This study analyzed sex differences in methylphenidate (MPH) sensitization and corresponding changes in glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotprhic factor protein (BDNF) in adolescent male and female rats. After habituation to a locomotor arena, animals were sensitized to MPH (5mg/kg) or saline from postnatal day (P) 33–49, tested every second day. On P50, one group of animals were injected with saline and behavior assessed for conditioned hyperactivity. Brain tissue was harvested on P51 and analyzed for GDNF protein. A second group of animals was also sensitized to MPH from P33 to 49, and expression of behavioral sensitization was analyzed on a challenge given at P60, and BDNF protein analyzed at P61. Females demonstrated more robust sensitization to MPH than males, but only females given MPH during sensitization demonstrated conditioned hyperactivity. Interestingly, MPH resulted in a significant increase in striatal and accumbal GDNF with no sex differences revealed. Results of the challenge revealed that females sensitized and challenged with MPH demonstrated increased activity compared to all other groups. Regarding BDNF, only males given MPH demonstrated an increase in dorsal striatum, whereas MPH increased accumbal BDNF with no sex differences revealed. A hierarchical regression analysis revealed that behavioral sensitization and the conditioned hyperactivity test were reliable predictors of striatal and accumbal GDNF, whereas sensitization and activity on the challenge were reliable predictors of accumbal BDNF, but had no relationship to striatal BDNF. These data have implications for the role of MPH in addiction and dopamine system plasticity.

Methylphenidate, a psychostimulant used for the treatment of attention deficit hyperactivity disorder and narcolepsy, is administered as a 50:50 racemic mixture, despite the fact that d‐methylphenidate has been shown to have greater pharmacologic activity. This paper presents a validated LC‐MS/MS approach to separation and quantification of methylphenidate enantiomers using a vancomycin column and triethylammonium acetate to enhance the chiral separation. The method is applicable to the monitoring of these enantiomers in mouse brain, with a limit of detection of 0.5 ng/mL and a lower limit of quantification of 7.5 ng/mL.

Synthetic cathinones are stimulant drugs of abuse that act at monoamine transporters e.g. the dopamine transporter (DAT) as releasing agents or as reuptake inhibitors. More than >150 new synthetic cathinones have emerged on the clandestine market and have attracted considerable attention from the medical and law enforcement communities. threo-Methylphenidate (tMP) is an FDA approved drug for the treatment of ADHD and narcolepsy, which also acts as a DAT reuptake inhibitor and is widely abused. tMP and synthetic cathinones share some structural similarities and extensive structure-activity relationship (SAR) studies on tMP have been conducted. However, much less is known about the SAR of synthetic cathinones, and the available MP literature might assist in understanding it. The main focus of this research was to compare SAR between methylphenidate-cathinone hybrids and available methylphenidate SAR in order to identify some guiding principles that might allow
us to predict their abuse potential and to identify which cathinones should be
targeted for more extensive evaluation. In the present study, we evaluated eight 2-benzoylpiperidine analogs and a descarbonyl analog to determine if tMP SAR can be applied to cathinone SAR. We conducted molecular modeling and docking studies and predicted the order of potency to be tMP > 2-benzoylpiperidine > 2-benzylpiperidine based on the number of hydrogen bonds. The synthesized analogs were evaluated in a competition assay using live-cell imaging against APP+ in HEK293 cells stably expressing hDAT. All compounds were found to be DAT reuptake inhibitors and, as the modeling studies predicted, the order of potency in our functional studies was also found to be tMP > 2-benzoylpiperidine > 2- benzylpiperidine. A significant correlation was obtained between the potency of the benzoylpiperidines and tMP binding data (r = 0.91) suggesting that the SAR of tMP analogs might be applicable to the synthetic cathinones as DAT reuptake inhibitors.

Thesis (M.A.)--Trinity Graduate School, 2000. / Abstract. Includes bibliographical references (leaves 47-59).

