Eficacia de los inhibidores selectivos de recaptación de serotonina en síntomas no cognitivos del alzhéimer: revisión sistemática

Introducción: El Alzhéimer tiene una prevalencia de 1,6% en las personas mayores de 65 años. Se caracteriza por la pérdida de memoria y otras funciones cognoscitivas, pero más del 70% de los afectados presentan síntomas no cognitivos entre los que se encuentran alteraciones del afecto, comportamiento y psicosis. Estos síntomas están asociados a mayores tasas de institucionalización, morbilidad y mortalidad. Métodos: Revisión sistemática de la literatura de artículos que proporcionaron información sobre la eficacia de los inhibidores selectivos de recaptación de serotonina en síntomas no cognitivos del Alzhéimer. Resultados: La búsqueda inicial arrojó un total de 495 resultados, 64 artículos fueron preseleccionados y 7 se incluyeron en la revisión; éstos se clasificaron como nivel de evidencia Ib; citalopram mostró ser más eficaz que el placebo y similar a antipsicóticos para síntomas comportamentales y psicóticos asociados al Alzhéimer con un perfil de efectos adversos más tolerable; sertralina no mostró eficacia en depresión y sí una mayor incidencia de efectos adversos con respecto al placebo. Discusión: Se obtuvieron resultados favorables en síntomas comportamentales y psicóticos pero no en afectivos. Las diferencias metodológicas de los estudios le dan complejidad a la interpretación de los resultados. Conclusión: La evidencia sugiere que el tratamiento con citalopram es eficaz en síntomas comportamentales y psicóticos asociados al Alzhéimer; para el tratamiento de la depresión asociado a esta demencia aún no existe un antidepresivo que pueda considerarse de elección.

Identificação dos princípios ativos presentes no extrato etanólico de cereus jamacaru e avaliação em ratos dos possíveis efeitos tóxicos e/ou comportamentais da exposição prolongada

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Involvement of dopamine receptors in diethylpropion-induced conditioning place preference

Diethylpropion (DEP) is an amphetamine-like agent used as an anorectic drug. Abuse of DEP has been reported and some restrictions of its use have been recently imposed. The conditioning place preference (CPP) paradigm was used to evaluate the reinforcing properties of DEP in adult male Wistar rats. After initial preferences were determined, animals weighing 250-300 g (N = 7 per group) were conditioned with DEP (10, 15 or 20 mg/kg). Only the dose of 15 mg/kg produced a significant place preference (358 ± 39 vs 565 ± 48 s). Pretreatment with the D1 antagonist SCH 23390 (0.05 mg/kg, sc) 10 min before DEP (15 mg/kg, ip) blocked DEP-induced CPP (418 ± 37 vs 389 ± 31 s) while haloperidol (0.5 mg/kg, ip), a D2 antagonist, 15 min before DEP was ineffective in modifying place conditioning produced by DEP (385 ± 36 vs 536 ± 41 s). These results suggest that dopamine D1 receptors mediate the reinforcing effect of DEP

Alterações do ciclo sono-vigília moduladas por Dopamina e suas consequências Mnemônicas

Neuroscience is on a rise of discoveries. Its wide interdisciplinary approach facilitates a more complex understanding of the brain, covering various areas in depth. However, many phenomena that fascinate human kind are far from being fully elucidated, such as the formation of memories and sleep. In this study we investigated the role of the dopaminergic system in the process of memory consolidation and modulation of the phases of sleep-wake cycle. We used two groups of animals: wildtype mice and hiperdopaminergic mice, heterozygous for the gene encoding the dopamine transporter protein. We observed in wild-type mice that the partial blockade of the D2 dopamine receptor by the drug haloperidol caused deficits in memory consolidation for object recognition, as well as a significant reduction in the duration of rapid eye movement sleep (REM). We also found a mnemonic deficit without pharmacological intervention in hiperdopaminergic animals; this deficit was reversed with haloperidol. The results suggest that dopamine plays a key role in memory consolidation for object recognition. The data also support a functional relationship between the dopaminergic system and the modulation of REM sleep

Estudo dos efeitos comportamentais do neuropeptídeos em camundongos submetidos a modelos animais de Parkinson

Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor. Preclinical studies have shown that NPSR receptor activation can promote arousal, anxiolytic-like behavioral, decrease in food intake, besides hyperlocomotion, which is a robust but not well understood phenomenon. Previous findings suggest that dopamine transmission plays a crucial role in NPS hyperactivity. Considering the close relationship between dopamine and Parkinson Disease (PD), and also that NPSR receptors are expressed on dopaminergic nuclei in the brain, the current study attempted to investigate the effects of NPS in motor deficits induced by intracerebroventricular (icv) administration of 6-OHDA and systemic administration of haloperidol. Motor deficits induced by 6-OHDA and haloperidol were evaluated on Swiss mice in the rota-rod and catalepsy test. Time on the rotating rod and time spent immobile in the elevated bar were measured respectively in each test. L-Dopa, a classic antiparkinsonian drug, and NPS were administrated in mice submitted to one of the animal models of PD related above. 6-OHDA injection evoked severe motor impairments in rota-rod test, while the cataleptic behavior of 6-OHDA injected mice was largely variable. The administration of L-Dopa (25 mg/kg) and NPS (0,1 and 1 nmol) reversed motor impairments induced by 6-OHDA in the rota-rod. Haloperidolinduced motor deficits on rota-rod and catalepsy tests which were reversed by L-Dopa (100 e 400 mg/kg), but not by NPS (0,1 and 1 nmol) administration. The association of L-Dopa 10 mg/kg and NPS 1 nmol was also unable to counteract haloperidol-induced motor deficits. To summarize, 6-OHDA-, but not haloperidol-, induced motor deficits were reversed by the central administration of NPS. These data suggest that NPS possibly facilitates dopamine release in basal ganglia, what would explain the overcome of motor performance promoted by NPS administration in animals pretreated with 6-OHDA, but not haloperidol. Finally, the presented findings point, for the first time, to the potential of NPSR agonist as an innovative treatment for PD.

Alterações cognitivas em ratos infectados com Toxoplasma gondii

Toxoplasma gondii is a protozoan parasite that induces behavioral changes in rodents. The aim of this study was to evaluate the effect of infection by T. gondii during the chronic phase in working memory and impulsivity in rodents as well as the effect of antipsychotics to reverse any behavioral changes resulting from infection. Female Wistar rats (n = 40) were infected with 25 cysts of the strain ME-49 T. gondii after 4 months the animals were subjected to behavioral tests: tolerance to delay gratification, in which the animal must choose between two rewards, a smaller and more immediate, but delayed and the test of spontaneous alternation, in which the animal must use spatial cues to remember previously visited arms. Antipsychotic drugs were intraperitoneally administered during the testing of the behavioral experiments, the antipsychotic is haloperidol (1.5 mg / kg) administered 60 min before the start of the session and the antipsychotic clozapine (2.5 mg / kg) 30 min before. Animals infected with the parasite did not show operating deficits of memory, and motor impairment did not develop, however motor impairment was observed only in animals treated with haloperidol. It was found that administration of clozapine and haloperidol increased the percentage of alternation in infected and control groups in task switching espontânea.Não no distinction between control animals and infected the test of tolerance to delay gratification in relation to the percentage of choices greatest reward, during the pre-training and training, in which there is a delay of 15 s to access the great reward, however it was observed that infected animals prefer the greatest reward, when there is a delay of 30 s when compared to control group. The administration of clozapine possible that infected animals chose the greatest reward in the delay of 30 seconds during the test. These data suggest that infected mice do not exhibit deficits in working memory and that clozapine has therapeutic efficacy in improving cognitive performance of mice infected

Actions of angiotensin II and dopamine in the medial preoptic area on prolactin secretion

Dopamine (DA) is known as a primary regulator of prolactin secretion (PRL) and angiotensin II (Ang II) has been recognized as one brain inhibitory factor of this secretion. In this work, estrogen-primed or unprimed ovariectornized rats were submitted to the microinjection of saline or Ang II after previous microinjection of saline or of da antagonist (haloperidol, sulpiride or SCH) both in the medial preoptic area (MPOA). Our study of these interactions has shown that 1) estrogen-induced PRL secretion is mediated by Ang II and da actions in the MPOA, i.e. very high plasma PRL would be prevented by inhibitory action of Ang II, while very low levels would be prevented in part by stimulatory action of da through D-2 receptors, 2) the inhibitory action of Ang II depends on estrogen and is mediated in part by inhibitory action of da through D, receptors and in other part by inhibition of stimulatory action of da through D2 receptors.

