Effects Of MPH Research Articles

TDAH : quels sont les effets cardiovasculaires du méthylphénidate et quelles sont les conséquences éventuelles pour la pratique clinique ?

ContextMethylphenidate is the first-line pharmacological treatment for ADHD, and its prevalence continues to grow, with an increase of 116% over the last ten years in France. Its use in hospitals has been extended to neurologists, psychiatrists and pediatricians, and its prescription can be renewed by a general practitioner. Cardiovascular complications are rare, but life-threatening. Management practices currently vary widely from one medical center or doctor to another. ObjectivesReviewing the cardiovascular effects of methylphenidate in adults and children with ADHD, aiming to propose a practical management plan without intending to replace existing recommendations. MethodsThe subject under study aimed to answer the following PICO question “What are the cardiovascular consequences (outcomes) when using MPH (intervention) for an ADHD population (population) regardless of age”. We carried out systematic review of international reviews and meta-analyses, selected using the PRISMA methodology via the PubMed, Cochrane Library and Google Scholar databases. Their methodological quality was assessed using the AMSTAR-2 scale. Cardiovascular events considered were the adrenergic effects of MPH on the cardiovascular system, looking for changes in blood pressure and heart rate, and the serious cardiovascular effects represented by sudden death/arrhythmia, myocardial infarction and stroke. A total of 17 systematic reviews and meta-analyses met the eligibility criteria. ResultsOf the 734 articles found, twelve were finally selected. Four concerned a population of children, five a mixed population of adults and children and three a population of adults only. They included two systematic reviews and ten meta-analyses. Three reviews included cohort studies and nine included randomized controlled trials. Three clinical situations can be distinguished depending on the age of the patient and the length of exposure to methylphenidate. The first, on initiation of treatment, there was a marked by a short-term increase in blood pressure and heart rate. The second involves a patient under the age of 35 with short- to medium-term exposure to MPH. A persistent adrenergic effect tends to increase the risk of sudden death by 12% (if the resting heart rate increases by ten beats per minute). This risk is further increased if the patient has psychiatric comorbidities and their associated treatments, congenital heart disease and uses recreational substances. Finally, the last situation involves a patient exposed to MPH for several years and aged over 35, whose main risk is the onset of atheromatous disease with myocardial infarction and ventricular arrhythmia. In this case, a comprehensive approach is required, identifying risk factors and behavioral factors likely to exacerbate the risk of CV disease. ConclusionsThe short-term cardiovascular effects of MPH are well documented and statistically significant, with a moderate but significant increase in blood pressure (+2mmHg) and heart rate (+5bpm). Longer-term cardiovascular safety data are often lacking, leading to conflicting conclusions. Meta-analyses of cohort studies conclude that there is an increase in cardiovascular risk, while meta-analyses of randomized trials find no significant statistical association. This means that patients and their families need to be made aware of this lack of data. Personalized management based on age, duration of exposure to MPH and the clinical profile of patients as defined by cohort studies seems to us to be the most appropriate approach. In people under 35, the main risk is sudden death. In this population, it is important to identify any congenital heart disease and to look for psychiatric comorbidities, and by assessing the substance abuse. For people over 35, the main risk is coronary heart disease. In this case, a comprehensive approach is required, identifying risk factors and behavioral factors likely to exacerbate the risk of CV disease. Our daily practice is more in line with cohort studies including patients with co-morbidities associated with their ADHD, as well as a significant risk of having risky behaviors, depressive episodes, heart disease and prolonged exposure to MPH and other drugs. Prescribing MPH in this context is tricky, with a higher risk of cardiovascular events. Close clinical monitoring is therefore necessary, and specialist advice may be required.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children’s-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don’t suggest significant negative long-term effects of MPH on sleep.

The Effects of Drug Treatments for ADHD in Measures of Cognitive Performance.

