Participação da neurotransmissão dopaminergica no efeito hiperlocomotor do neuropeptideo S

Neuropeptide S (NPS) is an endogenous 20-aminoacid peptide which binds a G protein-coupled receptor named NPSR. This peptidergic system is involved in the modulation of several biological functions, such as locomotion, anxiety, nociception, food intake and motivational behaviors. Studies have shown the participation of NPSR receptors in mediating the hyperlocomotor effects of NPS. A growing body of evidence suggests the participation of adenosinergic, dopaminergic and CRF systems on the hyperlocomotor effects of NPS. Considering that little is known about the role of dopaminergic system in mediating NPS-induced hyperlocomotion, the present study aims to investigate the locomotor actions of intracerebroventricular (icv) NPS in mice pretreated with α-metil-p-tirosine (AMPT, inhibitor of dopamine synthesis), reserpine (inhibitor of dopamine vesicle storage) or sulpiride (D2 receptor antagonist) in the open field test. A distinct group of animals received the same pretreatments described above (AMPT, reserpine or sulpiride) and the hyperlocomotor effects of methylphenidate (dopamine reuptake inhibitor) were investigated in the open field. NPS and methylphenidate increased the mouse locomotor activity. AMPT per se did not change the locomotion of the animals, but it partially reduced the hyperlocomotion of methylphenidate. The pretreatment with AMPT did not affect the psychostimulant effects of NPS. Both reserpine and sulpiride inhibited the stimulatory actions of NPS and methylphenidate. These findings show that the hyperlocomotor effects of methylphenidate, but not NPS, were affected by the pretreatment with AMPT. Furthermore, methylphenidate- and NPS-induced hyperlocomotion was impaired by reserpine and sulpiride pretreatments. Together, data suggests that NPS can increase locomotion even when the synthesis of catecholamines was impaired. Additionally, the hyperlocomotor effects of NPS and methylphenidate depend on monoamines vesicular storaged, mainly dopamine, and on the activation of D2 receptors. The psychostimulant effects of NPS via activation of dopaminergic system display clinical significance on the treatment of diseases which involves dopaminergic pathways, such as Parkinson s disease and drug addiction

Gaze pursuit and arm control of adolescent males diagnosed with attention deficit hyperactivity disorder (ADHD) and normal controls: evidence of a dissociation in processing visual information of short and long duration

Three-dimensional kinematic analysis of line of gaze, arm and ball was used to describe the visual and motor behaviour of male adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). The ADHD participants were tested when both on (ADHD-On) and off (ADHD-Off) their medication and compared to age-matched normal controls in a modified table tennis task that required tracking the ball and hitting to cued right and left targets. Long-duration information was provided by a pre-cue, in which the target was illuminated approximately 2 s before the serve, and short-duration information by an early-cue illuminated about 350 ms after the serve, leaving -500 ms to select the target and perform the action. The ADHD groups differed significantly from the control group in both the pre-cue and early-cue conditions in being less accurate, in having a later onset and duration of pursuit tracking, and a higher frequency of gaze on and off the ball. The use of medication significantly reduced the gaze frequency of the ADHD participants, but surprisingly this did not lead to an increase in pursuit tracking, suggesting a barrier was reached beyond which ball flight information could not be processed. The control and ADHD groups did not differ in arm movement onset, duration and velocity in the short-duration early-cue condition; in the long-duration pre-cue condition, however, the ADHD group's movement time onset and arm velocity differed significantly from controls. The results show that the ADHD groups were able to process short-duration information without experiencing adverse effects on their motor behaviour; however, long-duration information contributed to irregular movement control.

Effects of low doses of polyunsaturated fatty acids on the attention deficit/Hyperactivity disorder of children: A systematic review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

TDAH e infância contemporânea: um olhar a partir da psicanálise

Pós-graduação em Psicologia - FCLAS

Sociedade Tarja Preta: uma crítica à medicalização de crianças e adolescentes

Como breve análise do livro "Medicalização de crianças e adolescentes: conflitos silenciados pela redução de questões sociais a doenças de indivíduos", esta resenha contextualiza a importância da publicação na crítica contemporânea à invenção de (psico)patologias e tratamentos a elas destinados. O livro logra, de forma extremamente rigorosa, desconstruir as "bases científicas" que sustentam o transtorno de déficit de atenção e hiperatividade (TDAH), mostrando como a indústria farmacêutica vem ocultando sistematicamente os profundos efeitos colaterais do princípio ativo destinado a tratá-lo (o metilfenidato, presente na Ritalina® e Concerta®). Com textos de profissionais vinculados à saúde e educação, nas mais diferentes áreas do conhecimento, o livro representa uma notável coalizão de esforços em benefício da promoção dos direitos de crianças e adolescentes.

