This dissertation work investigated the effect of acute and repeated in vivo administration of lobeline on dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. The effects of lobeline were then compared to the effects of acute and repeated in vivo administration of methylphenidate and amphetamine to determine if lobeline produced similar effects compared to these Attention Deficit Hyperactivity Disorder (ADHD) medications. These medications are considered the first line of pharmacotherapy for ADHD, although there is a growing concern associated with their potential for abuse and other side effects. This merits the need for novel ADHD treatments that have a safer side effect profile. If lobeline alters DAT and VMAT2 function in the same way as methylphenidate or amphetamine, further investigation may be necessary to evaluate lobeline as a potential treatment for ADHD. Kinetic analysis of [3H]dopamine (DA) was utilized to determine the effect on DAT and VMAT2 function in rat striatum. Results from the DAT experiments, revealed that lobeline as well as amphetamine had no effect on DAT function. However, methylphenidate increased DAT function after acute and 7-day treatment. None of the drug treatment regimens altered Km. To determine if the methylphenidateinduced increase in DAT function was due to DAT trafficking, biotinylation and Western blot analyses were performed. Acute administration of methylphenidate did not alter surface DAT, however repeated administration of methylphenidate for 7 days decreased intracellular DAT, suggesting that methylphenidate redistributes DAT in a time-dependent manner. Similar results were found in the VMAT2 experiments. Lobeline and amphetamine had no effect on VMAT2 function after acute or repeated administration. Amphetamine decreased the Km after repeated administration for 7 days. Methylphenidate increased VMAT2 function after acute and repeated administration for 7 days. The overall results of these experiments suggest that methylphenidate interacts with DAT and VMAT2 in a different manner than amphetamine and lobeline. In addition, since lobeline and amphetamine had no effect on DAT and VMAT2 function, further investigation is warranted to elucidate the underlying mechanisms of the therapeutic actions of these agents. This additional information will aid in the development of novel treatments for ADHD.

INTRODUÇÃO: O transtorno de déficit de atenção / hiperatividade (TDAH) é observado em 30-40% das crianças e adolescentes com epilepsia. Estudos recentes relataram a segurança do metilfenidato em pacientes com epilepsia controlada, porém há uma carência de estudos em pacientes com epilepsia não controlada. OBJETIVO: Estudar a eficácia e segurança do metilfenidato em crianças e adolescentes com diagnóstico de TDAH e epilepsia não controlada. MÉTODOS: Avaliação prospectiva de 24 pacientes de 7 a 16 anos, com diagnóstico de epilepsia e TDAH, no Ambulatório de Especialidades da Universidade da Região de Joinville (Univille), que preencham os seguintes critérios: pacientes com diagnóstico de epilepsia que tenham tido pelo menos duas crises epilépticas nos últimos seis meses; diagnóstico de TDAH com base nos critérios definidos pelo DSM-IV; que não tivesse recebido tratamento prévio com metilfenidato. RESULTADOS: A amostra foi composta de 24 pacientes, classificados pelo subtipo do TDAH em 41,7% desatento, 37,5% combinado e 20,8% hiperativo/impulsivo. Os pacientes apresentaram epilepsia parcial em 58,3% e epilepsia generalizada em 41,7%. A dose média do metilfenidato utilizada foi 0,52 mg/kg/dia (22,3 mg/dia). Tempo de seguimento foi de seis meses para todos os pacientes. Em 70,8% houve melhora dos sintomas do TDAH após seis meses de tratamento, e em 22 dos 24 pacientes (91,6%) não houve aumento da freqüência de crises epilépticas. CONCLUSÕES: metilfenidato demonstrouse efetivo no tratamento dos sintomas do TDAH em pacientes com epilepsia não controlada, e nos primeiros seis meses de estudo, não houve aumento significativo da freqüência das crises epilépticas. / INTRODUCTION: Attention Deficit and Hyperactivity Disorder (ADHD) is observed in 30 to 40 % children and adolescents with epilepsy. Recent studies demonstrate the safety of methylphenidate (MPH) in patients with controlled epilepsy. There is a lack of studies of patients with uncontrolled epilepsy. OBJECTIVE: to study the efficacy and safety of MPH in children