Histone deacetylase activity and brain-derived neurotrophic factor (BDNF) levels in a pharmacological model of mania

Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity. .

Lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder: pharmacokinetics, efficacy and safety in children and adolescents / Dimesilato de lisdexanfetamina no tratamento do transtorno do déficit de atenção e hiperatividade: farmacocinética, eficácia e segurança em crianças e adolescentes

Background: Psychostimulants (methylphenidate and amphetamines) are considered first-line therapy for attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine dimesylate (LDX) is a new psychostimulant approved for the treatment of ADHD in Brazil. The pharmacologically active fraction, d-amphetamine, is gradually released by hydrolysis of the LDX prodrug. Objectives: To perform a systematic review of the literature of the efficacy and safety of LDX in the treatment of ADHD in children and adolescents. Methods: Medline/PubMed searches for “d-amfetamine”, “lisdexamfetamine” and “lisdexamfetamine dimesylate” were conducted including articles available from January 2000 to November 2013. Additional references were identified using references listed in those articles. Further data on LDX were requested from its manufacturer. Results: Thirty-one papers were found related to ADHD treatment in children and adolescents. Discussion: The therapeutic benefits of LDX in children with ADHD are achieved as early as 1.5 hours after its administration and last for up to 13 hours, with efficacy comparable or superior to that of other available psychostimulants. The literature also reports efficacy in long-term treatment, with safety and tolerability profiles comparable to those of other stimulants used for the treatment of ADHD. Most of the adverse events associated with LDX are considered to be mild or moderate in severity, with the most common being loss of appetite and insomnia...

Contexto: Psicoestimulantes (metilfenidato e anfetaminas) são considerados como tratamento farmacológico de primeira linha no tratamento do transtorno do déficit de atenção e hiperatividade (TDAH). O dimesilato de anfetamina é um novo psicoestimulante aprovado para uso no Brasil, cuja fração farmacologicamente ativa, a d-anfetamina, é gradualmente liberada por hidrólise da pró-droga. Objetivos Realizar uma revisão sistemática de literatura sobre eficácia e segurança da LDX no tratamento de TDAH de crianças e adolescentes. Métodos: Busca na base Medline/PubMed com os termos “d-amfetamine”, “lisdexamfetamine” e “lisdexamfetamine dimesilate”, de janeiro de 2000 até novembro de 2013. Referências adicionais foram retiradas das referências dos artigos obtidos; dados também foram obtidos do fabricante. Resultados: Trinta e um artigos foram encontrados, relacionados ao tratamento de TDAH em crianças e adolescentes. Conclusões: Os benefícios terapêuticos da LDX são obtidos em até 1,5 hora após administração e se estendem até 13 horas, com eficácia comparável ou superior à dos demais psicoestimulantes disponíveis. A literatura também documenta eficácia em longo prazo, com perfis de segurança e tolerabilidade comparáveis aos dos demais estimulantes usados no tratamento do TDAH. A maioria dos eventos adversos associados à LDX é considerada leve ou moderada quanto à gravidade, sendo os eventos mais comuns perda de apetite e insônia...

Advances and considerations in attention-deficit/hyperactivity disorder pharmacotherapy

Attention-deficit/hyperactivity disorder [ADHD] is a highly heritable neuropsychiatric disorder associated with significant impairments in occupational, academic, neuropsychological, and social functioning. Central nervous system [CNS] stimulants are recommended as first-line medication therapy for children. CNS stimulants include formulations of methylphenidate and amphetamine derivatives and are available in a large variety of immediate-and extended-release preparations. Extended-release preparations are often preferred to limit drug administration during school or work and may help to limit side effects associated with rapid fluctuations in serum concentration. Stimulant medication is by far the most commonly used treatment in managing children with ADHD, 10-20% of those who take such medication do now show clinically significant improvements in their primary ADHD symptom. Even when a favorable response is obtained, some children experience side effects that are of sufficient occurrence and severity to prevent continued use of stimulant medication. In such instances or when families are unwilling to consider a stimulant, non-stimulant medications may be appealing. This review focuses on etiology, assessment and treatment of ADHD with various stimulant and non-stimulant agents

Effects of buspirone on dopamine dependent behaviours in rats.

Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

Effects of dextromethorphan on dopamine dependent behaviours in rats.