What users think about the differences between caffeine and illicit,prescription stimulants for cognitive enhancement

Pharmacological cognitive enhancement (CE) is a topic of increasing public awareness. In the scientific literature on studentrnuse of CE as a study aid for academic performance enhancement, there are high prevalence rates regarding the use ofrncaffeinated substances (coffee, caffeinated drinks, caffeine tablets) but remarkably lower prevalence rates regarding the usernof illicit/prescription stimulants such as amphetamines or methylphenidate. While the literature considers the reasons andrnmechanisms for these different prevalence rates from a theoretical standpoint, it lacks empirical data to account for healthyrnstudents who use both, caffeine and illicit/prescription stimulants, exclusively for the purpose of CE. Therefore, wernextensively interviewed a sample of 18 healthy university students reporting non-medical use of caffeine as well as illicit/rnprescription stimulants for the purpose of CE in a face-to-face setting about their opinions regarding differences in generalrnand morally-relevant differences between caffeine and stimulant use for CE. 44% of all participants answered that there is arngeneral difference between the use of caffeine and illicit/prescription stimulants for CE, 28% did not differentiate, 28% couldrnnot decide. Furthermore, 39% stated that there is a moral difference, 56% answered that there is no moral difference andrnone participant was not able to comment on moral aspects. Participants came to their judgements by applying threerndimensions: medical, ethical and legal. Weighing the medical, ethical and legal aspects corresponded to the students’rnindividual preferences of substances used for CE. However, their views only partly depicted evidence-based medical aspectsrnand the ethical issues involved. This result shows the need for well-directed and differentiated information to prevent thernpotentially harmful use of illicit or prescription stimulants for CE.

Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants.

BACKGROUND: The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. METHODS: The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) and a saline control group (N = 9/group). All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13). Rats were then given an additional 25-day washout period, and re-challenged (day 38) with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39). Open-field locomotor activity was recorded using a computerized automated activity monitoring system. RESULTS: Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group), while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change in locomotor activity compared to control animals. CONCLUSION: MDMA sensitized to its own locomotor activating effects but did not elicit any cross-sensitization with amphetamine or methylphenidate.

Neuroenhancement and the strength model of self-control

Neuroenhancement (NE), the use of substances as a means to enhance performance, has garnered considerable scientific attention of late. While ethical and epidemiological publications on the topic accumulate, there is a lack of theory-driven psychological research that aims at understanding psychological drivers of NE. In this perspective article we argue that self-control strength offers a promising theory-based approach to further understand and investigate NE behavior. Using the strength model of self-control, we derive two theory-driven perspectives on NE-self-control research. First, we propose that individual differences in state/trait self-control strength differentially affect NE behavior based on one’s individual experience of NE use. Building upon this, we outline promising research questions that (will) further elucidate our understanding of NE based on the strength model’s propositions. Second, we discuss evidence indicating that popular NE substances (like Methylphenidate) may counteract imminent losses of self-control strength. We outline how further research on NE’s effects on the ego-depletion effect may further broaden our understanding of the strength model of self-control.

Stimulant medication and psychotic symptoms in offspring of parents with mental illness

BACKGROUND: Stimulants, such as methylphenidate, are among the most commonly used medications in children and adolescents. Psychotic symptoms have been reported as rare adverse reactions to stimulants but have not been systematically inquired about in most previous studies. Family history of mental illness may increase the vulnerability to drug-induced psychotic symptoms. We examined the association between stimulant use and psychotic symptoms in sons and daughters of parents with major mood and psychotic disorders. METHODS: We assessed psychotic symptoms, psychotic-like experiences, and basic symptoms in 141 children and youth (mean ± SD age: 11.8 ± 4.0 years; range: 6–21 years), who had 1 or both parents with major depressive disorder, bipolar disorder, or schizophrenia, and of whom 24 (17.0%) had taken stimulant medication. RESULTS: Psychotic symptoms were present in 62.5% of youth who had taken stimulants compared with 27.4% of participants who had never taken stimulants. The association between stimulant use and psychotic experiences remained significant after adjustment for potential confounders (odds ratio: 4.41; 95% confidence interval: 1.82–10.69; P = .001) and was driven by hallucinations occurring during the use of stimulant medication. A temporal relationship between use of stimulants and psychotic symptoms was supported by an association between current stimulant use and current psychotic symptoms and co-occurrence in cases that were assessed on and off stimulants. CONCLUSIONS: Psychotic symptoms should be monitored during the use of stimulants in children and adolescents. Family history of mood and psychotic disorders may need to be taken into account when considering the prescription of stimulants.