and adolescents diagnosed with ADHD and uncontrolled epilepsy. METHODS: We evaluated 24 patients with ages of 7 and 16 years, diagnosed with epilepsy and ADHD, outpacient speciality clinic which took place in the Ambulatório de Especialidades of the Universidade da Região de Joinville (Univille). Inclusions criterias: at least two seizures in the previous 6 months; the diagnosis of ADHD based on DSM-IV criteria. RESULTS: The results of 24 patients have been evaluated, classified according to subtype ADHD as the following: 41.7 % inattentive type, 37.5 % combined and 20.8% hyperactive/impulsive type. The sample was distributed as the following: parcial epilepsy 58.3 % and generalized epilepsy 41.7 %. An average dose of MPH was 0.52 mg/kg/daily (22.3 mg daily). This was given for a period of 6 months to all patients. In 70.8 % the patients showed signs of improvement from ADHD symptoms and there was not increase of frequency of epileptic seizure in 22 of the 24 patients (91.6%). CONCLUSIONS: MPH was effective in the treatment of ADHD in patients with uncontrolled epilepsy. In the first 6 months of this study there was no increase of epileptic seizures.

Objectives: Most weight loss medications target reductions in energy intake while neglecting energy expenditure, a critical predictor of weight loss/regain. This pilot study examined the effect of short-acting methylphenidate (MPH) on resting energy expenditure (REE), thermic effect of food (TEF), physical activity energy expenditure (PAEE), and how changes in energy expenditure relate to changes in body composition in youth and adults living with obesity. Methods: This study was a randomized, double-blind, placebo-controlled two-parallel arm study. In total, 19 participants were screened, of which 14 participants were randomized into the study, but complete data was only collected for 12, and only analyzed for 10 participants. Those 10 participants aged 28.8 ± 6.9 yrs. (5 Male, 5 Female) were randomized to receive either MPH (0.5 mg/kg) (n = 5) or placebo (n =5) twice daily for 60 days. Participants’ REE and TEF (indirect calorimetry), were measured at baseline (no drug/placebo), and day 60 post-treatment (drug/placebo). Participants’ PAEE (Actical) was measured between screening and baseline for a 1-week period (no drug/placebo), and on day 53 for a 1-week period (drug/placebo). Participants’ anthropometrics were measured using DEXA at baseline, and day 60 post-treatment. Results: From baseline to day 60, MPH showed a relative difference to placebo in relative REE (Relative REE: F(1, 8) = 4.235, p = 0.074, d = 0.83, 2 = 0.346) of 10%, evidenced by a 6% increase in relative REE kcal/kg (18.53 ± 1.97 Kcal/day/kg at baseline, 19.71 ± 2.52 Kcal/day/kg at final) for the MPH group, and a 4% decrease (19.08 2.36 Kcal/day/kg at baseline, 18.26 ± 2.04 Kcal/day/kg at final) in placebo, translating to moderate-effect size (Cohen’s d=0.63) favouring MPH. From baseline to day 60, there were no significant differences between groups on changes in TEF (TEF AUC: F(1, 8) = 0.079, p = 0.785, d = 0.15, 2 = 0.010) or any PAEE variables such as sedentary behavior (SB: F (1, 8) = 0.455, p = 0.52, d = 0.02, 2 = 0.054), light physical activity (LPA: F (1, 8) = 0.504, p = 0.50, d = 0.16, 2 = 0.059), moderate physical activity (MPA: F (1, 8) = 0.281, p = 0.61, d = 0.19, 2 = 0.034), moderate-to-vigorous physical activity (MVPA: F (1, 8) = 0.120, p = 0.74, d = 0.15, 2 = 0.015), or vigorous physical activity (VPA: F (1, 8) = 3.495, p = 0.098, d = 0.91, 2 = 0.304) . Mean change in body weight (kg) resulted in a weight loss of roughly -2.66 ± 2.00 kg in the MPH group and -1.64 ± 1.41 kg in the placebo group, differences that were not statistically significant. Mean change in both groups for body fat% of -0.33 ± 2.08 %, mean change in fat mass of -1.05 ± 2.59 kg, and finally a mean change in fat-free mass of -0.06 ± 1.19 kg was reported. Changes in relative REE were inversely correlated with changes in body weight (r = -0.599, p = 0.067), body fat (r = -0.524, p = 0.12) and fat mass (r = -0.599, p = 0.096). These associations were stronger in the MPH group. Conclusions: Our data suggests that MPH administration may lead to a meaningful increase in relative REE, and these suggested changes were associated with reductions in adiposity among individuals with obesity. These preliminary findings suggest that MPH should be further examined using a larger sample size and study duration to determine its effectiveness in promoting weight loss and maintenance of weight loss in individuals with obesity, a population at high risk of morbidity and premature mortality.