O transtorno do déficit de atenção e hiperatividade (TDAH) é uma condição que pode ser caracterizada pela falta de atenção, impulsividade e hiperatividade. A fisiopatologia do TDAH está relacionada, principalmente, a alterações no sistema dopaminérgico, noradrenérgico e serotoninérgico do sistema nervoso central. Dentre os tratamentos utilizados destaca-se a farmacoterapia com metilfenidato, potencial droga de abuso, que age como inibidor da recaptação de dopamina, noradrenalina e serotonina; por outro lado, o sal de sibutramina monoidratada, que possui mecanismo de ação farmacológico semelhante nestes sistemas de neurotransmissão central, ainda não teve sua utilização testada em um modelo do TDAH. Assim, o objetivo deste trabalho foi estudar os efeitos da administração prolongada (28 32 dias) de sibutramina e de metilfenidato em modelo animal do TDAH induzido pela exposição ao etanol no período pós-natal em camundongos, avaliando-se o ganho de peso semanal, o consumo de água e de ração, bem como o comportamento animal, por meio da avaliação geral no campo aberto e nos testes do labirinto em cruz elevado, da suspensão pela cauda, do reconhecimento de objetos e do labirinto em T. Foram avaliados também os níveis dos neurotransmissores e seus metabólitos em diferentes estruturas cerebrais. Os resultados mostraram que o modelo animal do TDAH induzido pela exposição ao etanol no período pós-natal apresentou hipoatividade no campo aberto seguida de aumento da atividade, não apresentou alterações nos níveis de ansiedade no labirinto em cruz elevado, como também mostrou comportamento tipo-depressivo no teste de suspensão pela cauda e marcante déficit na memória de trabalho e atenção no teste de reconhecimento de objetos e labirinto em T. Em relação ao tratamento prolongado com sibutramina e metilfenidato, não foram observadas alterações no ganho de peso semanal e consumo de água e ração. No campo aberto o metilfenidato normalizou a atividade dos camundongos, enquanto a sibutramina causou hiperatividade. No labirinto em cruz elevado não foram observadas alterações nos níveis de ansiedade. No teste de suspensão pela cauda o metilfenidato ocasionou comportamento tipo-depressivo nos camundongos salina, enquanto a sibutramina reverteu os efeitos depressivos dos etanol. O metilfenidato melhorou a memória de trabalho e atenção dos camundongos que receberam etanol tanto no teste de reconhecimento de objetos quanto no labirinto em T, já a sibutramina foi capaz de fazê-lo apenas no labirinto em T. / The attention deficit hyperactivity disorder (ADHD) is a condition that can be characterized by the lack of attention, impulsivity and hyperactivity. The pathophysiology of ADHD is related mainly to changes in the dopaminergic system, noradrenergic and serotoninergic of central nervous system. Among the treatments used stands out the pharmacotherapy with methylphenidate, potential drug of abuse, which acts as an inhibitor of the reuptake of dopamine, noradrenaline and serotonin; on the other hand, the salt of sibutramine monohydrate, which has a pharmacological mechanism of action similar in these systems of central neurotransmission, have not had their use tested in a model of ADHD. Thus, the objective of this work was to study the effects of prolonged administration (28 - 32 days) of sibutramine and methylphenidate in an animal model of ADHD induced by exposure to ethanol in the postnatal period in mice, evaluating the weight gain weekly, the consumption of water and feed, as well as animal behavior, through the general assessment in open field, and in the elevated plus maze, and in the tests of tail suspension, the recognition of objects and the T maze. We evaluated the levels of neurotransmitters and their metabolites in different brain structures. The results showed that the animal model of ADHD induced by exposure to ethanol in the postnatal period showed hypoactivity in the open field followed by increased activity, showed no changes in the levels of anxiety in the elevated plus maze, as also shown depressive-like behavior in the tail suspension test and striking deficit in working memory and attention in the test of recognition of objects and T maze. In relation to the prolonged treatment with sibutramine and methylphenidate, no alterations were observed in weight gain weekly, and consumption of water and food. In the open field, methylphenidate normalized the activity of mice, while sibutramine caused hyperactivity. In the elevated plus maze no changes were observed in anxiety levels. In the tail suspension test methylphenidate caused depressive-like behavior in mice salina, while sibutramine reversed the effects of depression of ethanol. Methylphenidate has improved the working memory and attention of mice that received ethanol both in the test of recognition of objects as the maze in T, since sibutramine was able to do it only in the maze in T.

