RESUMO
The main injuries among victims of the terrorist act in the Tokyo subway resulted from sub-lethal inhalation and whole body exposure to sarin vapor. In order to study the long term effects of such exposure and to simulate these conditions, freely moving rats were exposed to sarin vapor (27.2±1.7 µg/l) for 10 min. About 50% of the rats showed no overt symptoms and the rest had mild to moderate clinical symptoms that subsided within 4h following exposure. A reduction of weight was noted during the first 3 days with full recovery on the 4th day. Rat's heart was challenged with epinephrine 1 and 6 months post exposure. A significant reduction in the threshold for epinephrine-induced arrhythmia (EPIA) was noted in rats exposed to sarin. A time dependent increase in the kD and Bmax values of muscarinic auto receptors (M2) was recorded in the rat's cortex and striatum. No changes were recorded in the rats' brain trans locator protein (TSPO) levels, concomitant with no observed changes in the animals' performance in A Morris water maze test. A significant increase in open field activity was noted 6 months following exposure to sarin vapor as well as a significant decrease in prostaglandin E2 (PGE2) production in the brain. It is speculated that down regulation of the M2 auto receptor function, caused hyper reactivity of the cholinergic system which leads to the changes described above. The continuous reduction in M2 auto-receptor system through an unknown mechanism may be the cause for long lasting decline in sarin-exposed casualties' health.
Assuntos
Encéfalo/efeitos dos fármacos , Coração/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Sarina/administração & dosagem , Sarina/toxicidade , Animais , Encéfalo/fisiopatologia , Coração/fisiopatologia , Dose Letal Mediana , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , VolatilizaçãoRESUMO
Alterations of nitric oxide (NO) metabolism in the brain have been associated with modifications of stress-related behavior in animal models. It has been generally assumed that these behavioral changes are due to the neuronal nitrosative activity. On the other hand, glial NO production has been demonstrated mainly as a slow reaction to brain insults through the activity of an inducible nitric oxide synthase (NOS) isoform (NOS2). Recently we uncovered increased NOS activity in astrocytes of mice with a NOS2 mutation. Interestingly, these mice revealed a behavioral phenotype suggestive of increased susceptibility to stress. In the present study we investigated the responses of these mutants to stress by exposing them to predator scent. Seven days later, mutant mice exhibited significantly higher anxiety-like behavior in the elevated-plus maze, increased acoustic startle responses, and higher plasma corticosterone levels compared with their controls. Systemic administration of a NOS inhibitor prior to the stress exposure reversed these stress-related effects without affecting controls' behavior. These findings are in agreement with previous studies showing an association between increased NO levels and enhanced anxiety-like responses. In addition, mutant mice performed better in the Morris water maze prior to stress exposure, but the two animal groups performed alike in an object-recognition test. Taken together, our results suggest the involvement of astrocytic-derived NO in modulating behavior.
Assuntos
Astrócitos/metabolismo , Comportamento Animal/fisiologia , Mutação , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase/metabolismo , Estresse Psicológico , Análise de Variância , Animais , Astrócitos/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Mutantes , NG-Nitroarginina Metil Éster/farmacologia , Neocórtex/patologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Reconhecimento Psicológico/fisiologia , Estresse Psicológico/genética , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologiaRESUMO
This work focused on sex differences in rats exposed to sarin. Females were found to be more sensitive to sarin toxicity (LD50 67⯵g/kg) than males (88⯵g/kg), showed less acute hypothermic effects than males (at 120â¯min post sarin, 3.1⯱â¯1.1 and 4.5⯱â¯1⯰C decrease, respectively), but with a significant slower recovery over days. Females' temperature response to the cholinergic agonist oxotremorine (0.25â¯mg/kg, im) was more pronounced than that of males (at 30â¯min, 3.13⯱â¯0.27 and 2.13⯱â¯0.19⯰C decrease, respectively) and both sexes recovered within 2â¯h of exposure. 24â¯h after sarin exposure (80⯵g/kg) followed 1â¯min later by TA treatment (TMB4 7.5â¯mg/kg and atropine 5â¯mg/kg) a 255% increase in plasma MCP-1 in males but not in females was recorded. In the brain, TIMP-1 increased 43 fold in females and 25 fold in males, compared to control rats. MCP-1 increased 8 fold in females only. TNFα increased in both sexes, but the increase in female brain was higher than that recorded in males. IL-6 increased in females but not in males. IL-1ß increased in both sexes. This work clearly demonstrates significant sex modulation effects on measures of toxicity, hypothermia and inflammatory markers in brain and plasma 24â¯h following exposure to sarin. In general, females seem to be more sensitive to the toxicity of sarin, but may be better protected against its brain damage. In light of these and other findings, the efficacy of the various available treatments, as well as those being developed, should be evaluated in both sexes.
