RESUMO
Previous studies showed a prominent role of the medial prefrontal cortex (mPFC), especially the prelimbic (PL) and infralimbic (IL) subregions, in behavioral and physiological responses to stressful stimuli. Nevertheless, the local neurochemical mechanisms involved are not completely understood. In this sense, previous studies identified cholinergic terminals within the mPFC, and stressful stimuli increased local acetylcholine release. Despite these pieces of evidence, the specific role of cholinergic neurotransmission in different subregions of the mPFC controlling the cardiovascular responses to stress has never been systematically evaluated. Therefore, the purpose of this study was to investigate the involvement of cholinergic neurotransmission present within PL and IL in cardiovascular responses to an acute session of restraint stress in rats. For this, rats received bilateral microinjection of the choline uptake inhibitor hemicholinium-3 before exposure to restraint stress. The arterial pressure and heart rate (HR) increases and the decrease in tail skin temperature as an indirect measurement of sympathetically-mediated cutaneous vasoconstriction were recorded throughout the restraint stress session. The results showed that the depletion of acetylcholine within the PL caused by local microinjection of hemicholinium-3 decreased the tachycardia to restraint stress, but without affecting the pressor response and the drop in tail skin temperature. Conversely, IL treatment with hemicholinium-3 decreased the restraint-evoked pressor response and the sympathetically-mediated cutaneous vasoconstriction without interfering with the HR response. Taken together, these results indicate functional differences of cholinergic neurotransmission within the PL and IL in control of cardiovascular and autonomic responses to stressful stimuli.
Assuntos
Acetilcolina/fisiologia , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Colinérgicos/farmacologia , Frequência Cardíaca/fisiologia , Inibidores da Captação de Neurotransmissores/farmacologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemicolínio 3/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Restrição FísicaRESUMO
Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2â¯h) or chronic restraint (2â¯h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10â¯mg/kg) or saline was performed twice daily (12-12â¯h interval), for 7 consecutive days. EPM test was conducted 24â¯h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.
Assuntos
Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/lesões , Norepinefrina/metabolismo , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Estresse Psicológico , 5,7-Di-Hidroxitriptamina/farmacologia , Análise de Variância , Animais , Desipramina/farmacologia , Modelos Animais de Doenças , Tolerância a Medicamentos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Serotoninérgicos/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologiaRESUMO
(1) Background: Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. It is also the one with the highest percentage of drug-resistance to the current available anti-epileptic drugs (AED). Additionaly, most antiepileptic drugs are only able to control seizures in epileptogenesis, but do not decrease the hippocampal neurodegenerative process. TLE patients have a reduced population of interneuronal cells, which express Parvalbumin (PV) proteins. This reduction is directly linked to seizure frequency and severity in the chronic period of epilepsy. There is therefore a need to seek new therapies with a disease-modifying profile, and with efficient antiepileptic and neuroprotective properties. Parawixin2, a compound isolated from the venom of the spider Parawixia bistriata, has been shown to inhibit GABA transporters (GAT) and to have acute anticonvulsant effects in rats. (2) Methods: In this work, we studied the effects of Parawixin2 and Tiagabine (an FDA- approved GAT inhibitor), and compared these effects in a TLE model. Rats were subjected to lithium-pilocarpine TLE model and the main features were evaluated over a chronic period including: (a) spontaneous recurrent seizures (SRS), (b) neuronal loss, and (c) PV cell density in different regions of the hippocampus (CA1, CA3, DG and Hilus). (3) Results: Parawixin2 treatment reduced SRS frequency whereas Tiagabine did not. We also found a significant reduction in neuronal loss in CA3 and in the hilus regions of the hippocampus, in animals treated with Parawixin2. Noteworthy, Parawixin2 significantly reversed PV cell loss observed particularly in DG layers. (4) Conclusions: Parawixin2 exerts a promising neuroprotective and anti-epileptic effect and has potential as a novel agent in drug design.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Inibidores da Captação de Neurotransmissores/uso terapêutico , Venenos de Aranha/uso terapêutico , Ureia/análogos & derivados , Animais , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo/efeitos dos fármacos , Lítio , Masculino , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Ácidos Nipecóticos/farmacologia , Ácidos Nipecóticos/uso terapêutico , Pilocarpina , Ratos Wistar , Venenos de Aranha/farmacologia , Tiagabina , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
This commentary addresses some of the diverse questions of current interest with regard to the health effects of air pollution, including exposure-response relationships, toxicity of inhaled particles and risks to health, multipollutant mixtures, traffic-related pollution, accountability research, and issues with susceptibility and vulnerability. It considers the challenges posed to researchers as they attempt to provide useful evidence for policy-makers relevant to these issues. This commentary accompanies papers giving the results from the ESCALA project, a multi-city study in Latin America that has an overall goal of providing policy-relevant results. While progress has been made in improving air quality, driven by epidemiological evidence that air pollution is adversely affecting public health, the research questions have become more subtle and challenging as levels of air pollution dropped. More research is still needed, but also novel methods and approaches to address these new questions.