O transtorno do déficit de atenção e hiperatividade (TDAH) é uma condição que pode ser caracterizada pela falta de atenção, impulsividade e hiperatividade. A fisiopatologia do TDAH está relacionada, principalmente, a alterações no sistema dopaminérgico, noradrenérgico e serotoninérgico do sistema nervoso central. Dentre os tratamentos utilizados destaca-se a farmacoterapia com metilfenidato, potencial droga de abuso, que age como inibidor da recaptação de dopamina, noradrenalina e serotonina; por outro lado, o sal de sibutramina monoidratada, que possui mecanismo de ação farmacológico semelhante nestes sistemas de neurotransmissão central, ainda não teve sua utilização testada em um modelo do TDAH. Assim, o objetivo deste trabalho foi estudar os efeitos da administração prolongada (28 32 dias) de sibutramina e de metilfenidato em modelo animal do TDAH induzido pela exposição ao etanol no período pós-natal em camundongos, avaliando-se o ganho de peso semanal, o consumo de água e de ração, bem como o comportamento animal, por meio da avaliação geral no campo aberto e nos testes do labirinto em cruz elevado, da suspensão pela cauda, do reconhecimento de objetos e do labirinto em T. Foram avaliados também os níveis dos neurotransmissores e seus metabólitos em diferentes estruturas cerebrais. Os resultados mostraram que o modelo animal do TDAH induzido pela exposição ao etanol no período pós-natal apresentou hipoatividade no campo aberto seguida de aumento da atividade, não apresentou alterações nos níveis de ansiedade no labirinto em cruz elevado, como também mostrou comportamento tipo-depressivo no teste de suspensão pela cauda e marcante déficit na memória de trabalho e atenção no teste de reconhecimento de objetos e labirinto em T. Em relação ao tratamento prolongado com sibutramina e metilfenidato, não foram observadas alterações no ganho de peso semanal e consumo de água e ração. No campo aberto o metilfenidato normalizou a atividade dos camundongos, enquanto a sibutramina causou hiperatividade. No labirinto em cruz elevado não foram observadas alterações nos níveis de ansiedade. No teste de suspensão pela cauda o metilfenidato ocasionou comportamento tipo-depressivo nos camundongos salina, enquanto a sibutramina reverteu os efeitos depressivos dos etanol. O metilfenidato melhorou a memória de trabalho e atenção dos camundongos que receberam etanol tanto no teste de reconhecimento de objetos quanto no labirinto em T, já a sibutramina foi capaz de fazê-lo apenas no labirinto em T. / The attention deficit hyperactivity disorder (ADHD) is a condition that can be characterized by the lack of attention, impulsivity and hyperactivity. The pathophysiology of ADHD is related mainly to changes in the dopaminergic system, noradrenergic and serotoninergic of central nervous system. Among the treatments used stands out the pharmacotherapy with methylphenidate, potential drug of abuse, which acts as an inhibitor of the reuptake of dopamine, noradrenaline and serotonin; on the other hand, the salt of sibutramine monohydrate, which has a pharmacological mechanism of action similar in these systems of central neurotransmission, have not had their use tested in a model of ADHD. Thus, the objective of this work was to study the effects of prolonged administration (28 - 32 days) of sibutramine and methylphenidate in an animal model of ADHD induced by exposure to ethanol in the postnatal period in mice, evaluating the weight gain weekly, the consumption of water and feed, as well as animal behavior, through the general assessment in open field, and in the elevated plus maze, and in the tests of tail suspension, the recognition of objects and the T maze. We evaluated the levels of neurotransmitters and their metabolites in different brain structures. The results showed that the animal model of ADHD induced by exposure to ethanol in the postnatal period showed hypoactivity in the open field followed by increased activity, showed no changes in the levels of anxiety in the elevated plus maze, as also shown depressive-like behavior in the tail suspension test and striking deficit in working memory and attention in the test of recognition of objects and T maze. In relation to the prolonged treatment with sibutramine and methylphenidate, no alterations were observed in weight gain weekly, and consumption of water and food. In the open field, methylphenidate normalized the activity of mice, while sibutramine caused hyperactivity. In the elevated plus maze no changes were observed in anxiety levels. In the tail suspension test methylphenidate caused depressive-like behavior in mice salina, while sibutramine reversed the effects of depression of ethanol. Methylphenidate has improved the working memory and attention of mice that received ethanol both in the test of recognition of objects as the maze in T, since sibutramine was able to do it only in the maze in T.