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O Transtorno de DÃficit de AtenÃÃo/ Hiperatividade (TDAH) Ã um transtorno prevalente e debilitante, diagnosticado com base em persistentes nÃveis de hiperatividade, desatenÃÃo e impulsividade. FÃrmacos estimulantes tÃm sido eficazes no tratamento desse transtorno, sendo que o metilfenidato (MFD) Ã o agente terapÃutico mais prescrito e seu uso aumentou significativamente nos Ãltimos anos, entretanto, as conseqÃÃncias da sua utilizaÃÃo ainda sÃo pouco conhecidas. O MFD foi avaliado em modelos animais clÃssicos para screening de drogas com atividade em ansiedade, depressÃo e convulsÃo, tais como, labirinto em cruz elevado (LCE), campo aberto, rota rod, nado forÃado e convulsÃo induzida por pilocarpina, e em estudo neuroquÃmico, atravÃs da concentraÃÃo de monoaminas, tais como dopamina (DA), noradrenalina (NE) e 5-hidroxitriptamina (5-HT), alÃm da atividade da enzima Acetilcolinesterase (AChE). O MFD foi administrado de forma aguda em todos os testes, nas doses de 2,5; 5; 10 e 20 mg/Kg, atravÃs da via oral (v.o.) em camundongos jovens (21 dias) e adultos. Os resultados mostraram que o MFD apresentou efeito ansiolÃtico nos modelos LCE, pois aumentou todos os parÃmetros analisados no LCE, como NEBA, PEBA, TPBA e PTBA nas doses de 10 e 20mg/Kg nos animais jovens e apenas na de 20mg/Kg nos animais adultos. No teste do campo aberto, foi observado aumento na atividade locomotora em todas as doses nos animais jovens e apenas nas doses maiores (10 e 20mg/Kg) nos animais adultos. NÃo alterou o nÃmero de grooming e rearing. O MFD apresentou efeito antidepressivo no Sistema Nervoso Central (SNC), pois no teste do nado forÃado diminuiu o tempo de imobilidade nas doses de 10 e 20 mg/Kg nos animais jovens e apenas na dose de 20mg/Kg nos animais adultos. A avaliaÃÃo neuroquÃmica comprovou o efeito antidepressivo do MFD, pois se verificou um aumento da concentraÃÃo das monoaminas. No teste da convulsÃo induzida por pilocarpina, o metilfenidato diminuiu a latÃncia de convulsÃo, bem como a latÃncia de morte nos animais jovens e adultos, sugerindo que o MFD apresenta atividade proconvulsivante. O estudo sobre os efeitos sobre o sistema de neurotransmissÃo colinÃrgica demonstrou que o prÃ-tratamento com MFD reduziu a atividade da AChE apenas no corpo estriado. Em conclusÃo, esses efeitos mostraram que o MFD apresenta efeito ansiolÃtico, efeito antidepressivo e atividade proconvulsivante. / Attention-deficit hyperactivity disorder (ADHD) is a prevalent and debilitating disorder diagnosed on the basis in persistent levels of overactivity, inattention and impulsivity. Stimulant drugs have been effective in treating this disorder, and methylphenidate (MPH) is the most widely prescribed therapeutic agent and its use has increased significantly in recent years, however, the consequences of its use are still poorly known. The MFD was assessed in classical animal models to the screening of drugs with activity in anxiety, depression and convulsion, such as elevated plus maze (EPM), open field, rota rod, forced swimming and pilocarpine-induced seizures and a neurochemistry study, through the level of monoamines, such as dopamine (DA), norepinephrine (NE) and 5-hidroxytriptamine (5-HT) but the activity of the enzyme acetylcholinesterase (AChE). The MPH was administered acutely in all tests at doses of 2,5; 5; 10 e 20 mg/Kg, through the oral via (p.o.) in young mice (21 days) and adults. Results showed that the MPH presented an anxyolitic effects in the models of EPM, since increased all the parameters analyzed in the EPM, such as NEOA, PEOA, TPOA, PTOA, at doses of 10 and 20 mg/Kg in young animals, and only in animals of 20 mg/Kg in adults. In the open field, we observed an increase in locomotor activity at all doses in young animals and only at higher doses (10 e 20 mg/Kg) in adult animals. Not was observed no alteration the number of rearing and grooming. MPH presented antidepressant effect of Central Nervous System (CNS), since in the forced swimming, decreases the time of immobility in doses of 10 and 20 mg/Kg in young animals and only at a dose of 20 mg/Kg in adult animals. The neurochemistry evaluation comproved the antidepressant effect do MPH, because there was an increased concentration of monoamines. The test of the seizure by pilocarpine, MPH did decrease the latency of convulsion and latency of death in young and adult animals, suggesting that the MPH has proconvulsivante activity. The study of the effects of the cholinergic neurotransmission system has show that pretreatment with MPH reduced AChE activity only in the striatum. In conclusion, these effects showed that MPH presented anxiolitic effect, antidepressant effect and proconvulsivante activity.