Assuntos
Encefalite/induzido quimicamente , Hipotermia/induzido quimicamente , Agentes Neurotóxicos/toxicidade , Sarina/toxicidade , Caracteres Sexuais , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Quimiocina CCL2/sangue , Encefalite/metabolismo , Feminino , Masculino , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/sangueRESUMO
Severe poisoning by inhibitors of cholinesterase (ChE) enzymes is often associated with prolonged central or peripheral neuronal damage. Oxotremorine is a cholinergic agonist known to induce acute hypothermia. Central and peripheral cholinergic signaling is involved in the induction of hypothermia as well as in its recovery. These processes were used in the present study to reveal prolonged neuronal abnormalities in poisoned rats, using oxotremorine with and without concomitant administration of the peripheral muscarinic antagonist methyl scopolamine. In non-poisoned naïve rats, the hypothermic effect of oxotremorine appeared faster while its recovery was delayed following co-administration of methyl scopolamine, suggesting predominantly peripheral processes in counteracting the hypothermia. One month after exposure to approximately 1LD(50) of the carbamates aldicarb and oxamyl, the hypothermic effect of oxotremorine was similar to that found in saline-treated control group. However, the effect of methyl scopolamine on the recovery process was significantly diminished, indicating that the impaired cholinergic mechanisms were predominantly peripheral. In contrast, 1 month following organophosphate (OP) poisoning by the nerve agents sarin and VX, oxotremorine-induced hypothermia was reduced, indicating mainly impaired central cholinergic mechanisms. The development of severe convulsions during nerve agent poisoning may explain the central neuronal damage in OP-poisoned rats, displayed as reduced hypothermia. As convulsions were not part of the poisoning symptoms with the carbamates tested, their long-term damage was displayed at the recovery stage. This method might be used as a relatively simple means for detecting differential long-term central and peripheral cholinergic injuries, long after toxicity signs have receded.
Assuntos
Carbamatos/toxicidade , Sistema Nervoso Central/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Hipotermia/fisiopatologia , Compostos Organofosforados/toxicidade , Sistema Nervoso Periférico/efeitos dos fármacos , Testes de Toxicidade/métodos , Aldicarb/toxicidade , Animais , Temperatura Corporal/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Hipotermia/induzido quimicamente , Dose Letal Mediana , Masculino , Agonistas Muscarínicos , Antagonistas Muscarínicos/farmacologia , N-Metilescopolamina/farmacologia , Compostos Organotiofosforados/toxicidade , Oxotremorina , Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes , Sarina/toxicidade , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores de TempoRESUMO
Epinephrine-induced arrhythmias (EPIA) are known to be associated with local cardiac cholinergic activation. The present study examined the development of QT prolongation and the effect on EPIA of whole-body exposure of animals to a potent acetylcholine esterase inhibitor. Freely moving rats were exposed to sarin vapor (34.2 +/- 0.8 microg/liter) for 10 min. The electrocardiograms (ECG) of exposed and control animals were monitored every 2 weeks for 6 months. One and six months post exposure, rats were challenged with epinephrine under anesthesia, and the threshold for arrhythmias was determined. Approximately 35% of the intoxicated rats died within 24 h of sarin exposure. Additional occasional deaths were recorded for up to 6 months (final mortality rate of 48%). Surviving rats showed, agitation, aggression, and weight loss compared to non-exposed rats, and about 20% of them experienced sporadic convulsions. Sarin-challenged rats with severe symptoms demonstrated QT segment prolongation during the first 2-3 weeks after exposure. The EPIA that appeared at a significantly lower blood pressure in the treated group in the first month after intoxication lasted for up to 6 months. This decrease in EPIA threshold was blocked by atropine and methyl-atropine. Three months post exposure no significant changes were detected in either k(D) or B(max) values of (3)H-N-methyl scopolamine binding to heart homogenates, or in the affinity of carbamylcholine to cardiac muscarinic receptors. The increase in the vulnerability to develop arrhythmias long after accidental or terror-related organophosphate (OP) intoxication, especially under challenging conditions such as stress or intensive physical exercise, may explain the delayed mortality observed following OP exposure.