One of the most common childhood disorders, attention-deficit hyperactivity disorder (ADHD) places individuals at a higher risk for nicotine (NIC) dependence. Approximately 37.2% of individuals with ADHD currently smoke compared to the 18.3% of individuals with no record of mental illness. Methylphenidate (MPH; Trade name Ritalin) is the most commonly prescribed treatment for ADHD. Research regarding the synergistic effects of MPH and NIC, however, is divided. Some research indicates that MPH may enhance susceptibility to NIC effects, whereas other studies report that MPH may inhibit sensitization to NIC. The present study examines the effects of pre-exposure to MPH (1.0 mg/kg) on the behavioral effects of NIC (0.5 mg/kg) in adolescent male and female Sprague-Dawley rats. We used behavioral sensitization and conditioned place preference (CPP) on animals postnatal day (P)28-50; this is defined as adolescence in rats. For behavioral sensitization, results revealed a significant interaction between day of testing, drug pre-exposure, and adolescent drug treatment (p = .004). On the other hand, CPP results revealed a significant interaction between adolescent drug treatment and drug pre-exposure (p = .031). Findings suggest that pre-exposure to MPH reduces behavioral sensitization to NIC during adolescence. In addition, results indicate that MPH enhances NIC CPP in adolescent male and female rats, suggesting that MPH may enhance the rewarding effect of NIC.

Methylphenidate (trade name: Ritalin) produced a more robust conditioned place male as compared to female juvenile rats. This effect was blocked by a D1 antagonist (SCH 23390), which resulted in a conditioned place aversion in male as compared to female rats. Effects on Brain-derived neurotrophic factor (BDNF) will be reported.

OBJECTIVE: Methylphenidate is commonly used in the treatment of Attention Deficit Hyperactivity Disorder and narcolepsy. Methylphenidate is administered as

This study was designed to analyze the effects of adolescent exposure to methylphenidate (MPH; trade name: Ritalin) on nicotine self-administration, the motivation to obtain nicotine, and accumbal neuronal firing rate in female adolescent rats. MPH is the most commonly prescribed medication for Attention Deficit-Hyperactivity Disorder (ADHD) which is diagnosed in 3-5% of adolescents in the United States. However, this disorder is often misdiagnosed, and MPH is often prescribed to individuals not diagnosed with ADHD. Adolescent female Sprague-dawley rats were ip administered 1 mg/kg MPH or saline using a “school day” regimen of five days on, two days off, beginning on postnatal day (P)28 and this regimen was maintained throughout testing. A 1 mg/kg dose of MPH has been shown to result in brain plasma levels equivalent to clinical dosing in humans. Indwelling catheters were implanted in the jugular vein at P35, and one week later on P42, animals began nicotine self-administration. MPH (1 mg/kg) was administered each day approximately 6 h before each self-administration session began, which allows for nearly full plasma clearance of MPH (half-life = 1 h) before self-administration commenced. Rats were reduced to 85% of their free-feeding body weight and sipper tubes were made available to the rats in this paradigm, and responses to licking the tube produced an infusion of nicotine solution (15μg/kg) over a range of fixed ratio (FR) reinforcement schedules followed by a progressive ratio (PR) schedule, a measure of motivation. The schedule of reinforcement during 60 min sessions was increased from an FR5 to FR15 over approximately a three-week period. Results revealed that MPH pre-exposed rats self-administered significantly higher amounts of nicotine as compared to animals treated with saline throughout the FR5 and FR10 schedules. Further, MPH enhanced the motivation to self-administer nicotine on the PR schedule compared to controls, demonstrating an enhanced motivation to obtain nicotine produced by MPH. Finally, animals that had been pre-exposed to MPH and self-administered nicotine demonstrated a lower rate of basal accumbal firing as compared to controls, but a burst firing in response to nicotine that was higher than rats pre-exposed to saline. In conclusion, MPH altered the behavioral and neural response to nicotine in the nucleus accumbens.