It is increasingly recognised that the broadly defined behavioural phenotype of attention deficit – hyperactivity disorder (ADHD) is a heterogeneous condition and that this heterogeneity is seen across all levels of analysis from the genetic and environmental causes to the associated neuropsychological deficits, the clinical presentation and response to treatment. This work investigated whether the more restrictive and clinically homogeneous hyperkinetic disorder (HKD) phenotype is associated with reduced neuropsychological heterogeneity compared with the broader ADHD phenotype. Using a well known, broad based battery of neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and a computerised Go/NoGo task in a large well described group of boys with rigorously diagnosed HKD who were stimulant medication naïve at baseline, it was demonstrated that the neuropsychological heterogeneity in the HKD boys was very similar to that seen previously in children with ADHD. Interestingly, and contrary to popular opinion, the strongest associations were with more simple recognition memory tasks with a low executive demand. Although there were significant associations between HKD and deficits on a range of tasks with high executive demands these were less strong. Could this neuropsychological heterogeneity be a function of different developmental issues or comorbidity? With respect to development there was evidence that boys with HKD lagged behind the healthy boys with respect to the development of their neuropsychological performance. However the pattern of development was similar with the performance of the HKD boys paralleling that of the healthy boys, suggesting that the neuropsychological heterogeneity seen in HKD is not accounted for by developmental issues. With respect to the relationship between neuropsychological functioning and comorbidity, the impact of comorbid oppositional defiant disorder (ODD) and conductdisorder (CD), it was found that all three clinical groups (pure HKD, HKD + ODD and HKD + CD) demonstrated deficits on several tasks compared with the healthy boys. Compared with healthy boys each of the three clinical groups was associated with at least one unique neuropsychological deficit. This suggests that comorbidity between HKD and both ODD and CD may contribute to the neuropsychological heterogeneity in the HKD boys. Is there an association between clinical and neuropsychological responses to the treatment of HKD with the stimulant drug methylphenidate (MPH)? Detailed analyses were conducted to investigate heterogeneity of clinical and neuropsychological response in these boys to MPH. As predicted in previous studies there is evidence for clinical heterogeneity in response with between 68 and 78% of boys with HKD responding to MPH treatment at either one or both of the doses. The precise proportion responding was dependent on the scale and definition of response used. Clinical response was not predicted by age but was predicted to a degree by severity of symptoms at baseline and it was generally true that better response was predicted by lower (better) scores at baseline. Baseline performance on a component reflecting recognition memory performance at baseline predicted clinical response to the lower (0.3 mg/kg/dose), but not the higher (0.6, mg/kg/dose) dose of MPH with poorer baseline neuropsychological performance predicting a better clinical response. Whilst there was improvement on some neuropsychological measures following administration of MPH there was little association between clinical and neuropsychological responses to medication. Clinical response was only associated with neuropsychological response on a single measure from a single task (Go/NoGo Block 2 Errors to Distractors), a task that did not itself discriminate between the HKD boys and healthy Controls at baseline.