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Coração/efeitos dos fármacos , Sarina/toxicidade , Animais , Arritmias Cardíacas/fisiopatologia , Atropina/farmacologia , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Eletrocardiografia/efeitos dos fármacos , Epinefrina , Exposição por Inalação , Dose Letal Mediana , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Masculino , Antagonistas Muscarínicos/farmacologia , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Sarina/administração & dosagem , Escopolamina/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , VasoconstritoresRESUMO
Eye exposure to the extremely toxic organophosphorus sarin results in long-term miosis and visual impairment. As current treatment using atropine or homatropine eye drops may lead to considerable visual side effects, alternative combined treatments of intramuscular (im) oximes (16.8 µmol/kg, im) with atropine (0.5 mg/kg, im) or with the short acting antimuscarinic tropicamide (0.5%; w/v) eye drops were thus evaluated. The combined treatments efficacy following topical exposure to sarin (1 µg) was assessed by measuring pupil width and light reflex using an infra-red based digital photographic system. Results showed that the combined treatment of various oximes with atropine or with topical tropicamide eye drops rapidly reversed the sarin-induced miosis and presented a long-term improvement of 67-98% (oxime+tropicamide) or 84-109% (oxime+atropine) in pupil widening as early as 10-min following treatment. This recovery was shown to persist for at least 8-h following exposure. All combined treatments facilitated the ability of the iris to contract following sarin insult as tested by a light reflex response.Our findings emphasize the high efficacy of im oxime treatment combined with either atropine im or tropicamide eye drops in counteracting sarin-induced ocular insult. Therefore, in a mass casualty scenario the systemic combined treatment may be sufficient to ameliorate sarin-induced ocular insult with no need for additional, topical anticholinergic treatment at least in the initial stage of intoxication. For very mild casualties, who are unlikely to receive im treatment, the combined oxime (im) with topical tropicamide treatment may be sufficient in ameliorating the ocular insult.
Assuntos
Atropina/farmacologia , Reativadores da Colinesterase/farmacologia , Olho/efeitos dos fármacos , Oximas/farmacologia , Sarina/toxicidade , Administração Oftálmica , Animais , Atropina/uso terapêutico , Sinergismo Farmacológico , Masculino , Miose/tratamento farmacológico , Ratos , Ratos Long-Evans , Tropicamida/administração & dosagem , Tropicamida/farmacologiaRESUMO
The regulation of gene expression has been implicated in the etiology and treatment of depression. Transcription factors serve as the intermediates between intracellular cascades and gene expression, and may therefore be involved in the pathophysiology and pharmacotherapy of depression. We and others have previously reported an increase in the phosphorylation of the transcription factor cAMP response element binding protein (CREB) by antidepressants, alongside brain region-specific alterations in pCREB by stress. In the present study, we examined the expression of another member of the CREB/ATF family of transcription factors, ATF2, in the brains of rats chronically treated with two different antidepressants, and in rats 4 months after their exposure to prolonged stress. ATF2 phosphorylation was decreased by antidepressants and increased at the aftermath of prolonged stress, specifically in the frontal cortex. We also examined ATF2 expression in the ventral parieto-occipital region of post-mortem human brains of normal controls, depressed, bipolar, and schizophrenic patients, obtained from the Stanley Foundation Brain Consortium. No alterations were observed in the levels of ATF2. However, in the depressed group, the pATF2 levels were higher in unmedicated compared to medicated patients, suggesting an antidepressant-induced reduction in pATF2. We discuss the possible role of ATF2 in depression, and propose that an interplay between ATF2 and CREB, and possibly other transcription factors, determines the final gene expression pattern in the etiology and treatment of depression.