Methylphenidate (MPH) is widely prescribed during childhood and adolescence for treatment of attention deficit and hyperactivity disorder. MPH is also one of the most commonly abused prescription drugs. However, the effects of MPH exposure and MPH abuse on incentive motivation are not well known. Moreover, MPH abuse during adolescence could increase sensitivity to the incentive motivational effects of other abused drugs such as nicotine in adulthood. Thus, the goals of this experiment were to investigate the effects of MPH exposure on the motivation to obtain sucrose during adolescence and to examine whether adolescent methylphenidate exposure altered the incentive motivational effects of nicotine (NIC) in adulthood. Incentive motivation was measured using an operant conditioning paradigm with sucrose available under a progressive ratio schedule of reinforcement (PR). Adolescent female rats were used because our previous studies have shown stronger sensitization to the locomotor stimulant effects of MPH. Rats arrived at post-natal day 21 (P21) and were shaped to respond for sucrose (20% w/v) on the PR schedule beginning on P24. After stable operant responding was established, rats were randomly assigned to receive either MPH (n=7) or SAL (n=6) injections (intraperitoneal) 30 min prior to test sessions, with the constraint that sucrose rewards earned did not differ between groups. Injection tests began on P36 and were carried out on alternating days for 10 total tests (P36-54). Although there was a trend for increased motivation for sucrose in the MPH group, it did not reach statistical significance. No further testing occurred until the rats reached adulthood (P55-P78). Over the next 5 days (P79-P84), all rats were pretreated with subcutaneous NIC injections (0.4 mg/kg base) 15 min before testing sessions. Following this initial ‘sensitization’ period, rats were tested with different NIC doses (0-1 mg/kg base) from P85-P92. During the sensitization period, NIC increased responding equally in both groups. However, during the dose-response testing, rats in the MPH group were more sensitive to the incentive motivational effects of NIC - the median effective dose was significantly lower for rats exposed to MPH in adolescence. The findings suggest that MPH may have limited reinforcement enhancing effects in adolescents. However, exposure to MPH during adolescents may increase the incentive motivational effects of NIC in adulthood.

Methylphenidate (MPH) is the most commonly-prescribed medication for treating ADHD. Despite high prescription rates among kindergarten-aged children, MPH was not approved for use in children younger than nine, and research into its long-term consequences is lacking. Here, we examined the effects of early-life MPH exposure on anxiety-like behaviors in adulthood in normal rats and rats with dysfunctional central dopamine. On postnatal day (PD) 3, male and female rat pups were injected intracisternally with 6-OHDA or vehicle to generate normal and dopamine-deficient groups. In an initial pair of experiments, 6-OHDA (50, 100 and 150 µg/10µL infusion) was assessed for its ability to induce an ADHD-like phenotype. Subsequently, rats were lesioned with 6-OHDA (100 µg/infusion) or vehicle on PD3 and given MPH (0, 0.5, 2 or 5 mg/kg, i.p.) once daily for 10 days, starting on PD11. On PD60, anxiety-like behavior was assessed with light/dark box or social interaction tests. On PD65, all rats were tested on the elevated plus maze (EPM). Rats with neonatal 6-OHDA lesions exhibited anxiety-like behavior in the light/dark box test and on the EPM. However, there was a complex interaction between sex, lesion, and drug dose in the social interaction test. Pretreatment with 2 mg/kg MPH increased investigatory behaviors in non-lesioned females and decreased investigatory behaviors in lesioned females, suggesting that the long-term effects of early-life MPH in females depend on normal dopamine levels. Together, these experiments support the efficacy of preclinical ADHD models and diverse measures of anxiety-like behaviors when studying the effects of early-life MPH exposure.

