/day/animal, voluntary oral intake) for 15 days, followed by a 28-day washout period, increased the firing rate of PFC pyramidal neurons, assessed by in vivo extracellular single-cell electrophysiological recordings, without altering the responses to locally applied NMDA, via micro-iontophoresis. Furthermore, chronic MPH treatment resulted in decreased efficiency of extracellular dopamine to modulate NMDA-induced firing activities of medium spiny neurons in the striatum, together with lower MPH-induced (100 µM) dopamine outflow, suggesting desensitization to both dopamine and MPH in striatal regions. These results indicate that MPH can modulate neurotransmitter efflux in brain regions enriched with dopamine and/or norepinephrine terminals. Further, long-lasting alterations of striatal and prefrontal neurotransmission were observed, even after extensive washout periods. Further studies will be needed to understand the clinical implications of these findings.

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson's Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice.

Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy.

An Shen Ding Zhi Ling Ameliorates the Symptoms of Attention Deficit Hyperactivity Disorder via Modulating Brain-Derived Neurotrophic Factor-Related Signaling Pathways.

Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder. It may impact the cognitive and social functions throughout childhood and determine adult outcomes. Dopamine (DA) deficiency theory is the pathogenesis of ADHD that is recognized by most international literature. Existing studies have shown that DA deficiency is caused by the abnormal function of the DA transporter and an imbalance in the DA receptor functionality. Recent clinical and experimental studies have found that the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway acts a pivotal part in DA vesicle circulation and ADHD pathogenesis. An Shen Ding Zhi Ling (ASDZL) is a traditional Chinese medicine (TCM) prescription, which was widely prescribed to treat ADHD in Jiangsu, China, but its therapeutic mechanism is unclear. Therefore, we constructed a spontaneously hypertensive rat (SHR) model to explain its mechanism. SHRs were randomly assigned to four groups: SHR model group (vehicle), methylphenidate hydrochloride group (MPH), ASDZL group, and 7,8-dihydroxyflavone group (7,8-DHF). At the same time, the above groups were given continuous medication for four weeks. The results show that ASDZL, MPH, and 7,8-DHF group could significantly improve the spatial memory of SHRs in the Morris water maze tests. ASDZL increased the levels of BDNF, TrkB, p75 neurotrophin receptor (p75), C-Jun N-terminal kinases 1 (JNK1), and nuclear factor kappa B (NF-κB) in the prefrontal cortex (PFC) and hippocampus synaptosome of SHRs. The results of this study suggest that ASDZL can relieve the symptoms of ADHD in SHRs by regulating the balance between the BDNF/TrkB signaling pathway (promoting vesicle circulation) and the BDNF/P75/JNK1/NF-κB signaling pathway (inhibiting vesicle circulation) within the PFC and hippocampus synaptosome to increase the DA concentration in the synaptic cleft. The BDNF/TrkB signal pathway within the PFC and hippocampus synaptosome was activated by 7,8-DHF to increase DA concentration in the synaptic cleft. Whether 7,8-DHF can activate or inhibit the BDNF/P75 signaling pathway remains unclear.

Age differences to methylphenidate-NAc neuronal and behavioral recordings from freely behaving animals.

Methylphenidate (MPD) is a psychostimulant that is widely prescribed to treat attention deficit-hyperactivity disorder, but it is abused recreationally as well. The nucleus accumbens (NAc) is part of the motivation circuit implicated in drug-seeking behaviors. The NAc neuronal activity was recorded alongside the behavioral activity from young and adult rats to determine if there are significant differences in the response to MPD. The same dose of MPD elicits behavioral sensitization in some animals and behavioral tolerance in others. In adult animals, higher doses of MPD resulted in a greater ratio of tolerance/sensitization. Animals who responded to chronic MPD with behavioral sensitization usually exhibited further increases in their NAc neuronal firing rates as well. Different upregulations of transcription factors (ΔFOSB/CREB), variable proportions of D1/D2 dopamine receptors, and modulation from other brain areas may predispose certain animals to express behavioral and neuronal sensitization versus tolerance to MPD.

Fronto-striatal connectivity patterns account for the impact of methylphenidate on choice impulsivity among healthy adults

Choice impulsivity depicts a preference towards smaller-sooner rewards over larger-delayed rewards, and is often assessed using a delay discounting (DD) task. Previous research uncovered the prominent role of dopaminergic signaling within fronto-striatal circuits in mediating choice impulsivity. Administration of methylphenidate (MPH), an indirect dopaminergic agonist, was shown to reduce choice impulsivity in animals and pathological populations, although significant inter-individual variability in these effects was reported. Whether MPH impacts choice impulsivity among healthy individuals, and whether variability in the impact of MPH is related to fronto-striatal activation and connectivity patterns, has yet to be assessed. Here, fifty-seven healthy young adults completed the DD task twice during fMRI scans, after acute administration of either MPH (20 mg) or placebo, in a randomized double-blind placebo-controlled design. Acute MPH administration was found to reduce choice impulsivity at the group level, yet substantial variability in this behavioral response was observed. MPH was also found to increase activation in the bilateral putamen and the right caudate, and to enhance functional connectivity between the left putamen and medial prefrontal cortex (mPFC), particularly during non-impulsive choices. Notably, the more putamen-mPFC functional connectivity increased during non-impulsive choices following MPH administration, the less an individual was likely to make impulsive choices. These findings reveal, for the first time in healthy adults, that acute MPH administration is associated with reduced choice impulsivity and increased striatal activation and fronto-striatal connectivity; and furthermore, that the magnitude of MPH-induced change in fronto-striatal connectivity may account for individual differences in the impact of MPH on impulsive behavior.

Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood. In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications. The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism. The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs. The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur. Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

A Simulation Study of the Comparative Performance of Partial Area under the Curve (pAUC) and Partial Area under the Effect Curve (pAUEC) Metrics in Crossover Versus Replicated Crossover Bioequivalence Studies for Concerta and Ritalin LA.

Concerta and Ritalin LA are methylphenidate (MPH) drugs with different release mechanisms. Generic bioequivalence (BE) to these conventionally uses pAUC (partial area under the curve) as metrics in addition to Cmax (maximum concentration), AUC0-t (area from time 0 to time t), and AUC0-infinity. The recommended BE design was a standard two-formulation, two-sequence, and two-period crossover; however, the currently recommended design is a replicated crossover to better define subject-by-formulation interaction variance. The current purpose was to compare via simulation, using literature MPH models, the performance of the pAUC metrics in establishing BE via the standard crossover design versus a replicated design, and the relationship of the pAUC metrics to PD (pharmacodynamics) metrics, e.g., SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale) composite scores pAUEC (partial area under the effect curve). One-thousand, 40-subject studies were simulated with model literature parameters. An indirect response model described the SKAMP composite scores corrected for placebo. Performance of the pAUC metrics was demonstrated by the calculation of 90% confidence intervals (CIs) for each k0fast (fast absorption rate constant) and kaslow (slow absorption rate constant) test/reference (T/R) ratio. The 90% CIs resulting from changes in the k0fast and kaslow ratios, e.g., T/R, showed greater sensitivity to changes in the ratios at quotients below 0.8 than above for both Concerta and Ritalin LA. Ritalin LA pAUC values were insensitive to increases in either ratio once the ratio exceeded 1.0 and the study design. Correlations between least squares means (LSM) for pAUC and the SKAMP pAUEC for the composite scores were near 90%.

Stimulants.

Stimulants have been available for the treatment of attention-deficit/hyperactivity disorder (ADHD) for more than 70years and are the most effective medications available. During the past 2decades, several new immediate-release (IR) and extended-release methylphenidate (MPH) and amphetamine (AMPH) formulations have become available. These products differ by dose form (capsules, tablets, oral suspensions, oral disintegrating tablets, and patch), by onset and duration of effect, and by bioavailability. The side effect profile is generally similar for all compounds. Although the products are similar, individual patients may have a better response or tolerability to a particular class (MPH or AMPH) or formulation.

The Pharmacokinetics and Pharmacogenomics of Psychostimulants.

The psychostimulants-amphetamine and methylphenidate-have been in clinical use for well more than 60 years. In general, both stimulants are rapidly absorbed with relatively poor bioavailability and short half-lives. The pharmacokinetics of both stimulants are generally linear and dose proportional although substantial interindividual variability in pharmacokinetics is in evidence. Amphetamine (AMP) is highly metabolized by several oxidative enzymes forming multiple metabolites while methylphenidate (MPH) is primarily metabolized by hydrolysis to the inactive metabolite ritalinic acid. At present, pharmacogenomic testing as an aid to guide dosing and personalized treatment cannot be recommended for either agent. Few pharmacokinetically based drug-drug interactions (DDIs) have been documented for either stimulant.

Effect of Rehmanniae Radix Praeparata on energy metabolism in prefrontal cortex of rats with attention deficit hyperactivity disorder based on "static Yin and dynamic Yang" theory