Based on core symptoms of inattention and deficient impulse control, and the identification of effective pharmacotherapies such as amphetamine (AMP; Adderall®), methylphenidate (MPH; Ritalin®), and atomoxetine (ATX; Strattera®), ADHD is a clinical condition which provides opportunity for translational research. Neuropsychological tests such as the 5-Choice and Continuous Performance Tasks, which measure aspects of attention and impulse control in animals and humans, provide scope for both forward (animal to human) and reverse (human to animal) translation. Rodent studies support pro-attentive effects of AMP and MPH and effectiveness in controlling some forms of impulsive behavior. In contrast, any pro-attentive effects of ATX appear to be less consistent, the most reliable effects of ATX are recorded in tests of impulsivity. These differences may account for AMP and MPH being recognized as first-line treatments for ADHD with a higher efficacy relative to ATX. DSM-5 classifies three "presentations" of ADHD: predominantly inattentive type (ADHD-I), predominantly hyperactive/impulsive type (ADHD-HI), or combined (ADHD-C). Presently, it is unclear whether AMP, MPH, or ATX has differential levels of efficacy across these presentation types. Nonetheless, these studies encourage confidence for the forward translation of NCEs in efforts to identify newer pharmacotherapies for ADHD.

Synergistic Anti-Leishmanial Activities of Morphine and Imiquimod on Leishmania infantum (MCAN/ES/98/LIM-877).

Background:This study was performed to evaluate in vitro and in vivo Leishmanicidal potential of morphine (Mph), imiquimod (IQ), and their combination.Methods:Leishmania infantum promastigote and amastigote assays were performed at the presence of 0.015–150μM Mph, 0.04–416μM IQ, and their combination. The inhibition effects of these drugs on promastigotes were evaluated after 24, 48, and 72h. The cytotoxic effects of the drugs were evaluated by MTT as well as flow cytometry after 72h. We explored the therapeutic effects of Mph and IQ in BALB/c mice at the end of the treatment using parasite load determination and cytokine assay. One group of mice received Mph for three weeks before infection.Results:The results of promastigote and amastigote assays showed the cytotoxic effects of the drugs at low concentrations. The cytotoxic effects were higher on promastigotes than amastigotes (p< 0.05). There was a negative correlation between drug concentration and amastigote/promastigote viability. Imiquimod alone or combined with Mph showed remarkable cytotoxic effects at all concentrations (p< 0.05). Flow cytometry results revealed apoptosis in the parasite following exposure to the drug combinations. Accordingly, the reduction of parasite loads in the spleen and liver was observed (p< 0.05) with simultaneous increases in IFN-γ and IL-4. We believe that the in vivo leishmanicidal effect was mediated by Mph through IL-4 and by IQ through both IL-4 and IFN-γ.Conclusion:Results pointed out the promising effects of Mph and IQ at low concentrations, especially when combined.

Methylphenidate Improves Autonomic Functioning among Youth with Attention-Deficit/Hyperactivity Disorder.

Psychostimulants are commonly prescribed medications for youth with attention-deficit/hyperactivity disorder (ADHD). Limited studies have evaluated how psychostimulants (e.g., methylphenidate [MPH]) impact autonomic nervous system (ANS) indexes among youth with ADHD. Understanding the effects of MPH on autonomic functioning is essential, given that youth with ADHD have been shown to experience atypical autonomic functioning (i.e., reduced activity across both sympathetic and parasympathetic branches) compared to typically developing youth. The current study investigated how a specific psychostimulant, Osmotic Release Oral System [OROS] MPH, impacts parasympathetic (indexed by respiratory sinus arrhythmia [RSA]) and sympathetic (indexed by electrodermal activity [EDA]) functioning among youth with ADHD via a within-subjects, double-masked, cross-over design. Two hundred fifty-six participants (157 youth with ADHD), ages 5 to 13years, completed a two-minute resting baseline task while electrocardiograph and electrodermal data were obtained. Youth with ADHD completed the resting baseline task twice, 3weeks apart, once during active medication and once during placebo conditions (counterbalanced). Typically developing youth were assessed without medication or placebo. Youth with ADHD during the placebo condition exhibited reduced RSA and EDA compared to typically developing youth. In contrast, youth with ADHD during the medication condition did not differ significantly from typically developing youth with respect to either RSA nor EDA. As such, OROS MPH appears to normalize RSA and EDA levels among youth with ADHD to levels comparable to typically developing youth. Future studies including indexes of the ANS among youth with ADHD are urged to consider the impact of MPH.

