Background: Dopamine levels has been implicated in obesity, feeding behaviour, and hedonic control of appetite like olfactory cues and food palatability. Methylphenidate (MPH) is a dopamine reuptake inhibitor that increases brain dopamine levels and has been shown to reduce appetite and promote weight loss in patients with attention deficit hyperactivity disorder (ADHD). As such, the objectives of this study were to test the possible effect of MPH on appetite, olfaction, and food palatability as well as its effects on energy intake and body weight of healthy individuals with obesity. Methods: In a randomized, double-blind study, 12 participants (age 28.9±6.7 yrs) (BMI 36.1±4.5 kg/m2) were assigned to receive MPH (0.5mg/kg) (n=5) or placebo (n=7) twice daily for two months. Appetite and palatability (Visual Analog Scale (VAS)), odour threshold (Sniffin’ Sticks®), in-lab energy intake (ad libitum buffet), free-living energy intake (3-day food boxes) and body weight (DEXA scan) were measured at baseline (day 1) and final visit (day 60). Results: MPH intake caused significantly greater suppression of appetite sensations (desire to eat (p=0.001), hunger (p=0.008), and prospective food consumption (p=0.003)) and increase in fullness (p=0.028) over time compared to placebo. There was a significant increase in odour threshold scores in the MPH group (6.3±1.4 vs. 9.4±2.1) compared to placebo (7.9±2.3 vs. 7.8±1.9) (p=0.029). Both placebo and MPH groups showed decreases in their energy intake (p=0.021) and body weight (p=0.005) over time but with large effect sizes favouring greater reduction in the MPH group compared to placebo. Conclusions: Compared to placebo, MPH intake over 60 days suppressed appetite and improved olfactory sensitivity in individuals with obesity. These data provide novel findings into the possible efficacy of MPH to favourably impact appetite and therefore promoting weight loss in individuals living with obesity.

Attention deficit hyperactivity disorder (ADHD) is a commonly diagnosed disorder in children. Methylphenidate (MPH) or Ritalin, is a psychostimulant widely prescribed to treat ADHD from childhood to adulthood. Although patients take MPH for years, studies investigating long-term MPH use are lacking. Additionally, abuse of MPH is a growing problem in young adults. MPH blocks dopamine and norepinephrine transporters, which extends these neurotransmitters’ actions by preventing their reuptake from the cleft. Previous research has shown that long-term exposure to MPH causes dopamine-releasing neurons in the nigrostriatal pathway to become more susceptible to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here, the mechanism by which MPH sensitizes neurons to MPTP in a female model was investigated. The hypothesis was that oxidation of excess dopamine to a quinone causes neurons within this pathway to become more susceptible to MPTP. This dopamine quinone may be conjugated by the antioxidant glutathione (GSH); however, with an excess of dopamine and therefore quinones, GSH levels will become depleted. Without protection from GSH, quinones may lead to production of highly reactive free radicals, precipitating cell death. Estrogen is thought to be neuroprotective to MPTP, so it was further hypothesized that anestrus (low estrogen) females will show more dopamine cell loss, more quinone production, and more GSH depletion than proestrus (high estrogen) females. To test this hypothesis, MPTP-resistant adolescent female Swiss-Webster mice were divided into 3 treatment groups: saline (control), 1 mg/kg MPH (therapeutic dose), or 10 mg/kg (abusive dose). Within each group, mice were divided into proestrus and anestrus subgroups. All mice were injected twice daily with MPH or saline. After 12 weeks of injections followed by a 7 day washout period, half of each grouping received MPTP injections (4 x 20 mg/kg every 2 hours), while the other half received 4 injections of sterile saline. Mice were sacrificed either 3 or 7 days post-MPTP or saline injection. The substantia nigra and striatum of the nigrostriatal pathway that are affected by Parkinson’s disease were collected. Proestrus females in the saline group showed a significant (pmore dopamine quinone production (*p