The purpose was to analyze the role of dopamine D1 and D2 receptors in conditioned place preference (CPP) of a relatively high dose (5 mg/kg) of methylphenidate (MPH) in adolescent male and female rats, as well as the role of these receptors in the effects of MPH on brain-derived neurotrophic factor (BDNF). The primary mechanism of MPH in the brain is the blockade of the dopamine transporter, yielding an increase of dopamine in the synaptic cleft and is the basis for the rewarding properties of MPH. An initial preference given on postnatal day (P)32 yielded no preference for any context in a three-chambered shuttle box with removable dividers, thus, a biased procedure was used. Conditioning began the day after the initial preference test on P33. On conditioning trials, animals were first administered saline or their respective antagonist (D1 antagonist: 0.1 or 0.2 mg/kg SCH-23390; D2 antagonist: 0.01 or 0.03 mg/kg Eticlopride HCl), followed by methylphenidate (MPH; 5mg/kg). Approximately 10 min after MPH administration, rats were placed into the paired context for a 10 min trial. The choice of the paired context was balanced across animals. In a separate session, all animals received saline in the opposing context. One day post-conditioning on P38, a preference test was administered with dividers removed. Preference was determined through the amount of time spent in the paired context as compared to time spent in the unpaired context on the post-conditioning preference test. One day following the preference test on P39, brain tissue was removed, and nucleus accumbens and striatum analyzed for BDNF. Results showed that MPH produced an increased preference on the post-conditioning preference test that was blocked by either dose of SCH-23390, but was not affected by either dose of eticlopride. Additionally, the higher dose of SCH-23390 resulted in a conditioned place aversion in males, which may be due to the increased presence of dopamine D1 receptors in adolescent males. MPH produced a robust significant increase in BDNF in both nucleus accumbens and striatum, and this increase was alleviated by SCH-23390, but the effect on BDNF is still to be analyzed relative to D2 antagonism. These results show that MPH results in a conditioned place preference in adolescent male and female rats, and these effects appear to be mediated by the dopamine D1 receptor. Further, MPH results in a significant increase of BDNF in drug reward areas of the brain, which has implications towards synaptic plasticity in these regions in response to MPH.

This study analyzed the role of dopamine D1 and D2 receptors in methylphenidate (MPH) conditioned place preference (CPP) in adolescent male and female rats, in addition to the role of these receptors in the effects of MPH on brain-derived neurotrophic factor (BDNF) in the dorsal striatum and nucleus accumbens. Using a nonbiased CPP procedure, the animals were conditioned from postnatal day (PD) 33 to 37. On conditioning trials, animals were first administered saline or their respective antagonist (0.1 or 0.2 mg/kg SCH-23390; 0.01 or 0.03 mg/kg eticlopride HCl), followed by MPH (5 mg/kg). Approximately 10 min after MPH administration, the rats were placed into the paired context for a 10-min trial. One day after conditioning on PD38, a preference test was administered with dividers removed. One day following the preference test on PD39, brain tissue was removed, and the nucleus accumbens and striatum were analyzed for BDNF. Results revealed that MPH conditioning resulted in an increased preference that was blocked by either dose of SCH-23390, but generally not affected by either dose of eticlopride. Further, the higher dose of SCH-23390 resulted in a conditioned place aversion in males, presumably due to an increased number of dopamine D1 receptors in adolescent males. MPH produced a significant increase of striatal and accumbal BDNF alleviated by SCH-23390 or eticlopride. These results show that MPH results in CPP in adolescent male and female rats and these effects appear to be mediated by the dopamine D1 receptor, but the effects of MPH on BDNF appear to be mediated by both dopamine receptor families.