Experiência clínica com o uso de sedativos em terapia intensiva: estudo retrospectivo

JUSTIFICATIVA E OBJETIVOS: Dentre as indicações mais freqüentes de sedação em pacientes internados em Unidades de Terapia Intensiva (UTI) estão a instituição e a manutenção de ventilação artificial, a ansiedade e procedimentos desconfortáveis ou dolorosos. O objetivo deste estudo retrospectivo foi verificar as indicações e as técnicas mais comuns de sedação em pacientes graves internados na Unidade de Terapia Intensiva Cirúrgica da Escola Paulista de Medicina (EPM/UNIFESP) durante um período de 11 meses. MÉTODO: Após terem sido excluídos os pacientes que permaneceram na UTI menos de 24 horas ou estavam sem exames indispensáveis para o cálculo do índice de gravidade (APACHE II), a amostra ficou reduzida a 307 pacientes. Foram analisadas as técnicas mais utilizadas, as indicações de sedação e a associação de bloqueadores neuromusculares. RESULTADOS: A sedação foi administrada em 37,4% dos pacientes. Entre as indicações de sedação estão os distúrbios de natureza psiquiátrica, como delírio, agitação, medo e ansiedade. Estas corresponderam a 25,77% de todas as indicações. A maioria dos pacientes ventilados artificialmente também necessita de sedativos. Instalação e manutenção de ventilação mecânica corresponderam à maioria das indicações, em torno de 57,73% dentre os pacientes sedados. Procedimentos como intubação traqueal e broncoscopia tiveram 11,34% das indicações e controle do metabolismo (coma barbitúrico e tétano), 5,15%. As técnicas mais comumente utilizadas incluíram opióides isolados ou associados a benzodiazepínicos. Neste estudo, o fentanil foi utilizado em 58% das técnicas, isoladamente, e em 21,64% associado ao midazolam. Haloperidol, diazepam, propofol e tiopental somaram 19,5%. Bloqueadores neuromusculares foram utilizados em 22,7% dos casos em pacientes ventilados artificialmente. CONCLUSÕES: A sedação é recurso terapêutico freqüente em Terapia Intensiva, comumente utilizada para facilitar a ventilação artificial e tratar os problemas de natureza psiquiátrica. Fentanil, isoladamente ou em associação com midazolam, foi o agente mais utilizado.

Envolvimento do sistema dopaminérgico na sensibilização comportamental ao femproporex

The effects of repeated administration of fenproporex (FEN) on motor activity of rats were studied. FEN-treated group (5.0 mg/kg, i.p., single dose, 7 consecutive days), showed a marked increase in the motor activity of rats, indicating that the drug induced behavioral sensitization. Repeated coadministration of haloperidol prevented the development of sensitization to repeated administration of FEN. Repeated administration of FEN increased also locomotor activity measured in the open field, ratifying the occurence of sensitization. These findings indicated development of sensitization to repeated FEN administration and that the dopamine system might be involved in the mechanism of sensitization.

Validação farmacológica da preferência claro-escuro em Danio rerio

A ansiedade é uma desordem complexa e com grande relevância clínica, cujo estudo com modelos animais é importante para pesquisar sobre seus mecanismos e drogas para o seu tratamento. O zebrafish figura como um potencial modelo animal para pesquisas farmacológicas da ansiedade. Um modelo de ansiedade é a preferência claro-escuro, que já foi validado comportamentalmente em zebrafish, contudo necessita de uma validação farmacológica. Objetiva-se descrever a sensibilidade da preferência claro-escuro em zebrafish adultos para as drogas mais utilizadas na clínica da ansiedade, foram administradas pela imersão do animal na solução: Benzodiazepínicos (Clonazepam); Agonistas parciais 5-HT1A (Buspirona); Antidepressivo tricíclico (Imipramina); Antidepressivo ISRS (Fluoxetina e Paroxetina); Antipsicóticos (Haloperidol e Risperidona); Psicostimulante (Dietilpropiona); Beta bloqueadores (Propranolol) e Depressores do SNC (Etanol). Os parâmetros analisados foram o tempo despendido pelo animal no ambiente escuro, o tempo da primeira latência e número de alternâncias. O clonazepam administrado por 300s aumentou o tempo no escuro na menor concentração e reduziu a atividade locomotora, a administração durante 600s da concentração intermediária diminuiu o tempo no escuro e da primeira latência, assim como aumentou a atividade locomotora, indicando efeito ansiolítico. A buspirona aumentou o tempo de permanência no escuro provavelmente devido a redução da atividade motora. A imipramina e a fluoxetina aumentaram o tempo no escuro e da primeira latência e diminuíram o número de alternâncias, indicando ação ansiogênica. A paroxetina não alterou o tempo no escuro, entretanto aumentou o tempo da primeira latência e diminuiu a atividade locomotora. O haloperidol diminuiu a ansiedade na menor concentração, curiosamente aumentou a atividade motora na maior concentração, ao contrário da risperidona que diminuiu a atividade na maior concentração. A dietilpropriona não modificou o tempo no escuro, mas aumentou o tempo da primeira latência e diminuiu a atividade motora apenas na menor concentração. O propranolol reduziu somente o tempo no escuro. O etanol foi efetivo na redução da ansiedade com a concentração intermediária e diminuiu a atividade locomotora em uma concentração menor Os dados corroboram com relatos da literatura em Danio rerio tanto neste modelo em administração intraperitoneal como em outros modelos por administração hídrica e em roedores, quando foi possível a comparação.