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

Effects of d-amphetamine and haloperidol on modulation of the human acoustic startle response

This study aimed to examine the effects of haloperidol and amphetamine on human startle response modulated by emotionally-toned film clips. Sixty participants, in two groups [one receiving haloperidol and the other receiving amphetamine] were tested using electromyography [EMG] to measure eye-blink muscle [orbicular oculi] while different emotions were induced by six 2-minute film clips. An, affective rating shows the negative and positive effects of the two drugs on emotional reactivity, neither amphetamine nor haloperidol had any impact on the modulation of the startle response. The methodological and theoretical aspects of the study and findings will be discussed

D-Amphetamine Causes Dual Actions on Catecholamine Release from the Rat Adrenal Medulla

The present study was designed to examine the effect of d-amphetamine on CA release from the isolated perfused model of the rat adrenal gland, and to establish its mechanism of action. D- amphetamine (10~100microM), when perfused into an adrenal vein of the rat adrenal gland for 60 min, enhanced the CA secretory responses evoked by ACh (5.32x10-3 M), excess K+ (5.6x10-2 M, a membrane depolarizer), DMPP (10-4 M, a selective neuronal nicotinic Nn-receptor agonist) and McN-A-343 (10-4 M, a selective M1-muscarinic agonist) only for the first period (4 min), although it alone has weak effect on CA secretion. Moreover, d-amphetamine (30microM) in to an adrenal vein for 60 min also augmented the CA release evoked by BAY-K-8644, an activator of the dihydropyridine L-type Ca2+ channels, and cyclopiazonic acid, an inhibitor of cytoplasmic Ca2+ ATPase only for the first period (4 min). However, in the presence of high concentration (500microM), d-amphetamine rather inhibited the CA secretory responses evoked by the above all of secretagogues. Collectively, these experimental results suggest that d-amphetamine at low concentrations enhances the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization, but at high concentration it rather inhibits them. It seems that d-amphetamine has dual effects as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that these actions of d-amphetamine are probably relevant to the Ca2+ mobilization through the dihydropyridine L-type Ca2+ channels located on the rat adrenomedullary chromaffin cell membrane and the release of Ca2+ from the cytoplasmic store.

Effect of Psychostimulants on Distinct Attentional Parameters in Attentional Deficit/Hyperactivity Disorder

Although there is extensive literature about the effects of stimulants on sustained attention tasks in attentional deficit/hyperactivity disorder (ADHD), little is known about the effect of these drugs on other attentional tasks involving different neural systems. In this study we measured the effect of stimulants on ADHD children, both in the electroencephalographic (EEG) activity during sustained attentional tasks and in psychometric performance during selective attentional tasks. These tasks are known to rely on different cortical networks. Our results in children medicated with 10 mg of d-amphetamine administered 60 min before the study indicate (i) a significant increase in amplitude but not latency of the P300 component of the event-related potential (ERP) during the sustained attentional task and (ii) a significant improvement in the reaction times and correct responses in the selective attentional task. In addition to supporting the use of stimulants in children with attentional deficit/hyperactivity disorder, these results show a multifocal activity improvement of cortical structures linked to dopamine, and interestingly, to attention. All these analyses are framed in a wider study of diverse attentional functions in this syndrome.

Participaçäo de fatores exteroceptvos e interoceptivos na sensibilizaçäo comportamental induzida por anfetamina / Participation of exterorceptives and interoreceptives factors amphetamin-induced behavioral sensitization

O efeito estimulante motor induzido pela anfetamina em roedores intensifica-se após administraçoes repetidas. Diversas evidências experimentais sugerem que esse fenômeno, denominado Sensibilizaçao Comportamental, compartilha as bases mecanicísticas inerentes às propriedades reforçadoras da droga e, conseqüentemente, à dependência farmacológica. De importancia, tanto a sensibilizaçao como a dependência à anfetamina parecem ser marcantemente potencializada pelo pareamento entre o efeito da droga e condiçoes exteroceptivas específicas. Paralelamente evidências mais recentes sugerem que além dos fatores exteroceptivos, o condicionamento do efeito farmacológico de psicoestimulantes a fatores interoceptivos poderia ser fundamental para o desenvolvimento do fenômeno de Sensibilizaçao Comportamental. Nesse contexto, o presente trabalho teve como proposiçao geral verificar a possível participaçao de fatores exteroceptivos ambientais e sociais bem com de fatores interoceptivos relacionados à ativaçao do Sistema Nervoso Autonômico Simpático no fenômeno de sensibilizaçao ao efeito estimulante motor induzido pela anfetamina em camundongos. Com o a intuito de detectar nao apenas alteraçoes quantitativas como também modificaçoes qualitativas nesse fenômeno, diversos parâmetros da atividade geral dos animais em campo aberto foram analisados...(au)

Effect of the 5-HT3 receptor antagonist ondansetron on amphetamine-induced hyperactivity and stereotypy in rats.