Is sensitization to stimulants time dependent and mediated via NMDA receptors?

Chronic administration of psychomotor stimulants has been reported to produce behavioral sensitization to its effects on motor activity. This adaptation may be related to the pathophysiology of recurrent psychiatric disorders. Since disturbances in circadian rhythms are also found in many of these disorders, the relationship between sensitization and chronobiological factors became of interest. Therefore, a computerized monitoring system investigated the following: whether repeated exposure to methylphenidate (MPD) and amphetamine (AMP) could produce sensitization to its locomotor effects in the rat; whether sensitization to MPD and AMP was dependent on the circadian time of drug administration; whether the baseline levels of locomotor activity would be effected by repeated exposure to MPD and AMP; whether the expression of a sensitized response could be affected by the photoperiod; and whether MK-801, a non-competitive NMDA antagonist, could disrupt the development of sensitization to MPD. Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days served as baseline for each rat, and on day 3 each rat received a saline injection. The locomotor response to 0.6, 2.5, or 10 mg/kg of MPD was tested on day 4, followed by five days of single injections of 2.5 mg/kg MPD (days 5–9). After five days without injection (days 10–14) rats were re-challenged (day 15) with the same doses they received on day 4. There were three separate dose groups ran at four different times of administration, 08:00, 14:00, 20:00, or 02:00 (i.e. 12 groups). The same protocol was conducted with AMP with the doses of 0.3, 0.6, and 1.2 mg/kg given on day 4 and 15, and 0.6 mg/kg AMP as the repeated dose on days 5 to 9. In the second set of experiments only sensitization to MPD was investigated. The expression of the sensitized response was dose-dependent and mainly observed with challenge of the lower dose groups. The development of sensitization to MPD and ANT was differentially time-dependent. For MPD, the most robust sensitization occurred during the light phase, with no sensitization during the middle of the dark phase. (Abstract shortened by UMI.) ^

Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice

Cocaine and methylphenidate block uptake by neuronal plasma membrane transporters for dopamine, serotonin, and norepinephrine. Cocaine also blocks voltage-gated sodium channels, a property not shared by methylphenidate. Several lines of evidence have suggested that cocaine blockade of the dopamine transporter (DAT), perhaps with additional contributions from serotonin transporter (5-HTT) recognition, was key to its rewarding actions. We now report that knockout mice without DAT and mice without 5-HTT establish cocaine-conditioned place preferences. Each strain displays cocaine-conditioned place preference in this major mouse model for assessing drug reward, while methylphenidate-conditioned place preference is also maintained in DAT knockout mice. These results have substantial implications for understanding cocaine actions and for strategies to produce anticocaine medications.

Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.

The ability of cocaine to inhibit the dopamine transporter (DAT) appears to be crucial for its reinforcing properties. The potential use of drugs that produce long-lasting inhibition of the DAT as a mean of preventing the "high" and reducing drug-seeking behavior has become a major strategy in medication development. However, neither the relation between the high and DAT inhibition nor the ability to block the high by prior DAT blockade have ever been demonstrated. To evaluate if DAT could prevent the high induced by methylphenidate (MP), a drug which like cocaine inhibits the DAT, we compared the responses in eight non-drug-abusing subjects between the first and the second of two MP doses (0.375 mg/kg, i.v.) given 60 min apart. At 60 min the high from MP has returned to baseline, but 75-80% of the drug remains in brain. Positron-emission tomography and [11C]d-threo-MP were used to estimate DAT occupancies at different times after MP. DAT inhibition by MP did not block or attenuate the high from a second dose of MP given 60 min later, despite a 80% residual transporter occupancy from the first dose. Furthermore some subjects did not perceive a high after single or repeated administration despite significant DAT blockade. These results indicate that DAT occupancy is not sufficient to account for the high, and that for DAT inhibitors to be therapeutically effective, occupancies > 80% may be required.