In two experiments, we analyzed the effects of methylphenidate (MPH) on conditioned place preference (CPP) in adolescent male and female rats, and the effects of MPH on the dopamine transporter (DAT). In Experiment 1, male and female rats were conditioned for 5 consecutive days from postnatal day (P)44 to P48 with saline, 1, or 5mg/kg MPH. On the post conditioning preference test, the group administered the 1mg/kg dose of MPH resulted in no significant preference compared to controls, whereas the 5mg/kg dose of MPH produced a robust significant preference for the paired context, but there were no sex differences. Analysis of the DAT revealed that animals conditioned with the 5mg/kg dose of MPH demonstrated a significant decrease of the dopamine transporter (DAT) in the nucleus accumbens and striatum compared to controls. In Experiment 2, animals were conditioned using an every second day paradigm from P33–41 to model a previous MPH treatment regimen that had revealed sex differences in behavioral sensitization. MPH produced an increased preference for the paired context on a post-conditioning preference test in Experiment 2, but as in Experiment 1, no sex differences were observed. These data show that a relatively high dose of MPH has rewarding associative effects in both adolescent male and female rats reliably across two different conditioning paradigms and ages in adolescence, but no sex difference. In addition, MPH results in a significant decrease of the DAT in drug reward brain areas which has implications toward plasticity of the brain's reward system.

This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain-derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a “school day” regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45–P63 and tested after a three-day drug washout on the forced swim stress task on P67–P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44–P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre-exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent.

Methylphenidate (MPH) is a psychostimulant that is used for the treatment of attention-deficit hyperactivity disorder that is often recreationally abused. Past studies have primarily analyzed the effects of MPH on behavior and BDNF using males as subjects, with studies showing a lack of behavioral sensitization, although the effect of MPH on BDNF has yielded contradictory results. BDNF is a neurotrophin ubiquitously found throughout the brain that plays an important role in synaptic maintenance and development and has been implicated in addiction. This study analyzed sex differences in induction and expression of MPH locomotor sensitization in adolescent male and female rats as well as the effects of MPH on BDNF protein in two brain areas of drug reward: the nucleus accumbens (NAcc) and striatum (STR), after both induction and expression of sensitization. After habituation to a locomotor arena, animals (N=6-8 per group) were administered MPH (5 mg/kg) or saline every other day from postnatal day (P)33 to 49 and tested for 30 min in the same arena with activity counts recorded. In one group, brain tissue was removed one day following testing and the NAcc and STR assayed for BDNF at P50. A different group of animals was raised to P60 and given an MPH (or saline) challenge. One day following the challenge, brain tissue was removed and the NAcc and STR were assayed for BDNF at P61. Females administered MPH demonstrated behavioral sensitization from P33 to P41, and then decreased in activity from P41 to P49. Females demonstrated a robust increase in locomotor activation as compared to males, which failed to demonstrate sensitization to MPH. However, both groups given MPH demonstrated an increase in activity compared to controls throughout sensitization testing. On the challenge at P60, females administered MPH demonstrated higher levels of activity compared to all other groups and were equivalent to their final day of sensitization. Males administered MPH also expressed sensitization, as they demonstrated increased behavioral activation as compared to saline-treated controls. Neurochemical analyses at P50 revealed that MPH produced a significant increase in striatal BDNF in males, but a significant decrease in striatal BDNF in females. There were no changes in the NAcc. At P61, BDNF was increased in both STR and NAcc in males, and female data will be presented. These data demonstrate robust sex differences in behavioral activation and sensitization to MPH that is both induced and expressed in females, but only expressed in males. Further, MPH produces sex-dependent effects on BDNF, indicating sex differences in the brain plasticity response to MPH in adolescence.