Assuntos
Antidepressivos/uso terapêutico , Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Estresse Fisiológico/metabolismo , Fatores de Transcrição/metabolismo , Fator 2 Ativador da Transcrição , Adulto , Análise de Variância , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Doença Crônica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Estresse Fisiológico/tratamento farmacológico , Estresse Fisiológico/patologia , Fatores de Transcrição/genéticaRESUMO
Wistar-Kyoto (WKY) rats were tested as a potential animal model for memory dysfunction. These animals were reported to be highly reactive to stress and this was associated with findings of alterations in their hippocampal cholinergic activity. Since hippocampal cholinergic hypofunction is often associated with deficits in memory processes, untreated WKY rats were tested here in a working memory task in the Morris water maze. Animals were tested for five daily sessions, with two identical trials per day, and their performance was compared to that of Sprague-Dawley (SD) rats. Results show that WKY rats failed to improve their performance both from day to day and within the two trials each day. This suggests impaired memory capabilities of WKY rats and may support their use as an animal model of memory dysfunction. However, because of their increased tendency to float, speed of performance was also reduced in WKY compared to SD rats. This difference may be associated with their increased reactivity to stress. The combination of memory dysfunction and stress hyper-reactivity seen in WKY rats may be used to study the association between these two functions, particularly the possible interaction between memory and depression.
Assuntos
Transtornos da Memória/psicologia , Memória de Curto Prazo/fisiologia , Percepção Espacial/fisiologia , Estresse Psicológico/psicologia , Animais , Masculino , Transtornos da Memória/etiologia , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Especificidade da Espécie , Estresse Psicológico/complicaçõesRESUMO
Apolipoprotein E-deficient mice provide a useful system for studying the role of apolipoprotein E (apoE) in the function of distinct neuronal systems. In the present study we focused on the cholinergic system of these mice. This was pursued by measurements of specific biochemical, physiological and cognitive parameters. Morris Water Maze tasks revealed impairments in working memory but not in reference memory of the apoE-deficient mice. Measurements of brain choline acetyltransferase activities revealed them to be markedly lower in the hippocampus and frontal cortex of the apoE-deficient mice than in the corresponding brain areas of the controls, but unaltered in other brain areas. In addition, hypothermia induced by the centrally acting muscarinic agonist, oxotremorine, was reduced in the apoE-deficient mice as compared to controls. These results show that apoE-deficient mice have cholinergic deficits and highlight the importance of this mouse model for studying the interactions between apoE and the cholinergic nervous system.
Assuntos
Apolipoproteínas E/fisiologia , Doenças do Sistema Nervoso Autônomo/metabolismo , Transtornos da Memória/metabolismo , Sistema Nervoso Parassimpático/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Doenças do Sistema Nervoso Autônomo/psicologia , Encéfalo/enzimologia , Colina O-Acetiltransferase/metabolismo , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Lobo Frontal/enzimologia , Hipocampo/enzimologia , Hipotermia Induzida , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Knockout , Agonistas Muscarínicos/farmacologia , Oxotremorina/farmacologia , Sistema Nervoso Parassimpático/enzimologiaRESUMO
1. The effects of inositol (20 g/day, oral) on spatial learning and spontaneous home-cage behavior of four Rhesus monkeys, were studied in a crossover design. 2. Results indicate no marked inositol effect on learning, memory, or behavior. There was a suggestion of an effect of chronic inositol in reducing cage-induced repetitive behavior as indicated by increased switching between modes of behavior, and reduction in length of longest behavioral about. Furthermore inositol may increase time spent in environmentally- rather than self-oriented behavior. 3. Previous behavioral studies of inositol were performed in rats, which maintain low brain inositol levels compared to primates, including humans. The present study demonstrates the feasibility of primate behavioral studies with inositol, and shows the need for longer time experiments and increased variety of behavioral tests.