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders of childhood. It is theorized to be caused by catecholamine dysfunction in the striatum (Str) and frontal cortex (FC). The spontaneously hypertensive rat (SHR) has been used as a model for ADHD because of its attention deficits, impulsiveness, and hyperactivity. Prior studies of dopamine (DA) in the Str and FC have revealed conflicting results in the SHR compared to control, indicative of a need for a better understanding of DA dynamics in this model. In addition to the DA hypothesis, studies have begun implicating glutamate in the etiology of ADHD. Previous evaluations of the SHR model of ADHD found that the SHR have increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity and elevated calcium levels in the FC, suggesting that altered glutamatergic neurotransmission exists in the SHR. The first set of studies presented here suggest that increased surface expression of DA transporters may exist in the SHR model of ADHD, lowering basal DA levels. Second, we discovered that the glutamate system in the FC of the SHR model of ADHD is hyperfunctional, thus raising the possibility that targeting glutamate dysfunction in the FC could lead to the development of novel therapeutics for the treatment of ADHD. The third and fourth set of studies explored glutamate signaling in the awake rodent to fully understand glutamate neurotransmission as well as the effects of methylphenidate (MPH) on glutamate signaling in the prelimbic cortex, a region heavily implicated in ADHD. The SHR displayed similar phasic glutamate signaling compared to control; however, in the SHR but not the WKY control, chronic treatment with MPH lowered phasic glutamate amplitude. Additionally, intermediate treatment with MPH increased tonic glutamate in the SHR only, whereas chronic MPH treatment increased tonic levels in both the SHR and WKY compared to saline. Taken together, this body of work characterizes DA and glutamate signaling in the anesthetized SHR model of ADHD. Additionally, glutamate dynamics and the effects of the stimulant medication MPH were explored in the awake animal, providing evidence that glutamate is a likely target for future neuropharmacology for the treatment of ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neuropsychiatric disorders in childhood among school-aged children. It is characterized by behavior disinhibition, overactivity and/or difficulty in sustaining attention. Psychotherapy and pharmacotherapy are reported ways of treating ADHD. Around 35% of individuals diagnosed with ADHD also met the criteria for anxiety disorders that commonly coexist with ADHD. If not treated up to 70% of children with ADHD continue to meet the diagnostic criteria into adolescence. Psychostimulants (Methylphenidate) are the first line of treatment in Turkey. The first aim of this present study was to introduce Spence Children&amp / #8217 / s Anxiety Scale Parent version (SCAS-P) by conducting Turkish translation, factor structure, and reliability-validity studies of the scale. Results of the principle component analysis extracted five factors for the Turkish version of SCAS-P. Inter-correlations among the factors (r=0.28 &amp / #8211 / 0.45) were found to be satisfactory indicating for convergent validity. Criterion validity of the scale was found to be significant as well. Analysis indicated that the top 27th percentile of the sample was significantly differenciated from the bottom 27th percentile of the sample (t(74)=9.63, p&lt / .05). Results revealed Cronbach alpha of .88, and the split half reliability of .79 for the total scale score. Internal consistency of the subscales of the SCAS-P ranged from 0.56 to 0.78. The second aim of this study was to examine the effects of Methylphenidate (MPH) on cognitive abilities, hyperactivity and anxiety level of children with ADHD since MPH is known to be a first line of treatment for Attention Deficit Hyperactivity Disorder (ADHD). Thirty-six elementary school children, from age seven to twelve were gathered from the local Hospital for the Social Security Office Child Psychiatry Clinic in Ankara via using purposive sampling. Seventeen children who met the DSM-IV diagnostic criteria for ADHD were assigned to the drug group, and nineteen children without ADHD were assigned to the comparison group. Bender Gestalt Visual Motor Perception Test, Wechsler Intelligence Scale for Children-Revised subscales, and Vigilance Task developed by the researcher were administered to participant children, for measuring cognitive abilities. Hacettepe ADHD Scale and SCAS-P were administered to parents of the participants for measuring hyperactivity level and child anxiety. Measurements were repeated after a 12-week follow up both for the drug group (N=17) and the comparison group (N=19). In the 12-week period, drug group received MPH treatment, and the comparison group received no interventions regarding ADHD. 2 (Drug group vs. Comparison group) x 2 (Pretest vs. Posttest) mixed ANOVA with repeated measures on the last factor was conducted for the results of each measurement scale separately. As expected, MPH treatment revealed improvement in cognitive abilities and hyperactivity level of children with ADHD. All participants were found to have high anxiety scores when first referred to the hospital, and were found to have lower scores of anxiety on posttest. The findings were discussed on the basis of literature and limitations of the present study.

Thesis (M.A.)--Trinity Graduate School, 2000. / Abstract. Includes bibliographical references (leaves 47-59).

Thesis (M.A.)--Trinity Graduate School, 2000. / Abstract. Includes bibliographical references (leaves 47-59).