The neonatally 6-hydroxydopamine (n6-OHDA)-lesioned rat has been the standard for 40 years, as an animal model of attention-deficit hyperactivity disorder (ADHD). Rats so lesioned during postnatal ontogeny are characterized by ∽99% destruction of dopaminergic nerves in pars compacta substantia nigra, with comparable destruction of the nigrostriatal tract and lifelong ∽99 % dopaminergic denervation of striatum, with lesser destructive effect on the ventral tegmental nucleus and associated lesser dopaminergic denervation of nucleus accumbens and prefrontal cortex. As a consequence of striatal dopaminergic denervation, reactive serotoninergic hyperinnervation of striatum ensues. The striatal extraneuronal milieu of DA and serotonin is markedly altered. Also, a variety of sensitization changes occur for dopaminergic D1 and D2 receptors, and for serotoninergic receptors. Behaviorally, these rats in adulthood display spontaneous hyperlocomotor activity, attentional deficits, and cognitive impairment-all of which are acutely attenuated by the psychostimulants amphetamine (AMPH) and methylphenidate (MPH) (i.e.,opposite to the acute effects of AMPH and MPH in intact control rats). The acute behavioral effects of AMPH and MPH in intact and lesioned rats are analogous to their respective acute effects in non-ADHD and in ADHD humans. The neurochemical template of brain, and behavioral series of changes in n6-OHDA-lesioned rats, is described in the review. Despite the fact that nigrostriatal damage is not an underlying pathophysiological process of human ADHD (i.e.,lacking construct validity), the described animal model has face validity (behavioral profile) and predictive validity (mirror of ADHD/MPH effects, as well as putative and new ADHD treatment effects). Also described in this review is a modification of the n6-OHDA rat, produced by adulthood partial lesioning of the serotoninergic fiber overgrowth. This ADHD model has even more accentuated hyperlocomotor and attentional deficits, counteracted by AMPH-thus providing a more robust means of animal modeling of ADHD. The n6-OHDA rat as a model of ADHD continues to be important in the search for new ADHD treatments.

OBJECTIVE: Methylphenidate is commonly used in the treatment of Attention Deficit Hyperactivity Disorder and narcolepsy. Methylphenidate is administered as a racemic mixture of the d- and l-threo enantiomers; however, the d-enantiomer is primarily responsible for the pharmacologic activity. Previous studies of the behavioral effects of methylphenidate have highlighted sex differences in the responsiveness to the drug, namely an increased sensitivity of females to its stimulatory effects. These differences may be due to differences in the uptake, distribution, and elimination of methylphenidate from male and female brains. Therefore, we compared the pharmacokinetics of d- and l-threo methylphenidate in the brains of male and female rats. MATERIALS AND METHODS: Adult male and female Sprague-Dawley rats were injected with 5 mg/kg d, l-threo methylphenidate, and whole brains were collected at various time points following injection. We measured methylphenidate concentrations utilizing chiral high pressure liquid chromatography followed by mass spectrometry. RESULTS: Females exhibited consistently higher brain concentrations of both d- and lmethylphenidate and a slower clearance of methylphenidate from brain as compared to males, particularly with the active d-enantiomer. CONCLUSIONS: The increased sensitivity of females to methylphenidate may be partially explained by an increase in total brain exposure to the drug

Objective: The strong association between ADHD and cigarette smoking and the known effects of nicotine on cognition has lead to interest in the role of cholinergic function in ADHD cognitive deficits. We have previously demonstrated that acute nicotine improves behavioral inhibition in adolescents with ADHD. This study examined acute nicotine in young adults with ADHD-Combined type on cognitive domains including behavioral inhibition, delay aversion, and recognition memory. Methods: 15 non-smoking young adults (20 ± 1.7 years) diagnosed with ADHD-C received acute nicotine (7 mg patch for 45 min) and placebo on separate days. Cognitive tasks included the Stop Signal Task, Choice Delay task, and the High-Low Imagery Task (a verbal recognition memory task). Three subjects experienced side effects and their data was excluded from analysis of cognitive measures. Results: There was a significant (p < .05) positive effect of nicotine on the Stop Signal Reaction Time measure of the Stop Signal Task. The SSRT was improved without changes in GO reaction time or accuracy. There was a trend (p = .09) for nicotine to increase tolerance for delay and a strong trend (p = .06) for nicotine to improve recognition memory. Conclusions: Non-smoking young adults with ADHD-C showed improvements in cognitive performance following nicotine administration in several domains that are central to ADHD. The results from this study support the hypothesis that cholinergic system activity may be important in the cognitive deficits of ADHD and may be a useful therapeutic target.

For more than 50 years, heavy metal exposure during pre- or post-natal ontogeny has been known to produce long-lived hyperactivity in rodents. Global brain injury produced by neonatal hypoxia also produced hyperactivity, as did (mainly) hippocampal injury produced by ontogenetic exposure to X-rays, and (mainly) cerebellar injury produced by the ontogenetic treatments with the antimitotic agent methylazoxymethanol or with polychlorinated biphenyls (PCBs). More recently, ontogenetic exposure to nicotine has been implicated in childhood hyperactivity. Because attention deficits most often accompany the hyperactivity, all of the above treatments have been used as models of attention deficit hyperactivity disorder (ADHD). However, the causation of childhood hyperactivity remains unknown. Neonatal 6-OHDA-induced dopaminergic denervation of rodent forebrain also produces hyperactivity - and this model, or variations of it, remain the most widely-used animal model of ADHD. In all models, amphetamine (AMPH) and methylphenidate (MPH), standard treatments of childhood ADHD, typically attenuate the hyperactivity and/or attention deficit. On the basis of genetic models and the noted animal models, monoaminergic phenotypes appear to most-closely attend the behavioral dysfunctions, notably dopaminergic, noradrenergic and serotoninergic systems in forebrain (basal ganglia, nucleus accumbens, prefrontal cortex). This paper describes the various pharmacological models of ADHD and attempts to ascribe a neuronal phenotype with specific brain regions that may be associated with ADHD.