Paternal exposure to a common pharmaceutical (Ritalin) has transgenerational effects on the behaviour of Trinidadian guppies

Evidence is emerging that paternal effects, the nongenetic influence of fathers on their offspring, can be transgenerational, spanning several generations. Methylphenidate hydrochloride (MPH; e.g. Ritalin) is a dopaminergic drug that is highly prescribed to adolescent males for the treatment of Attention-deficit/hyperactivity disorder. It has been suggested that MPH could cause transgenerational effects because MPH can affect the male germline in rodents and because paternal effects have been observed in individuals taking similar drugs (e.g. cocaine). Despite these concerns, the transgenerational effects of paternal MPH exposure are unknown. Therefore, we exposed male and female Trinidadian guppies (Poecilia reticulata) to a low, chronic dose of MPH and observed that MPH affected the anxiety/exploratory behaviour of males, but not females. Because of this male-specific effect, we investigated the transgenerational effects of MPH through the paternal line. We observed behavioural effects of paternal MPH exposure on offspring and great-grandoffspring that were not directly administered the drug, making this the first study to demonstrate that paternal MPH exposure can affect descendants. These effects were not due to differential mortality or fecundity between control and MPH lines. These results highlight the transgenerational potential of MPH.

The Effects of Methylphenidate (Ritalin) on the Neurophysiology of the Monkey Caudal Prefrontal Cortex

Methylphenidate (MPH), commonly known as Ritalin, is the most widely prescribed drug worldwide to treat patients with attention deficit disorders. Although MPH is thought to modulate catecholamine neurotransmission in the brain, it remains unclear how these neurochemical effects influence neuronal activity and lead to attentional enhancements. Studies in rodents overwhelmingly point to the lateral prefrontal cortex (LPFC) as a main site of action of MPH. To understand the mechanism of action of MPH in a primate brain, we recorded the responses of neuronal populations using chronic multielectrode arrays implanted in the caudal LPFC of two macaque monkeys while the animals performed an attention task (N = 2811 neuronal recordings). Over different recording sessions (N = 55), we orally administered either various doses of MPH or a placebo to the animals. Behavioral analyses revealed positive effects of MPH on task performance at specific doses. However, analyses of individual neurons activity, noise correlations, and neuronal ensemble activity using machine learning algorithms revealed no effects of MPH. Our results suggest that the positive behavioral effects of MPH observed in primates (including humans) may not be mediated by changes in the activity of caudal LPFC neurons. MPH may enhance cognitive performance by modulating neuronal activity in other regions of the attentional network in the primate brain.