The purpose of this study was to quantify the amounts of the d- and l-threo enantiomers of methylphenidate in maternal plasma, placenta, and maternal and fetal brain tissue following prenatal exposure and to establish a pharmacokinetic profile for MPH during pregnancy. Due to increasing rates of use of methylphenidate amongst females of childbearing age, it is important to understand the extent of exposure to the fetus. Briefly, pregnant mice were injected with 5 mg/kg methylphenidate at 18 days gestation, and tissue was collected 1, 5, 10, 30, 60, and 120 min following injection. Methylphenidate was extracted from tissue via solid phase extraction, and concentrations were determined using liquid chromatography–mass spectrometry (LC–MS). Because methylphenidate is administered as a racemic mixture of d- and l-threo enantiomers and the d-enantiomer is more pharmacologically active, the enantiomers were quantified separately. Interestingly, we found that methylphenidate does cross the placenta and enter the fetal brain. Although the highest concentrations were achieved in maternal brain, the concentrations of d- and l-methylphenidate in fetal brain were comparable to those of maternal plasma. Additionally, both d- and l-methylphenidate had longer half-lives in placenta than in maternal or fetal brain. Interestingly, there was a bimodal peak in maternal brain concentrations, at 5 min and again at 60 min, which was not observed in maternal plasma. Finally, the total exposure (as represented by area under the curve) was statistically significantly higher for the active d-enantiomer than the l-enantiomer in maternal brain tissue. In conclusion, methylphenidate crosses the placenta and reaches measurable concentrations in fetal brain. Although long-term behavioral and developmental studies are needed to determine specific outcomes of prenatal exposure, discussion with pregnant patients on the potential risks of methylphenidate exposure is warranted.

Theses (MSc.(Med.)(Pharmacy))--University of Limpopo, 2009. / Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is the current diagnostic label for children presenting with significant problems with attention, and typically with impulsiveness and excessive activity as well. It is the most common neurobehavioural disorder of childhood, and therefore critical to clarify the diagnosis. ADHD is a seemingly heterogeneous group of behaviour disorders affecting between 5% - 10% of primary school children. Overdiagnosis of ADHD and overprescribing of stimulants are considered problems in some communities, emphasising the need for careful evaluation and diagnosis. Methylphenidate is currently the first choice of treatment. The main focus of this study was to investigate whether the diagnosis of these children was done by field experts according to the criteria as set in the DSM-IV TR. This influences the decision to prescribe methylphenidate and the monitoring of the child during treatment. Method: The parents of 50 clinically diagnosed ADHD children, from various primary schools situated in Polokwane, were interviewed and completed a questionnaire. Results: The findings indicated that 20% of the sample did not meet the DSM-IV TR criteria. 28% of the sample was advised to take methylphenidate by people without appropriate clinical knowledge of ADHD. The final diagnosis and prescribing of methylphenidate is overwhelmingly done by General Practitioners (47%). ADHD symptomatology (hyperactivity - impulsiveness and inattention) was not taken in account when prescribing methylphenidate. There was no definite monitoring of patients before and while on methylphenidate. Positive improvements in ADHD symptoms after methylphenidate therapy, shows that methylphenidate is still prominent and successful in the pharmacotherapy of the ADHD child. Conclusion: Based on the results of the study there does not appear to be enough evidence that proper protocols or guidelines were followed. Some children were diagnosed as having ADHD with insufficient evaluation and in some cases stimulant medication was prescribed when treatment alternatives might exist. It seems that not all clinicians prescribing methylphenidate have the necessary professional experience and/or qualifications regarding ADHD. This is an indication that there is a need for South African guidelines similar to The American Academy of Pediatrics’ Clinical Practice Guidelines and the European Clinical Guidelines for Hyperkinetic Disorder. However, with correct diagnosis and individualised prescribing and usage of methylphenidate, there will be positive improvements in ADHD symptoms after methylphenidate therapy.