The present study investigated the effect of Rehmanniae Radix Praeparata(RRP) on the energy metabolism of prefrontal cortex(PFC) of spontaneously hypertensive rats with attention deficit hyperactivity disorder(ADHD) based on the &quot;static Yin and dynamic Yang&quot; theory.Thirty spontaneously hypertensive male rats aged 3 weeks were randomly divided into a model group, a methylphenidate(MPH) group(2 mg·kg~(-1)), and an RRP group(2.4 g·kg~(-1)).Wistar-Kyoto(WKY) male rats of the same age were assigned to the normal group.Rats were treated with corresponding drugs twice per day, and those in the model group and the normal group received the same volume of 0.9% sodium carboxymethyl cellulose(CMC-Na) solution by gavage.The open-field test was performed to evaluate the spontaneous and impulsive behaviors of rats before treatment and on the 4~(th) week after treatment.Four weeks after treatment, PFC was isolated and mitochondria were prepared.The content of adenosine triphosphate(ATP), adenosine diphosphate(ADP), and adenosine monophosphate(AMP) in the PFC was determined by high-performance liquid chromatography(HPLC), and energy charge(EC) was calculated.The parameters related to mitochondrial respiratory function were measured by the Clark oxygen electrode, specifically, state 3 respiration(ST3), state 4 respiration(ST4), and respiratory control rate(RCR).Enzymatic activities of succinate dehydrogenase(SDH), cytochrome C oxidase(COX), Na~+-K~+-ATPase, and Ca~(2+)-Mg~(2+)-ATPase were measured by chemical colorimetry.Mitochondrial permeability transition pore(mPTP) opening was measured by spectrophotometry.Protein expression of glucose transporter 1(GLUT1) and GLUT3 in PFC was tested by Western blot.Compared with the results in the model group, RRP could significantly reduce the total distance of movement, vertical times, and distance in the central area in the open field test(P&lt;0.05 or P&lt;0.01), increase the content of ATP and EC, decrease the content of AMP(P&lt;0.05), elevate ST3 and RCR(P&lt;0.05), potentiate activities of SDH, COX, Na~+-K~+-ATPase, and Ca~(2+)-Mg~(2+)-ATPase(P&lt;0.05 or P&lt;0.01), inhibit the opening of mPTP, and increase the expression levels of GLUT1 and GLUT3 proteins(P&lt;0.05).It was inferred that RRP could inhibit hyperacti-vity and impulsivity by improving the energy metabolism disorder in PFC of ADHD rats, and its mechanism may be related to the improvement of mitochondrial respiratory function, potentiation of Na~+-K~+-ATPase, Ca~(2+)-Mg~(2+)-ATPase, and mitochondrial respiratory enzymes, inhibition of the opening of mPTP, and up-regulation of the expression of glucose transporter proteins.This study initially reveals the biological connotation of the &quot;static Yin and dynamic Yang&quot; theory in ADHD.

Abstinence following intermittent methylphenidate exposure dose-dependently modifies brain glucose metabolism in the rat brain.

Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays," which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3weeks on-treatment and 1week off-treatment for a period of 13weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD model.

Prepubertal methylphenidate leads to sex-dependent differences in probabilistic discounting

Prescription psychostimulants, such as methylphenidate (MPH), have served as a first line treatment for ADHD and associated developmental disorders since 1961. Psychostimulants has been shown to improve attention, response inhibition, and reduce hyperactivity in patients with ADHD, as well as in non-clinical human populations and animals. While there is a considerable amount of preclinical research investigating the effects of stimulant medications on reward sensitivity and basic learning in male rats, less is understood about their effects in females. Further, there are competing theories on the long-term cognitive impact of MPH, specifically in children who do not have ADHD. To this end, Long-Evans female and male rats were exposed to methylphenidate (0, 2.5, 5 mg/kg, BID, IP) for 20 days during early development (PD10–29). After discontinuation of MPH into adulthood, rats (beginning PD 60) were trained and tested for risk-preference using a 2-choice probabilistic discounting task. For this task, rats were given an option between a ‘large-risky’ choice (3 sugar pellets delivered on a probabilistic VR schedule) and ‘small-certain’ choice (1 sugar pellet delivered on a FR schedule). Rats were subsequently tested on an open field conflict test. The results demonstrate that prepubertal exposure to MPH can have lasting effects on decision-making. Specifically, female rats treated with 2.5 mg/kg MPH displayed a decrease in preference for the risky option, whereas male rats treated with the same dose showed an overall increase in preference compared to sex-matched controls. Irrespective of sex, rats treated with 2.5 mg/kg MPH also demonstrated a decrease in anxiety/inhibitory behavior on the modified open field test compared to controls. These results were not due to differences in locomotor behavior. Overall, the study contributes to the growing body of evidence to suggest that MPH exposure early in development can have a sex-dependent impact on decision-making in adulthood.

Methylphenidate Fast Dissolving Films: Development, Optimization Using Simplex Centroid Design and In Vitro Characterization.

The focus of this study was to design and optimize methylphenidate hydrochloride mouth dissolving film (MDF) that can be beneficial in an acute condition of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Solvent casting method was used for the preparation of this film. Optimization of the effect of independent variables such as the number of polymers and active pharmaceutical ingredients [hydroxypropyl methyl cellulose (HPMC) E5, HPMC E15, and maltodextrin], % of drug release, disintegration time, and tensile strength of the film done using simplex centroid design. Complex formation of the film was tested using fourier-transform infrared spectroscopy and differential scanning calorimetry study. The multiple regression analysis was obtained from equations of the results that adequately describe influence of the independent variables on the selected responses. Polynomial regression analysis, contour plots, and 3-D surface plots were used to relate dependent and independent variables. Experimental results indicated that different polymer amounts had complex effects on % drug release from the film, disintegration time as well as the tensile strength of the film. The observed responses were in near alignment with expected values calculated from the developed regression equations as shown by percentage relative error. Final formulation showed more than 95% drug release within 2 min and was shown to disintegrate within a minute that had good tensile strength. These findings suggest that MDF containing methylphenidate hydrochloride is likely to become a choice of methylphenidate hydrochloride preparations for treatment in ADHD and narcolepsy conditions.

Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus.

In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.