EVALUATION OF EXECUTIVE FUNCTIONING AND BEHAVIOUR IN YOUNG ADOLESCENTS WITH ADHD: A FOLLOW-UP STUDY

Abstract BACKGROUND Executive functioning (EF) impairment is frequent in the ADHD population. Psychostimulant medications (e.g. Methylphenidate [MPH]) are considered effective in reducing EF symptomatology. Limited studies have investigated the long-term effects of MPH on EF in young adolescents with ADHD (A-ADHD). OBJECTIVES To evaluate EF and behaviour challenges across three time points in A-ADHD who were involved in a MPH treatment trial. EF and behavioural functioning were evaluated using two separate parent questionnaires. DESIGN/METHODS A total of 21 A-ADHD (males=62%; n=13), ages 9–14 (M=12.33 years, SD=1.55 years) were evaluated at three separate time points: 1) Baseline (BL: no medication); 2) Best Dose (BD: following a 4-week trial of MPH treatment); and 3) long term Follow-Up (FU: defined as up to 2 years following best dose). Parents completed two behaviour rating scales: Behaviour Rating Inventory of Executive Functioning (BRIEF) and Behaviour Assessment System for Children (BASC-2). Repeated measures analyses of variance (RmANOVA) were conducted measuring changes in EF and behavioural challenges over the three time points (BL, BD, and FU). RESULTS Significant differences were obtained in EF ratings over time on the BRIEF Behavioural Regulation Index (BRIEF-BRI; F (2,36) = 20.71, p &lt; 0.001) and Metacognition Index (BRIEF-MI; F (2,36) = 26.83, p &lt; 0.001). Pairwise comparison indicated a) significant decrease in symptom ratings for both indexes between time points BL and BD, and b) significant increase in symptom ratings for indexes between time points BD and FU. Similarly, behavioural ratings obtained on all BASC-2 indexes (Externalizing Problems, Internalizing Problems, Behavioral Symptoms, and Adaptive Skills) revealed a significant effect of time (F (2,36) range = 4.55 to 26.28, p range = &lt;.001 to &lt;.05). Pairwise comparison indicated a) significant decrease in symptom ratings across all BASC-2 indexes between BL and BD, and b) increase in symptom ratings across all BASC-2 indexes between BD and FU time points. Therefore, parent ratings indicated clinically significant difficulties with EF and behaviour during BL and FU and average EF and behaviour scores during BD. CONCLUSION During follow-up, parents of A-ADHD continue to report challenges in EF and in all aspects of behaviours and adaptive skills. Although parents reported positive changes during the MPH trial (BD), these behavioural improvements were not seen at follow-up. The combined use of screening tools for EF (BRIEF) and behaviour (BASC-2) might be of interest to paediatricians when monitoring medication responses in young adolescents with ADHD.

METHYLPHENIDATE FOR BIPOLAR DEPRESSION

There is close association between Bipolar Disease (BPD) and Attention DeficitHyperactivity Syndrome (ADHD). It has been reported that patients who suffer ADHD inchildhood are more prone to BPD in adult life. So, there seems to be a same pathophysiologyof both the diseases. Bipolar depression is one of most difficult challenge for psychiatristto deal with; because of inconsistent results of available drugs authorized for use in BPD.Methylphenidate (MPH) is drug of choice in ADHD but not used in bipolar depression. MPHis considered contraindicated in BPD because it can switch on mania in BPD patients. Thiscase report is written, based on the effects of MPH seen in this specific case along with otherantidepressant in BPD. MPH may serve as a miracle for BPD patient and may reduce theirsuffering to a great extent.

English

There is close association between Bipolar Disease (BPD) and Attention DeficitHyperactivity Syndrome (ADHD). It has been reported that patients who suffer ADHD inchildhood are more prone to BPD in adult life. So, there seems to be a same pathophysiologyof both the diseases. Bipolar depression is one of most difficult challenge for psychiatristto deal with; because of inconsistent results of available drugs authorized for use in BPD.Methylphenidate (MPH) is drug of choice in ADHD but not used in bipolar depression. MPHis considered contraindicated in BPD because it can switch on mania in BPD patients. Thiscase report is written, based on the effects of MPH seen in this specific case along with otherantidepressant in BPD. MPH may serve as a miracle for BPD patient and may reduce theirsuffering to a great extent.