Le MPH est le médicament le plus prescrit pour le traitement du trouble déficitaire de l'attention/hyperactivité (TDA/H). Sa prescription de l’enfance à l’âge adulte et notamment chez les femmes en âge de procréer soulève des questions sur les effets à long terme d’un tel traitement sur le cerveau en développement. À ce jour, aucune information n’est disponible concernant la présence ou non de modifications neurobiologiques à l’âge adulte consécutives à une exposition prénatale au MPH. Nous avons utilisé un modèle d'exposition prénatale au MPH chez le rat pour étudier les conséquences d'un tel traitement sur le fonctionnement du cerveau adulte. L'imagerie scintigraphique a été réalisée pour comparer les profils métaboliques cérébraux des rats exposés en prénatal au MPH vs témoins. L'aspect structural de leur système dopaminergique a été évalué avec un immunomarquage de la TH et l'aspect fonctionnel à l'aide de microdialyse in vivo et d'immunohistochimie c-Fos dans des conditions basales et après stimulation dopaminergique. Parallèlement, l'évaluation comportementale de ces animaux vis-àvis de récompense naturelle ou synthétique ainsi que leur réactivité vis-à-vis de l'effet locomoteur de la cocaïne a été étudiée. Les animaux exposés en prénatal au MPH affichent des altérations neurobiologiques structurales et fonctionnelles associées au système dopaminergique et à sa réactivité suite à une administration de cocaïne. Nos résultats montrent aussi que ces animaux présentent une altération de la préférence et de la motivation au sucre (renforçateur naturel) alors qu'aucune différence de motivation pour s'auto-administrer de la cocaïne (renforçateur synthétique) n'a été décelée. Cependant, ces animaux montrent une baisse de sensibilité aux effets locomoteurs de la cocaïne. À notre connaissance, notre étude préclinique est la première qui rapporte des modifications neurobiologiques à long terme après une exposition prénatale au MPH. / MPH is the gold standard medication for Attention-Deficit/Hyperactivity Disorders (ADHD). MPH extended prescription to adult patients raises the question of MPH's long-term effects during brain development when it is administered to ADHD women of childbearing age. There is still no information regarding the neurobiological modifications consecutive to a prenatal exposure to MPH. We used a rat model of prenatal exposure to MPH to investigate the consequences of such treatment on adult brain functioning. Rats prenatally exposed to MPH displayed structural and functional neurobiological alterations related to dopaminergic system and its reactivity to cocaine administration. Furthermore, these animals showed behavioral changes towards natural or synthetic rewards. To our knowledge, this is the first preclinical study reporting long-lasting neurobilogical modifications after a prenatal exposure to MPH.

O artigo apresenta um ensaio clínico cujo objetivo foi avaliar a eficácia e tolerabilidade, a curto prazo, da Risperidona e do Metilfenidato na redução de sintomas do Transtorno de Déficit de Atenção/Hiperatividade (TDAH) em crianças e adolescentes com Retardo Mental Moderado (RMM) que preencheram os critérios do DSM-IV para TDAH. Foram acompanhados, durante 4 semanas, 46 pacientes com diagnóstico de RMM e TDAH que receberam metilfenidato ou risperidona. As medidas de eficácia foram avaliadas através da aplicação das escalas “Swanson, Nolan, and Pelham” – SNAP-IV e do Formulário Nisonger Para Avaliação do Comportamento da Criança. Os efeitos colaterais das medicações foram detectados através da aplicação das escalas “Barkley’s Side-Effects Rating Scale” (SERS) e da “Ugvald for Kliniske Undersgelser”(UKU). Não foram detectadas diferenças significativas entre os dois grupos no final do ensaio (todos os TE ≤ 0.27). Ocorreu uma significativa redução de peso nos pacientes do grupo do metilfenidato e um significativo ganho de peso nos pacientes do grupo da risperidona. Nossos achados preliminares sugerem que tanto a risperidona como o metilfenidato podem ser eficazes na redução de sintomas do TDAH nestes pacientes com Retardo Mental Moderado. O perfil dos efeitos colaterais pode ser importante na decisão da medicação a ser escolhida. / The article describes a clinical trial. The objective was to evaluate the short-term efficacy and tolerability of risperidone and methylphenidate (MPH) in reducing symptoms related to attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with Moderate Mental Retardation (MMR) who fulfilled DSM-IV criteria for ADHD. In a 4-week, 46 subjects with MMR and ADHD were enrolled and randomized for Risperidone or Methylphenidate (MPH). The outcome measurements for efficacy were the Swanson, Nolan, and Pelham Scale (SNAPIV), and the Nisonger Child Behavior Rating Form (NCBRF). Side effects were assessed by Barkley’s Side-Effects Rating Scale and Ugvald for Kliniske Undersgelser (UKU). There were no significant differences between the two groups in any scale at end of the trial (all ES ≤ 0.27). There was a significant weight reduction in MPH patients and a significant weight gain in the risperidone group. Our preliminary findings suggest that both risperidone and MPH might be effective in reducing ADHD symptoms in patients with moderate mental retardation. The profile of side effects might be of some importance in deciding which medication should be chosen.