This investigation was an analysis of the effects of methylphenidate (MPH; trade name: Ritalin) on drug reward using the conditioned place preference (CPP) behavioral paradigm in a rodent model and underlying mechanisms of this effect. Animals were conditioned in adolescence from postnatal day (P)33-39) or P44-49 with saline, 1 or 5 mg/kg MPH. Rats administered 5 mg/kg but not 1 mg/kg MPH, resulted in a significant preference that was more robust in younger male adolescent rats. The 5 mg/kg dose of MPH also resulted in a significant decrease of the dopamine transporter in both the nucleus accumbens and striatum, revealing dopamine clearance is decreased by MPH in brain areas that mediate reward. Finally, MPH-induced CPP was blocked by the dopamine D1 but not D2 antagonist, demonstrating the importance of the D1 receptor in the rewarding effects of MPH. These results demonstrate that dopamine mediates the rewarding effects of MPH in adolescence.

Introduction: Attention deficit hyperactivity disorder (ADHD) is a common disease in childhood and adolescence. In about 60% of pediatric patients, the symptoms persist into adulthood. Treatment guidelines for adult ADHD patients suggestmultimodal therapy consisting of psychostimulants and psychotherapy.Many adult ADHD patients also suffer frompsychiatric comorbidities, among others obsessive–compulsive disorder (OCD). The treatment of the comorbidity of ADHD and OCD remains challenging as the literature is sparse. Moreover, the impact of psychostimulants on obsessive–compulsive symptoms is still unclear. Case Presentation: Here, we report on a 33-year-old patient with an OCD who was unable to achieve sufficient remission under long-term guideline-based treatment for OCD. The re-examination of the psychological symptoms revealed the presence of adult ADHD as a comorbid disorder. The patient has already been treated with paroxetine and quetiapine for the OCD. Due to the newly established diagnosis of ADHD, extendedrelease methylphenidate (ER MPH) was administered in addition to a serotonin reuptake inhibitor. After a dose of 30mg ER MPH, the patient reported an improvement in both the ADHD and the obsessive–compulsive symptoms. After discharge, the patient reduced ER MPH without consultation with a physician due to subjectively described side effects. The discontinuation of medication led to a renewed increase in ADHD and obsessive– compulsive symptoms. The readjustment to ER MPH in combination with sertraline and quetiapine thereafter led to a significant improvement in the compulsive symptoms again. Conclusion: The present case shows that in ADHD and comorbid obsessive–compulsive disorder, treatment with psychostimulants can improve the obsessive–compulsive symptoms in addition to the ADHD-specific symptoms. To our knowledge, this is only the second case report describing a treatment with ER MPH for an adult patient with OCD and ADHD comorbidity in the literature. Further research, especially randomized controlled trials, is needed to standardize treatment options.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-01-30T10:43:20Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Tese - Claudia Santos Goncalves Barreto Bezerra.pdf: 2059173 bytes, checksum: 45f41522691fac0d28d22bbc3d3ec16b (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-01-30T12:49:14Z (GMT) No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Tese - Claudia Santos Goncalves Barreto Bezerra.pdf: 2059173 bytes, checksum: 45f41522691fac0d28d22bbc3d3ec16b (MD5) / Made available in DSpace on 2015-01-30T12:49:14Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Tese - Claudia Santos Goncalves Barreto Bezerra.pdf: 2059173 bytes, checksum: 45f41522691fac0d28d22bbc3d3ec16b (MD5) Previous issue date: 2014-04-28 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / The attention deficit/hyperactivity disorder is a neurodevelopmental disorder provided in the International C lassification of Diseases (ICD) characterizing a continuing pattern of attention deficit and/or hyperactivity/impulsivity with more intense and higher rates than what presented by individuals at the same development level. This dissertation was organized u sing the models of scientific articles analyzing the results from school performance by students of the Colégio de Aplicação (a school maintained by a university) of the Federal University of Goiás, 7 to 14 age group with and without ADHD diagnosis. Initia lly, the prospective observational study to assess comparative effectiveness involved 355 students and investigated the results from school performance by 60 of them before and during Methylphenidate - based treatment (MPH) and psychotherapy compared with th e control group. The students had their school performance