The Effect of Methylphenidate on the Microstructure of Schedule-Induced Polydipsia in an animal model of ADHD

Schedule-induced polydipsia (SIP) was established in spontaneously hypertensive rats (SHR), Wistar Kyoto rats (WKY), and Wistar rats, using a multiple fixed-time (FT) schedule of food delivery, with 30- and 90-s components. Thereafter, animals were exposed to methylphenidate (MPH; 2.5mg/kg/d) for six consecutive SIP sessions. A test to assess possible sensitization effects was also conducted four days after termination of the drug treatment. At baseline, FT 90-s produced longer and more frequent drinking episodes in SHR than in WKY. An analysis of the distribution of inter-lick intervals revealed that drinking was organized in bouts, which were shorter in SHR than in WKY. Across strains and schedules, MPH shifted drinking episodes towards the beginning of inter-food intervals, which may reflect a stimulant effect on SIP. MPH transiently reduced the frequency of drinking episodes in WKY in FT 30-s, and more permanently reduced the frequency of licking bouts in Wistar rats. MPH also increased the length of licking bouts in Wistar rats. Overall, SHR displayed a hyperactive-like pattern of drinking (frequent but short bouts), which 2.5mg/kg MPH appears to reduce in WKY and Wistar but not in SHR rats. It appears that therapeutic effects of MPH on hyperactive-like SIP require higher doses in SHR relative to control strains.

Blood glycemia-modulating effects of melanian snail protein hydrolysates in mice with typeII diabetes.

Freshwater animal proteins have long been used as nutrient supplements. In this study, melanian snail (Semisulcospira libertina) protein hydrolysates (MPh) were found to exert anti-diabetic and protective effects against liver and kidney damage in mice with type II diabetes adapted to a 45% kcal high-fat diet (HFD). The hypoglycemic, hepatoprotective and nephroprotective effects of MPh were analyzed after 12 weeks of the continuous oral administration of MPh at 125, 250 and 500 mg/kg. Diabetic control mice exhibited an increase in body weight, and blood glucose and insulin levels, with a decrease in serum high-density lipoprotein (HDL) levels. In addition, an increase in the regions of steatohepatitis, hepatocyte hypertrophy, and lipid droplet deposit-related renal tubular vacuolation degenerative lesions were detected, with noticeable expansion and hyperplasia of the pancreatic islets, and an increase in glucagon- and insulin-producing cells, insulin/glucagon cell ratios in the endocrine pancreas and hepatic lipid peroxidation, as well as decreased zymogen contents. Furthermore, a deterioration of the endogenous antioxidant defense system was observed, with reduced glucose utilization related hepatic glucokinase (GK) activity and an increase in hepatic gluconeogenesis-related phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6pase) activity. However, all of these diabetic complications were significantly inhibited by oral treatment with MPh in a dose-dependent manner. In addition, the marked dose-dependent inhibition of hepatic lipid peroxidation, the depletion of the liver endogenous antioxidant defense system, and changes in hepatic glucose-regulating enzyme activities were also observed. The results of this study suggest that MPh exerts potent anti-diabetic effects, along with the amelioration of related complications in mice with type II diabetes. The overall effects of MPh at a dose of 125 mg/kg on HFD-induced diabetes and related complications were similar or more potent than those of metformin (250 mg/kg).

Short- and Long-Term Effects of Methylphenidate on Cost-Benefit Decision Making in Adult Rats

Decision making is one of the most complicated and controversial topics in neuroscience. Today, there are important classes of chemicals that increase cognitive performance; in particular these are psychostimulants (e.g., methylphenidate, MPH). However, the long-term effects of MPH on cost-benefit decision making in healthy animals remain unknown. Therefore, we aimed to compare the short- and long-term effects of MPH in adult healthy male rats on the decision making in two distinct T-maze tasks and the ability of the animals to adjust the height of the obstacle in a T-maze or to process information on the reward amount. We found that short-term effects of MPH (2 weeks) played a significant role in making the correct decision in T-maze tasks, while the respective effects of long-term administration (12 weeks) were much weaker. These data suggest that chronic application of MPH has short- but not long-term effects on cost-benefit decision making in healthy adult animals.