The effects of different doses of ondansetron (0.1, 0.5, 1, 2 mg/kg) administered intra-peritoneally were studied on amphetamine-induced hyperactivity and stereotypy in wistar rats. Ondansetron was administered 30 minutes prior to d-amphetamine (3 mg/kg, i.p.). Ondansetron in doses of 0.5 and 1 mg/kg significantly decreased the mean number of head dippings and crossings in the hole board test and in doses of 0.1 and 0.5 mg/kg significantly decreased the average stereotypic score. Since the hyperactivity and stereotypy are dopamine mediated, the effect of ondansetron to reduce these states suggests a potential role for ondansetron in conditions with dopamine excess.

Tratamiento del trastorno por déficit atencional con hiperactividad / Treatment of the attention deficit disorder with hyperactivity

El comportamiento impulsivo, hiperactivo y con poca capacidad de atención en niños se considera un trastorno cuando éste es severo, inapropiado y altera las funciones en el hogar y en el colegio. Actualmente existen dos términos para denominar este trastorno: trastorno de déficit atencional con hiperactividad (TDAH) y trastorno hiperkinético (TH), término ya poco usado. Resulta a veces difícil distinguir el TDAH de otras patologías como por ejemplo: trastorno de conducta, trastornos emocionales, síndrome depresivo, problemas de aprendizaje, ya que éstos suelen asociarse a las características que presentan los niños con TDAH

O emprego de psicoestimulantes no adulto / The use of psychostimulant agents in adults

Os psicoestimulantes vêm sendo empregados como potencializadores de drogas antidepressivas no tratamento de transtornos do humor refratários. Mesmo nao associados a antidepressivos, os estimulantes sao considerados úteis no paciente deprimido portador de doença física e no idoso deprimido apático, nos quais os antidepressivos encontram obstáculos, especialmente efeitos colaterais e longa latência para o início da açao terapêutica. Sao particularmente interessantes para o paciente deprimido portador de doença física crônica terminal, como a AIDS e o câncer, e para o deprimido portador de lesao encefálica residual. No transtorno de déficit de atenção e hiperatividade residual do adulto, os psicoestimulantes sao indicados. Pacientes com transtornos do humor relacionados ao complexo demencial da AIDS também parecem beneficiar-se de terapêutica com psicoestimulante. Em casos da síndrome de fadiga crônica, psicoestimulantes também têm sido considerados úteis

Observación longitudinal de casos con déficit atencional, hiperactividad motora e inestabilidad emocional en niños provenientes del sector público de salud y educación del Area Norte de la ciudad de Santiago / Longitudinal study of cases with attention deficit, motor hyperactivity and emotional instability in children from health public area and education of nort area from Santiago city

Se analizaron 84 pacientes con las manifestaciones clínicas características del DAHI (Déficit Atencional con Hiperactividad y Excesiva Impulsividad) en un estudio de observación longitudinal a partir de 1983 hasta 1994 en el sector norte de Santiago. Se decidió incluir en el estudio a los pacientes referidos a la clínica ambulatoria de Neurología del Hospital Roberto del Río, durante el mencionado período, desde los Consultorios de Atención Primaria. En casi todos los casos se empleó dextroanfetamina (en casos justificados se empleó metilfenidato), que era entregada a los pacientes si asistían a los controles periódicamente, observándose un adecuado efecto terapéutico, con efectos adversos en pocos casos y sin evidencias de dependencia o aumento de tolerancia. A pesar de ser pacientes complicados desde el punto de vista biológico, económico y social, el plan terapeútico fue satisfactorio en términos generales, siendo los resultados más efectivos y consistentes en quienes la sintomatología del déficit atencional no se acompañaba de alteraciones conductuales, fueron menos favorables cuando hubo manifestaciones de disfunción cerebral orgánica y más problemáticos en la medida que habían evidencias de disfunción psicosocial en el entorno familiar. Los resultados sugieren que la dextroanfetamina puede ser considerada como favorable en una alta proporción de casos independientemente de las condiciones biológicas y del desarrollo psicomotor, pero fueron fundamentales la continuidad y adherencia al plan terapeútico, tanto el manejo ambiental y al uso adecuado del fármaco por parte del paciente y de la familia

Role of striatal dopamine in the lordosis behaviour.

Effects of intrastriatal injections of haloperidol (Dopamine antagonist) and D-amphetamine (Dopamine agonist) on lordosis behaviour were studied in ovariectomized female albino rats, after priming with subcutaneous injections of estrogen and progesterone. The lordosis quotient (LQ) significantly increased after haloperidol, and decreased following D-amphetamine treatment. However, the inhibitory effect of D-amphetamine was transient and could be reversed by haloperidol in the same animal when given one hour after the D-amphetamine injection. The ovarian hormones probably act centrally to suppress the DA system in the striatum thereby enhancing the tonic and dorsal immobility responses associated with lordosis.