and treatment adherence monitored for the first eight months. The literature review on the theme is presented in the first article submitted to the journal “Revista Ciência & Saúde Coletiva” (Journ al of Science and Collective Health), entitled “ Methylphenidate - based treatment and school performance by students with attention deficit/hyperactivity disorder : integrative literature review”. The review included scientific articles published from 2006 to 2013. Six hundred and sixteen out of the 629 articles found did not meet the criteria for inclusion and 13 were part of the sample. Most of the studies emphasized that the group of children with ADHD undergoing methylphenidate - based treatment improved the ir performance compared with the group of children with ADHD with no records for the treatment and stimulant - based therapies are more beneficial in the long term. The second article, entitled “Re/Assessment on the diagnosis of attention deficit/hyperactivi ty disorder in students ” presents the results from the clinical reassessment of 29 children previously diagnosed with ADHD or suspected ADHD. The reassessment confirmed the diagnosis of 74% of the children previously diagnosed and 70% of suspected ADHD. Th e third article, entitled “The use of methylphenidate for students with attention deficit/hyperactivity disorder and poor school performance” presents the major results of this study and proves that the use of methylphenidate - based treatment for students A DHD was associated with improved school records for basic mandatory disciplines . The medication had positive influence on school performance however even undergoing drug - based treatment the students were not able to achieve the levels of performance by stu dents without ADHD with typical school performance. / xii RESUMO O Transtorno de Déficit de Atenção/Hiperatividade é um transtorno do neurodesenvolvimento previsto no Código Internacional de Doenças e caracterizado por um quadro persistente de déficit de atenção e/ou de hiperatividade/impulsividade mais acentuado e grave do que o observado em outros indivíduos com o mesmo nível de desenvolvimento. A presente tese foi construída no modelo de artigos científicos que an alisou os resultados do desempenho acadêmico de escolares do Colégio de Aplicação da Universidade Federal de Goiás, de 7 a 14 anos com e sem diagnóstico de TDA/H. O estudo de caráter prospectivo, observacional e comparativo teve a participação inicial de 3 55 estudantes e investigou os resultados de desempenho escolar de 60 deles, antes e durante o tratamento com metilfenidato (MPH) e psicoterapia em comparação com um grupo controle. Os estudantes foram acompanhados em seu desempenho escolar e em adesão supe rvisionada ao tratamento durante o período de oito meses. A revisão de literatura do tema investigado é apresentada no primeiro artigo, submetido à “Revista Ciência & Saúde Coletiva”, intitulado “Tratamento com Metilfenidato e o desempenho de escolares com Transtorno de Déficit de Atenção/Hiperatividade: revisão integrativa da literatura”. A revisão incluiu artigos científicos publicados no período 2006 a 2013. Dos 629 artigos encontrados, 616 não atenderam aos critérios de inclusão e 13 fizeram parte da am ostra. A maioria dos estudos evidenciou que o grupo de crianças com TDA/H, em tratamento com MPH, mostrou melhor desempenho escolar em relação ao grupo com TDA/H sem histórico de tratamento. E que os tratamentos com estimulantes trazem mais benefícios quan do adotados em longo prazo. O segundo artigo intitulado “Re/Avaliação diagnóstica de Transtorno de Déficit de Atenção/Hiperatividade em escolares” apresenta os resultados da reavaliação clínica de 29 crianças, anteriormente, diagnosticadas com TDA/H ou cas os suspeitos. A re/avaliação confirmou o diagnóstico de 74% das crianças portadoras de diagnóstico e 70% dos casos suspeitos. Já o terceiro artigo intitulado: “A utilização do Metilfenidato por escolares com Transtorno de Déficit de Atenção/Hiperatividade e baixo desempenho escolar” apresenta os resultados principais desse estudo e constatou que o tratamento com Metilfenidato pelos escolares com TDA/H foi associado ao aumento das médias nos resultados da avaliação escolar das disciplinas elementares. A medi cação influenciou positivamente no desempenho dos estudantes, entretanto, mesmo em tratamento medicamentoso esses estudantes não atingiram o nível de desempenho dos escolares sem TDA/H com desempenho escolar típico.

This study examined the effect of preweanling methyphenidate exposure on later drug reward. We examined the induction, extinction, and reinstatement of morphine induced conditioned place preference (CPP) in rats that received methylphenidate pretreatment during the preweanling period.