Assuntos
Inositol/farmacologia , Memória/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Macaca mulatta , Atividade Motora/efeitos dos fármacosRESUMO
Exposure to the nerve agent soman, an irreversible cholinesterase (ChE) inhibitor, results in changes in blood-brain barrier permeability attributed to its seizure-induced activity. However, smaller BBB changes may be independent of convulsions. Such minor injury may escape detection. A nonneuroinvasive neurovirulent Sindbis virus strain (SVN) was used as a marker for BBB permeability. Peripheral inoculation of mice with 2 x 10(3) plaque forming units (PFU) caused up to 10(5) PFU/ml viremia after 24 hours with no signs of central nervous system (CNS) infection and with no virus detected in brain tissue. Intra-cerebral injection of as low as 1-5 PFU of the same virus caused CNS infection, exhibited 5-7 days later as hind limb paralysis and death. Soman (0.1-0.7 of the LD50) was administered at peak viremia (1 day following peripheral inoculation). Sublethal soman exposure at as low as 0.1 LD50 resulted in CNS infection 6-8 days following inoculation in 30-40% of the mice. High virus titer were recorded in brain tissue of sick mice while no virus was detected in healthy mice subjected to the same treatment. No changes in the level of viremia or changes in viral traits were observed in the infected mice. The reversible anticholinesterases physostigmine (0.2 mg/kg, s.c.) and pyridostigmine (0.4 mg/kg, i.m.) injected at a dose equal to 0.1 LD50, induced similar results. Thus, both central and peripheral anticholinesterases (anti-ChEs) induce changes in BBB permeability sufficient to allow, at least in some of the mice, the invasion of this otherwise noninvasive but highly neurovirulent virus. This BBB change is probably due to the presence of cholinesterases in the capillary wall. SVN brain invasion served here as a highly sensitive and reliable marker for BBB integrity.
Assuntos
Infecções por Alphavirus/sangue , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/virologia , Inibidores da Colinesterase/toxicidade , Sindbis virus , Soman/toxicidade , Infecções por Alphavirus/virologia , Animais , Barreira Hematoencefálica/fisiologia , Doenças do Sistema Nervoso Central/virologia , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Camundongos , Camundongos Endogâmicos ICR , Permeabilidade/efeitos dos fármacos , Fisostigmina/toxicidade , Brometo de Piridostigmina/toxicidade , Viremia/sangue , Viremia/virologiaRESUMO
A paired discrimination (PD) task in which visual and spatial discrimination trials were combined is offered as a method for the evaluation of drug effects on various behavioral parameters. Acquisition of the PD task is characterized by six different parameters simultaneously recorded each session. Analysis of memory requirements suggest that intact reference memory is involved in the performance of both types of trials while working memory is involved only in the performance of the spatial trial. Benactyzine (1-4 mg/kg), an anticholinergic drug, was tested for its effects on visual and spatial tasks presented either separately or in the PD combination. Benactyzine-induced mydriasis was also determined for its possible role in photophobic-induced errors. Benactyzine was found to differentially increase the number of errors performed during the spatial but not during the visual trials. The data are in accord with earlier finding of specific cholinergic involvement in working memory processes. Thus, low doses of benactyzine, and the PD task, can prove useful in the cognitive analysis of cholinergic hypofunction and its reversal by memory-enhancing drugs.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Visão Ocular/efeitos dos fármacos , Animais , Benactizina/farmacologia , Sinais (Psicologia) , Aprendizagem por Discriminação , Masculino , Memória/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Pupila/efeitos dos fármacos , RatosRESUMO
Working and reference memory processes were simultaneously evaluated during the performance of a paired discrimination (PD) task in which visual and spatial discrimination trials were combined within the same session. Atropine (1 and 5 mg/kg), scopolamine (0.02-0.20 mg/kg), benactyzine (1-4 mg/kg), trihexyphenidyl (1-10 mg/kg), and aprophen (5-20 mg/kg) were all found to increase the number of errors performed by overtrained rats during the spatial but not during the visual trials. Although all the anticholinergic drugs tested induced specific working memory impairment at low doses, they differentially affected other, simultaneously recorded, behavioral parameters. Thus, while atropine affected most of the recorded parameters, aprophen induced only a mild effect. Benactyzine was found to have the most specific effect on working memory, with only minimal side effects, a combination that supports its use as the preferred psychopharmacological model of working memory impairment.