Psychoactive drug induced alteration of tryptamine tetrazolium reductase activity in rat brain.

The psychoactive drugs imipramine, chlorpromazine and lithium chloride inhibit tryptamine tetrazolium reductase activity in vitro by 68, 60 and 33% respectively at a concentration of 1 x 10(-3) M while amphetamine negligibly inhibits the enzyme activity. No change in enzyme activity is observed in vivo.

A comparative study of the driving effects of dextroamphetamine and yogic meditation on muscle control for the performance of balance on balance board.

The work is aimed to compare the relative strength of dextroamphetamine and yogic meditation on the performance of 3 different groups of medical students to concentrate on the task to balance on a balance board. Group A subjects were mediators, group B subjects were given orally 5 and 10 mg of dextroamphetamine in a capsule, 1 hr prior to the test. Group C subjects were given same capsule but with lactose in place of the drug (placebo). This last groups served as control for the study. The balance index calculated taking into account their balance time and error score at each trial of 5 min duration showed that the performance of the group B (drug) had declined with overall percentile fall of 40.6% as compared to the performance of the controls (placebo) whereas, the performance of Group A (meditators) went on steadily and progressively increasing throughout the period of 10 trial days with overall percentile rise of 27.8%. The results were conclusive to confirm earlier reports that amphetamine is not of use for improvement of task rather, it deteriorates the task performance. Contrary to that, yogic meditation is of merit to achieve concentration for mental as well as physical task.

Effects of phenylethylamine on rat locomotor behavior and avoidance learning

1. The effects of ß-phenylethylamine (PEA) alone and in association with caroxazone, a potent inhibitor of monoamine oxidase B (MAO B), on the activity and long-term memory in the wheel-shaped activity monitor and on fixed-interval two-way avoidance acquisition were studied in rats. In a separate study, we determined the effects of PEA and of d-amphetamine on the variable-internal two-way avoidance acquisition. 2. The action of PEA was markedly different from that of aplhetamine in several aspects. The stimulating effects of PEA in the wheel-shaped activity monitor were of a more subtle nature than those of amphetamine and in the variable-interval two-way avoidance acquisition PEA had no effect, while amphetamine improved performance. 3. PEA did not induce an increase in path-choice stereotypy, but caroxazone did. The absence of any caroxazone-session interaction effects on the path interation frequency suggested that there were no long-term memory effects. 4. In the fixed-interval two-way avoidance acquisition experiments, PEA increased the avoidance responses of tats while caroxazone had no effect. The association of the two drugs did not potenciate either

Función adaptativa de MSH, potenciales cerebrales y atención selectiva en el hombre / The adaptative function of MSH, brain potentials and selective attention in man

Se valoró el efecto de la hormona estimulante de melanocitos (MSH) sobre la atención selectiva en el hombre por medio de los cambios de amplitud en los componentes temprano y tardío de los potenciales somáticos evocados (PSE). Se tuvo cuidado especial de valorar los cambios concomitantes en el nivel de alerta general y en las pruebas de memoria reciente o de discriminación espacial. Este efecto se comparó con los producidos por fármacos del tipo de la noradrenalina (dextroanfetamina) y morfínicos (fentanil y naloxona). Ninguno de estos compuestos cambió la amplitud de los PSE tempranos, pero modificaron de manera diferencial los tardíos; la MSH y la naloxona aumentaron la amplitud de los PSE tardíos, en tanto que la dextroanfetamina y el fentanil la disminuyeron. La MSH y la naloxona aumentaron la velocidad de reacción, lo mismo que las pruebas de retención visual y discriminación espacial, sin cambios en el nivel de alerta general. La dextroanfetamina y el fentanil disminuyeron las pruebas de retención visual o de discriminación espacial, pero en tanto la primera aumentó la velocidad de reacción y el estado de alerta general, la última disminuyó la velocidad de reacción sin producir cambios en el estado de alerta general. Estos dados sugieren que MSH y otros compuestos relacionados producen cambios en el proceso de la atención del hombre al modificar la excitabilidad de los componentes tardíos de los PSE mediadores del sistema extralemniscal, pero no los propios del sistema lemnisco. Sugieren además que los cambios producidos en los PSE por MSH, fentanil y naloxona ocurrieron a nivel cortical pero no en la parte reticular del sistema extralemniscal, puesto que estos compuestos modificaron la velocidad de reacción y las pruebas de retención visual o de discriminación espacial (parte cortical) sin cambios en el nivel de alerta general (parte reticular). Sin embargo, los cambios producidos por la destroanfetamina en los PSE tardíos y la atención, deben considerarse consecuencias de la activación de los circuitos reticular y motor, que son independientes del relacionado con la atención selectiva