Avaliação da judicialização da saúde no município de Ribeirão Preto/SP

A Constituição Federal Brasileira institucionalizou o direito a saúde no Brasil, o artigo 196 que diz: A saúde é um direito de todos e um dever do Estado apresenta esse direito. Ao regulamentar a criação do Sistema Único de Saúde a lei 8.080 reafirma a obrigação do Estado com a Saúde da população. Dentro desse contexto a Assistência Farmacêutica (AF) tem importante papel de garantir medicamentos seguros, eficácias, em tempo e quantidade necessária para atender a demanda dos cidadãos, porém apesar das constantes atualizações em prol de promover maior eficiência dos processos da AF, ainda acontecem situações em que o paciente não tem o medicamento requerido, seja por falta nas unidades dispensadoras ou a não presença nas listas de medicamentos padronizados. Essa situação faz com que o cidadão recorra à via judicial na tentativa de garantir o acesso ao medicamento pleiteado, fenômeno conhecido como judicialização da saúde, que traz grandes implicações sobre a gestão da assistência farmacêutica. Diante disso o objetivo do trabalho foi descrever o panorama geral das ações judiciais pleiteando medicamentos e insumos para insulina que foram assumidos pela prefeitura de Ribeirão Preto. Para alcançar esses objetivos, foi realizado um estudo do tipo descritivo. Foram analisados ao todo 1861 processos judiciais sendo 1083 ainda ativos e 778 que já haviam sido encerrados. Na maioria dos processos o juiz dava como prazo máximo 30 dias (99%) para se cumprir a ação, o que é insuficiente para realizar uma licitação pública obrigando a gestão a utilizar via paralela de compra. O Ministério Público foi o principal representante legal (71,7%) utilizado e a maioria das prescrições foram advindas de hospitais e clínicas particulares (50,1%). Os principais diagnósticos referidos nas ações foram diabetes e o transtorno de déficit de atenção e hiperatividade (TDAH). Já os medicamentos mais prevalentes foram as insulinas e o metilfenidato. Dentre os médicos prescritores 3% somam aproximadamente 30% das prescrições. Diante dos resultados expostos, o presente estudo evidenciou o impacto da judicialização da saúde no município de Ribeirão Preto, demandando da gestão pública organização estrutural e financeira para lidar com as demandas judiciais.

An n-of-1 trial service in clinical practice: Testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder

OBJECTIVE. We sought to describe the clinical use of n-of-1 trials for attention-deficit/hyperactivity disorder in publicly and privately funded family and specialized pediatric practice in Australia. METHODS. We used a within-patient randomized, double-blind, crossover comparison of stimulant (dexamphetamine or methylphenidate) versus placebo or alternative stimulant using 3 pairs of treatment periods. Trials were conducted from a central location using mail and telephone communication, with local supervision by the patients' clinicians. PATIENTS. Our study population included children with clinically diagnosed attention-deficit/ hyperactivity disorder who were aged 5 to 16 years and previously stabilized on an optimal dose of stimulant. They were selected because treatment effectiveness was uncertain. MAIN OUTCOME MEASURES. Our measures included number of patients recruited, number of doctors who used the service, geographic spread, completion rates, response rate, and post-n-of-1 trial decisions. RESULTS. Forty-five doctors across Australia requested 108 n-of-1 trials, of which 86 were completed. In 69 drug-versus-placebo comparisons, 29 children responded better to stimulant than placebo. Immediately posttrial, 19 of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 of 24 nonresponders ceased or switched stimulants. In 40 of 63 for which data were available, posttrial management was consistent with the trial results. For all types of n-of-1 trials, management changed for 28 of 64 children for whom information was available. DISCUSSION. Attention-deficit/hyperactivity disorder n-of-1 trials can be implemented successfully by mail and telephone communication. This type of trial can be valuable in clarifying treatment effect when it is uncertain, and in this series, they had a noticeable impact on short-term management.

Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder

Objective To compare the efficacy and safety of two methylphenidate (MPH) formulations—once-daily modified-release MPH (EqXL, Equasym™ XL) and twice-daily immediate-release methylphenidate (MPH-IR, Ritalin®)—and placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD). Methods Children aged 6–12 years on a stable dose of MPH were randomized into a double-blind, three-arm, parallel-group, multi-center study and received 3 weeks of EqXL (20, 40, or 60 mg qd), MPH-IR (10, 20, or 30 mg bid) or placebo. Non-inferiority of EqXL to MPH-IR was assessed by the difference in the inattention/overactivity component of the overall teacher’s IOWA Conners’ Rating Scale on the last week of treatment (per protocol population). Safety was monitored by adverse events, laboratory parameters, vital signs, physical exam, and a Side Effect Rating Scale. Results The lower 97.5% confidence interval bound of the difference between MPH groups fell above the non-inferiority margin (−1.5 points) not only during the last week of treatment but during all three treatment weeks. Both MPH-treatment groups experienced superior benefit when compared to placebo during all treatment weeks (P < 0.001). All treatments were well tolerated. Conclusions EqXL given once-daily was non-inferior to MPH-IR given twice-daily. Both treatments were superior to placebo in reducing ADHD symptoms.