Assuntos
Antagonistas Colinérgicos/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Animais , Atropina/farmacologia , Comportamento Animal/efeitos dos fármacos , Benactizina/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Ratos , Ratos Sprague-Dawley , Escopolamina/farmacologia , Triexifenidil/farmacologiaRESUMO
Previously, we reported an ability of NE to promote processes of plasticity in neuroblastoma cells, as observed by morphological changes such as an elongated granule-rich cell body and neuritegenesis, in addition to a progressive decrease in the pluripotent marker Oct4 and an increase in the growth cone marker GAP-43. This was accompanied by the induction of three plasticity genes forming a functional cluster, the cell adhesion molecule L1 (CAM-L1), laminin, and CREB, all involved in neuronal plasticity and neurite outgrowth. In the present study, we hypothesized that the regulation of CAM-L1, laminin, and CREB/pCREB by NE could mediate processes of plasticity in the mode of action of antidepressants, as well as in the long-term effects of stress, in rats, given the association of both with NE alterations and neuronal plasticity. In the first experiment, rats were chronically administered with antidepressants (21 days). In the second experiment, rats were exposed to chronic stress and examined 4 months later, a model shown to exhibit behavioral indices of stress. We found brain region-specific alterations in mRNA and protein levels of CAM-L1, laminin, and pCREB in rats chronically treated with the noradrenergic antidepressant desipramine and, to a lesser extent, in those treated with fluoxetine. Stressed rats presented a decrease in CAM-L1, laminin, and pCREB, specifically in brain areas implicated in stress. Our findings suggest that noradrenergic-regulated plasticity genes such as CAM-L1, laminin, and CREB play an important role both in stress and in the treatment of depression.
Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Laminina/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Estresse Psicológico/metabolismo , Animais , Antidepressivos Tricíclicos/farmacologia , Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Desipramina/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Laminina/genética , Masculino , Molécula L1 de Adesão de Célula Nervosa/genética , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
A conditioned emotional response (CER) paradigm was presented to two groups of rats during intracranial self-stimulation (ICSS). One group bar pressed for medial forebrain bundle (MFB) stimulation reward; the other group bar pressed for septal stimulation reward. The MFB ICSS was found to be suppressed by the CER procedure, but this procedure failed to suppress septal ICSS. This difference between the two sites was found only when both MFB and septal ICSS current intensities were available at their optimal levels. When ICSS current intensities were lowered to either threshold or medium level, both groups exhibited the CER suppression effect. The animals were also tested for a possible analgesic effect produced by the ICSS. The MFB stimulation was found to produce some degree of analgesia, but septal stimulation failed to produce any analgesic effect. Thus, the possibility that the attenuation of the CER suppression effect in the septal group was due to analgesia was excluded. The difference in MFB and septal ICSS behavior during the presentation of the aversive stimulus suggested a possible qualitative distinction between the reward functions of these two sites, and a possible fear-reduction property of the septal area.
Assuntos
Condicionamento Psicológico/fisiologia , Medo/fisiologia , Feixe Prosencefálico Mediano/fisiologia , Vias Neurais/fisiologia , Autoestimulação/fisiologia , Núcleos Septais/fisiologia , Animais , Estimulação Elétrica , Emoções/fisiologia , Hipotálamo/fisiologia , Masculino , Nociceptores/fisiologia , Ratos , Ratos Endogâmicos , Limiar SensorialRESUMO
Corticosterone or placebo sustained-release pellets (4 pellets of 200 mg each, released over 90 days) were implanted subcutaneously in young Fischer-344 rats, fed with either regular food or with food containing 860 ppm of nimodipine. Following 2 weeks of treatment, the habituation of the rats to a new environment was studied. On the first test day, placebo-implanted rats explored the new environment and exhibited a characteristic habituation. On the second test day, 48 hr later, low activity was measured in the already familiar environment. This habituation was absent in corticosterone-implanted rats fed with regular food. However, corticosterone-implanted rats fed with food containing nimodipine behaved during the second test similarly to the placebo-implanted group. The data indicated that the behavioral deficit, induced in Fischer-344 rats by the high corticosterone levels, was reversed by the nimodipine treatment. Thus, nimodipine may be useful in counteracting certain prolonged stress-related cognitive impairments.