Este comentario aborda algunos de los temas de interés actual en relación con los efectos de la contaminación del aire sobre la salud, tales como las relaciones exposición-respuesta, la toxicidad y riesgos para la salud de las partículas inhaladas, las mezclas de contaminantes múltiples, la contaminación relacionada con el tráfico, la investigación sobre responsabilidad, y los problemas de susceptibilidad y vulnerabilidad. Considera los retos que se presentan a los investigadores que intentan proporcionar evidencia para los responsables políticos en estas cuestiones. Este texto acompaña otros trabajos con resultados del proyecto ESCALA, un estudio en varias ciudades de América Latina que tiene como objetivo general proporcionar resultados relevantes para la política pública. Aunque ha habido avances para mejorar la calidad del aire, gracias a la evidencia epidemiológica de que la contaminación aérea está afectando negativamente a la salud pública, las preguntas de investigación se han vuelto más sutiles y difíciles a medida que los niveles de contaminación se reducen. Se necesita más investigación, pero también nuevos métodos y enfoques capaces de enfrentar estas preguntas.
Assuntos
Animais , Camundongos , Colina/análogos & derivados , Junção Neuromuscular/metabolismo , Neurotransmissores/metabolismo , Pró-Fármacos/metabolismo , Colina/metabolismo , Inibidores da Colinesterase/farmacologia , Edrofônio/farmacologia , Estimulação Elétrica , /farmacologia , Metilaminas/farmacologia , Camundongos Endogâmicos , Neostigmina/farmacologia , Fármacos Neuromusculares Despolarizantes/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Piperidinas/farmacologia , Rana pipiensRESUMO
This study was undertaken in order to characterize the role of the glutamate/aspartate transporter (GLAST) in the glutathione (GSH) efflux induced by glutamate. Our results demonstrated that retinal cell cultures exhibit two mechanisms of GSH release, one Na(+)-independent and other Na(+)-dependent. Glutamate and aspartate induced GSH efflux only in presence of Na(+). Treatment with PCD (L-trans-Pyrrolidine-2,4-dicarboxylate), a transportable glutamate uptake blocker, increased GSH release indicating that GSH can be carried by glutamate transporters in retinal cell cultures. Added to this, treatment with zinc ion cultures, a recognized inhibitor of GLAST blocked GSH efflux evoked by glutamate. Treatment with NMDA antagonist (MK-801) did not have any effect on the GSH release induced by glutamate. These results suggest that glutamate induces GLAST-mediated release of GSH from retinal cell cultures and this could represent an important mechanism of cellular protection against glutamate toxicity in the CNS.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Ácido Glutâmico/farmacologia , Glutationa/metabolismo , Retina/citologia , Animais , Ácido Aspártico/farmacologia , Células Cultivadas , Embrião de Galinha , Ácidos Dicarboxílicos/farmacologia , Ácido Glutâmico/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Pirrolidinas/farmacologia , Retina/efeitos dos fármacosRESUMO
OBJECTIVE: To review the published data that include Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), especially desvenlafaxine, on vasomotor symptoms (VMS). METHODS: This review is based on published data in Medline (1990-2009) for studies on SSRI and SNRIs, especially desvenlafaxine, and VMS. RESULTS: There is increasing evidence that both norepinephrine and serotonin are associated with the communication and modulation of the temperature homeostasis maintained by the hypothalamus. Different studies demonstrated the modest efficacy of SSRIs and SNRIs on VMS. Recently, a program of clinical trials with desvenlafaxine (a salt from the major metabolite of venlafaxine) has been developed for VMS. Currently, there are three randomized, double-blind clinical trials published, showing a significantly higher efficacy of desvenlafaxine versus placebo on VMS. There were also increased minor side effects with desvenlafaxine, especially nausea, at the beginning of the treatment. CONCLUSIONS: A non-hormonal alternative--desvenlafaxine--has proven efficacy for VMS. There was also an increase in minor side effects, especially nausea, at the beginning of the treatment. There are clear subgroups of patients with VMS eligible, such as women with hormone-dependent cancers, women who do not want to be treated with hormone therapy or just want to get relief of their vasomotor symptoms.