Iptakalim: A Potential Antipsychotic Drug with Novel Mechanisms?

Iptakalim is a novel putative adenosine triphosphate (ATP)-sensitive potassium (KATP) channel opener. In the brain, iptakalim is thought to act on the neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels. Because iptakalim demonstrates an action on the regulation of dopamine and glutamate release in the forebrain regions, we examined its potential antipsychotic efficacy in several preclinical tests. First, we show that iptakalim is effective in reducing amphetamine- and phencyclidine-induced hyperlocomotion as well as selectively disrupting conditioned avoidance responding. Next, we show that combined iptakalim and amphetamine treatment produces a reduction on prepulse inhibition of acoustic startle and this combined drug effect is also found with haloperidol, but not with clozapine. Finally, we show that iptakalim and clozapine preferentially increase c-Fos expression in the medial prefrontal cortex, nucleus accumbens and lateral septal nucleus, whereas haloperidol induces a greater increase in the nucleus accumbens, the dorsolateral striatum and lateral septal nucleus. Collectively, our findings indicate that iptakalim is likely to be a potential antipsychotic drug with distinct mechanisms of action. This study also suggests that neuronal and astrocytic plasma membrane and/or mitochondrial KATP channels may be a novel target that deserves attention for antipsychotic drug development. Future research using other sensitive tests is needed to confirm this property of iptakalim.

Anxiolytic-Like Property of Risperidone and Olanzapine as Examined in Multiple Measures of Fear in Rats

Atypical antipsychotics are also used in the treatment of anxiety-related disorders. Clinical and preclinical evidence regarding their intrinsic anxiolytic efficacy has been mixed. In this study, we examined the potential anxiolytic-like effects of risperidone and olanzapine, and compared them with haloperidol, chlordiazepoxide (a prototype of sedative–anxiolytic drug) or citalopram (a selective serotonin reuptake inhibitor). We used a composite of two-way avoidance conditioning and acoustic startle reflex model and examined the effects of drug treatments during the acquisition phase (Experiment 1) or extinction phase (Experiments 2 and 3) on multiple measures of conditioned and unconditioned fear/anxiety-like responses. In Experiment 4, we further compared risperidone, olanzapine, haloperidol, citalopram and chlordiazepoxide in a standard elevated plus maze test. Results revealed three distinct anxiolytic-like profiles associated with risperidone, olanzapine and chlordiazepoxide. Risperidone, especially at 1.0 mg/kg, significantly decreased the number of avoidance responses, 22 kHz ultrasonic vocalization, avoidance conditioning-induced hyperthermia and startle reactivity, but did not affect defecations or time spent on the open arms. Olanzapine (2.0 mg/kg, sc) significantly decreased the number of avoidance responses, 22 kHz vocalization and amount of defecations, but it did not inhibit startle reactivity and time spent on the open arms. Chlordiazepoxide (10 mg/kg, ip) significantly decreased the number of 22 kHz vocalization, avoidance conditioning-induced hyperthermia and amount of defecations, and increased time spent on the open arms, but did not decrease avoidance responses or startle reactivity. Haloperidol and citalopram did not display any anxiolytic-like property in these tests. The results highlight the importance of using multiple measures of fear-related responses to delineate behavioral profiles of psychotherapeutic drugs.