6.59 EFFECTS OF LONG-ACTING METHYLPHENIDATE ON NESFATIN-1 LEVELS IN MALE CHILDREN WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

Underlying pathophysiological mechanisms of appetite and weight loss or decreased rate of weight gain related with psychostimulants for the treatment of ADHD have not been fully clarified yet. Nesfatin-1, discovered in recent years, released by mainly hypothalamus, is a peptide responsible for the appetite regulation, weight loss and metabolic regulation. We aimed to investigate whether there is an association between nesfatin-1 and etiopathogenesis of ADHD, treatment response and metabolic side effects of MPH by comparing pre-and post-treatment serum levels of Nesfatin-1 in prepubertal boys with ADHD.

An acute, non-therapeutic dose of methylphenidate disrupts partner preference in female rats

The present study was designed to test the effects of an acute, high dose of methylphenidate (MPH; trademarked as Ritalin) on sexual behavior in female Long-Evans rats. In Experiment 1, naturally cycling subjects in estrus were tested for partner preference 20min after receiving an i.p. injection of MPH 10mg/kg (n=8) or saline (n=7). During the partner-preference test, female subjects were given the choice to interact with a sexually active male stimulus or a sexually receptive female stimulus. Physical contact was limited by placing the stimulus animals behind a wire mesh during the no-contact phase of the test, whereas physical contact was not limited during the contact phase. Female subjects that received MPH spent significantly less time with the male stimulus than the saline-treated subjects during both phases (no-contact and contact) of the partner-preference test. This acute dose of MPH did not affect visits to the female stimulus; however, MPH-treated subjects made fewer visits to the male stimulus than the saline-treated subjects during the contact phase of the partner-preference test. Consistent with previous findings, MPH increased line crossings when subjects were tested in an open field immediately after the partner-preference test. In Experiment 2, female subjects were ovariectomized (OVX), primed with estradiol benzoate and progesterone, and tested for partner preference 20min after receiving an injection of MPH 10mg/kg (n=8) or saline (n=8). Similar to the results of Experiment 1, OVX hormone-primed subjects that received MPH spent significantly less time with the male stimulus than the saline-treated subjects during both phases of the partner-preference test. Although MPH-treated subjects were sexually receptive, they displayed fewer proceptive behaviors (i.e., hops and darts) than saline-treated subjects. Two-weeks later, the subjects from Experiment 2 were tested in an open field 20min after receiving an injection of MPH 10mg/kg or saline (counterbalancing previous MPH exposure). Once again MPH increased locomotor activity. In conclusion, the effects of MPH were equally as robust in naturally cycling subjects as in the more commonly used OVX-hormone primed subjects. The results of the present study suggest that an acute, non-therapeutic dose of MPH disrupts approach and interest in a male stimulus during a test of partner preference. This avoidance of the male stimulus may be the result of a decrease in the incentive value of a sexual partner.

Methylphenidate does not enhance visual working memory but benefits motivation in macaque monkeys

Working memory is a limited-capacity cognitive process that retains relevant information temporarily to guide thoughts and behavior. A large body of work has suggested that catecholamines exert a major modulatory influence on cognition, but there is only equivocal evidence of a direct influence on working memory ability, which would be reflected in a dependence on working memory load. Here we tested the contribution of catecholamines to working memory by administering a wide range of acute oral doses of the dopamine and norepinephrine reuptake inhibitor methylphenidate (MPH, 0.1–9 mg/kg) to three female macaque monkeys (Macaca mulatta), whose working memory ability was measured from their performance in a visual sequential comparison task. This task allows the systematic manipulation of working memory load, and we therefore tested the specific hypothesis that MPH modulates performance in a manner that depends on both dose and memory load. We found no evidence of a dose- or memory load-dependent effect of MPH on performance. In contrast, significant effects on measures of motivation were observed. These findings suggest that an acute increase in catecholamines does not seem to affect the retention of visual information per se. As such, these results help delimit the effects of MPH on cognition.