Assuntos
Cicloexanóis/uso terapêutico , Menopausa , Inibidores da Captação de Neurotransmissores/uso terapêutico , Sistema Vasomotor/efeitos dos fármacos , Succinato de Desvenlafaxina , Feminino , Humanos , Sistema Vasomotor/fisiopatologiaRESUMO
Patients with major depressive disorder (MDD) usually suffer from altered cognitive functions of episodic memory, working memory, mental processing speed and motor response. Diverse studies suggest that different antidepressant agents may improve cognitive functions in patients with MDD. The aim of this work is to study the effects of serotonergic reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments to improve the performance on memory tasks and mental processing speed in MDD. Seventy-three subjects meeting criteria for major depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same neuropsychological battery used prior to the treatment. Both treatments improved importantly the episodic memory and to a lesser extent, working memory, mental processing speed and motor performance. Our results suggest that cognition is partially independent from improvement in clinical symptoms. Both groups achieved remission rates in the HAM-D-17 after 24 weeks of treatment, but SNRI was superior to SSRI at improving episodic and working memory. Our work indicates that the superiority of SNRI over the SSRI at episodic memory improvement is clinically relevant.
Assuntos
Antidepressivos/uso terapêutico , Cognição/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Memória/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Adulto , Análise de Variância , Citalopram/uso terapêutico , Transtorno Depressivo Maior/diagnóstico , Cloridrato de Duloxetina , Humanos , Masculino , Testes Neuropsicológicos , Inibidores da Captação de Neurotransmissores/uso terapêutico , Escalas de Graduação Psiquiátrica , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Índice de Gravidade de Doença , Pensamento/efeitos dos fármacos , Tiofenos/uso terapêuticoRESUMO
RATIONALE: Conditioned fear to context causes freezing and cardiovascular changes in rodents and has been used to measure anxiety. It also activates the dorsolateral column of the periaqueductal gray (dlPAG). Microinjections of cannabinoid agonists into the dlPAG produced anxiolytic-like effects in the elevated plus maze, but the effects of these treatments on fear conditioning remains unknown. OBJECTIVE: The objective of this study was to verify if intra-dlPAG injection of the CB1 cannabinoid receptor agonist anandamide (AEA) or the anandamide transport inhibitor AM404 would attenuate behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats submitted to a contextual fear-conditioning paradigm. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Fifteen minutes before the test, the animals received a first intra-dlPAG injection of vehicle or AM251, a CB1 receptor antagonist (100 pmol/200 nl), followed 5 min later by vehicle, AEA (5 pmol/200 nl) or AM404 (50 pmol/200 nl). Freezing and cardiovascular responses were recorded for 10 min. RESULTS: Freezing and cardiovascular responses were reduced by administration of either AEA or AM404 into the dlPAG before re-exposition to the aversively conditioned context. These effects were abolished when the animals were locally pretreated with AM251. The latter drug, even at a higher dose (300 pmol), was ineffective when administered alone into the dlPAG. CONCLUSION: The results suggest that facilitation of endocannabinoid-mediated neurotransmission in the dlPAG, through activation of local CB1 receptors, attenuates the expression of contextual fear responses.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Medo/psicologia , Substância Cinzenta Periaquedutal/fisiologia , Receptor CB1 de Canabinoide/agonistas , Animais , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endocanabinoides , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microinjeções , Inibidores da Captação de Neurotransmissores/farmacologia , Substância Cinzenta Periaquedutal/anatomia & histologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidoresRESUMO
INTRODUCTION: Tonic immobility is the last defense against predation in animals and is characterized by paralysis and analgesia. In humans, it has only been reported in women victims of sexual abuse. OBJECTIVE: This study evaluated the prevalence of peritraumatic tonic immobility (PTI) in patients with PTSD and investigated its association with response to treatment. METHOD: Victims of urban violence with PTSD diagnosed through the SCID-IV (n=23) underwent a naturalistic pharmacological treatment according to the recommended guidelines for PTSD. The Post-Traumatic Stress Disorder Checklist--Civilian Version (PCL-C) and the Clinical Global Impressions (CGI) Severity scores were applied at baseline and endpoint. PTI was assessed using the Tonic Immobility Scale. RESULTS: PTI was reported by both genders in 43% of the sample. Patients with PTI responded significantly poorly to treatment than those without it, either considering the PCL-C or the CGI scores. LIMITATIONS: This study probed PTI retrospectively and was based on a small sample recruited in a tertiary clinic. CONCLUSIONS: We have expanded the scope of the two previous investigations on PTI by showing its occurrence also in men and during non-sexual violence. In addition, the finding of a significant relationship between PTI and poor response to treatment of PTSD indicates that PTI may carry a prognostic value in this disorder and suggests that PTI should be routinely assessed in traumatized patients.
Assuntos
Vítimas de Crime/psicologia , Resposta de Imobilidade Tônica/fisiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , População Urbana/estatística & dados numéricos , Violência/psicologia , Adulto , Feminino , Humanos , Masculino , Inibidores da Captação de Neurotransmissores/uso terapêutico , Inventário de Personalidade , Prognóstico , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Estudos Retrospectivos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Índice de Gravidade de Doença , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/psicologia , Resultado do Tratamento , Violência/estatística & dados numéricosRESUMO
CF-1 male mice were trained in an inhibitory avoidance task using a high footshock (1,2 mA, 50 Hz, 1 sec) in order to reduce the influence of extinction on retention performance. At 2, 7, 14, or 30 d after training, the first retention test was performed and hemicholinium (HC-3, 1.0 microg/mice), a specific inhibitor of high-affinity choline uptake in brain cholinergic neurons, was given intracerebroventricularly immediately after. Twenty four hours after treatment, mice were tested in an inhibitory avoidance task during five consecutive days, each 24 h apart. Retention performance was impaired by HC-3 when the first re-exposure took place at 2, 7, or 14 d, but the effect was no longer seen when re-exposure occurred 30 d after training. We did not find spontaneous recovery 21 d after training, when memory was retrieved 2 d after training and HC-3 was given immediately after. Although we cannot definitively discard a retrieval deficit, this lack of spontaneous recovery is in accordance with the storage-deficit interpretation. These results confirm and extend previous ones, suggesting that central cholinergic mechanisms are involved in the hypothetical reconsolidation memory processes of an inhibitory avoidance task in mice and also suggest that this participation depends on the "age" of the original memory trace. This implies that the vulnerability of a reactivated memory to a specific treatment, as the one used in this study, inversely correlates with the age of the original memory, and it is likely to determine memory reconsolidation processes.