Similar and Different? Subjective Effects of Methylphenidate and Cocaine in Opioid-Maintained Patients

ABSTRACTMethylphenidate (MPH) is commonly prescribed for attention deficit hyperactivity disorder (ADHD). Recreational nonmedical use has been described and also occurs in patients on opioid maintenance treatment (OMT). MPH has been proposed for use as replacement therapy in cocaine dependence, although evidence for efficacy is inconclusive. We conducted a cross-sectional interview study on patterns of MPH use in a sample of 20 MPH-using patients on OMT with a history of cocaine use. We assessed symptoms of depression, ADHD during childhood, and retrospective subjective-effects profiles of MPH and cocaine. Risky patterns of MPH use were common, in particular illicit acquisition, use of high doses, and parenteral administration. Sixty percent of patients reported having used MPH as a substitute for cocaine. Correspondingly, the subjective-effect profiles of MPH and cocaine showed striking parallels, with overall effects of MPH being rated more positively than those of cocaine. Proportions of patients with elevated scores for depression or childhood ADHD were large, highlighting the importance of treating dual disorders in this population. Clinical studies on MPH substitution in cocaine-dependent patients on opioid maintenance treatment could benefit from consideration of the patterns of application of MPH in this population. Results are preliminary due to small sample size.

Effects of chronic and acute stimulants on brain functional connectivity hubs

The spatial distribution and strength of information processing ‘hubs’ are essential features of the brain׳s network topology, and may thus be particularly susceptible to neuropsychiatric disease. Despite growing evidence that drug addiction alters functioning and connectivity of discrete brain regions, little is known about whether chronic drug use is associated with abnormalities in this network-level organization, and if such abnormalities could be targeted for intervention. We used functional connectivity density (FCD) mapping to evaluate how chronic and acute stimulants affect brain hubs (i.e., regions with many short-range or long-range functional connections). Nineteen individuals with cocaine use disorders (CUD) and 15 healthy controls completed resting-state fMRI scans following a randomly assigned dose of methylphenidate (MPH; 20mg) or placebo. Short-range and long-range FCD maps were computed for each participant and medication condition. CUD participants had increased short-range and long-range FCD in the ventromedial prefrontal cortex, posterior cingulate/precuneus, and putamen/amygdala, which in areas of the default mode network correlated with years of use. Across participants, MPH decreased short-range FCD in the thalamus/putamen, and decreased long-range FCD in the supplementary motor area and postcentral gyrus. Increased density of short-range and long-range functional connections to default mode hubs in CUD suggests an overrepresentation of these resource-expensive hubs. While the effects of MPH on FCD were only partly overlapping with those of CUD, MPH-induced reduction in the density of short-range connections to the putamen/thalamus, a network of core relevance to habit formation and addiction, suggests that some FCD abnormalities could be targeted for intervention.This article is part of a Special Issue entitled SI:Addiction circuits.

Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity

Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.

Effect of age on methylphenidate-induced conditioned taste avoidance and related BDNF/TrkB signaling in the insular cortex of the rat

Drug use and abuse is thought to be a function of the balance between its rewarding and aversive effects, such that the rewarding effects increase the likelihood of use while the drug's dissociable aversive effects limit it. Adolescents exhibit a shift in this balance toward reward, which may ultimately lead to increased use. Importantly, recent work shows that adolescents are also protected from the aversive effects of many abusable drugs as measured by conditioned taste avoidance (CTA). However, such effects of methylphenidate (MPH, widely prescribed to adolescents with ADHD) have not been characterized. The effect of age on MPH-induced CTA was assessed. In addition, MPH-induced changes in brain-derived neurotrophic factor (BDNF) activity in the insular cortex (IC) and central nucleus of the amygdala (CeA), known to be important to CTA, were examined and related to CTAs in adolescents and adults. CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adolescent (n = 34) and adult (n = 33) male Sprague Dawley rats. Following MPH CTA, IC and CeA tissue was probed for differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) using Western blots. Blunted expression of MPH CTA was observed in the adolescents versus adults, which correlated with generally attenuated adolescent BDNF/TrkB activity in the IC, but the drug effects ran contrary to the expression of CTA. Adolescents are protected from the aversive effects of MPH versus adults, but further work is needed to characterize the possible involvement of BDNF/TrkB.