Assuntos
Corticosterona/farmacologia , Habituação Psicofisiológica/efeitos dos fármacos , Nimodipina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Placebos , RatosRESUMO
Apolipoprotein-E-deficient mice provide a useful model system for studying the role of apolipoprotein E (apoE) in brain function. In the present study, we characterized the cholinergic function of these mice and the extent of phosphorylation of their cytoskeletal protein tau. Morris water maze tasks revealed deficits in working memory that were accompanied by a specific decrease in hippocampal and cortical choline acetyltransferase activities. Immunoblot experiments utilizing native and dephosphorylated tau and antibodies directed against specific phosphorylated and unphosphorylated tau epitopes revealed that tau of the apoE-deficient mice is hyperphosphorylated. These results show that apoE-deficient mice have cognitive cholinergic and cytoskeletal derangements and point out the importance of this model for studying the role of apoE in neuronal function.
Assuntos
Apolipoproteínas E/deficiência , Transtornos Cognitivos/genética , Cognição , Memória , Proteínas tau/metabolismo , Animais , Colina O-Acetiltransferase/metabolismo , Lobo Frontal/enzimologia , Hipocampo/enzimologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , FosforilaçãoRESUMO
Bioscavengers of organophophates (OP) have been examined as potential substitutes for the currently approved drug treatment against OP toxicity. The present work was designed to assess the ability of butyrylcholinesterase, purified from human serum (HuBChE), to prevent the toxicity induced by soman and VX in rhesus monkeys. The consistency of the data across species was then evaluated as the basis for the extrapolation of the data to humans. The average mean residence time of the enzyme in the circulation of monkeys following an intravenous loading was 34 hr. High bioavailability of HuBChE in blood (>80%) was demonstrated after intramuscular injection. A molar ratio of HuBChE:OP approximately 1.2 protected against an i.v. bolus injection of 2.1 x LD50 VX, while a ratio of 0.62 was sufficient to protect monkeys against an i.v. dose of 3.3 x LD50 of soman, with no additional postexposure therapy. A remarkable protection was also seen against soman-induced behavioral deficits detected in the performance of a spatial discrimination task. The consistency of the results across several species offers a reliable prediction of both the stoichiometry of the scavenging and the extent of prophylaxis with HuBChE against nerve agent toxicity in humans.
Assuntos
Butirilcolinesterase/uso terapêutico , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Compostos Organotiofosforados/toxicidade , Soman/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Butirilcolinesterase/sangue , Butirilcolinesterase/metabolismo , Substâncias para a Guerra Química/metabolismo , Inibidores da Colinesterase/metabolismo , Humanos , Injeções Intramusculares , Injeções Intravenosas , Dose Letal Mediana , Macaca mulatta , Modelos Biológicos , Compostos Organotiofosforados/metabolismo , Intoxicação/prevenção & controle , Distribuição Aleatória , Soman/metabolismo , Comportamento Espacial/efeitos dos fármacos , Estatística como AssuntoRESUMO
The peripherally acting cholinesterase inhibitor pyridostigmine was widely used during the Gulf War as a pretreatment against possible chemical warfare attack. Following consistent reports on long-term illness among Gulf War veterans, pyridostigmine was examined for its possible long-term effects. These effects were suggested to be induced by the combination of pyridostigmine administration and stress exposure that allowed this quaternary compound to enter the brain through stress induced changes in blood-brain barrier (BBB) permeability. Recently, pyridostigmine administration was demonstrated to inhibit brain cholinesterase following acute stress in mice. However, the effect was not replicated under similar conditions in guinea pigs. Because of the significant implication of these findings, we tested brain cholinesterase (ChE) inhibition following the administration of pyridostigmine, or the tertiary carbamate physostigmine, with or without stress in mice. Different experiments were performed to examine the contribution of gender, age (young and adults), stress (type and intensity), or strain (CD-1 and FVB/n) parameters. No inhibition of brain ChE was detected in any of these experiments. At the same time, physostigmine induced the expected decrease in brain ChE in all the experiments. Thus, we could not replicate the findings that suggest pyridostigmine can affect brain cholinesterase following stress.
Assuntos
Encéfalo/enzimologia , Inibidores da Colinesterase/farmacologia , Brometo de Piridostigmina/farmacologia , Estresse Fisiológico/enzimologia , Animais , Colinesterases/metabolismo , Temperatura Baixa , Feminino , Masculino , Camundongos , Fisostigmina/farmacologia , Estresse Fisiológico/etiologia , NataçãoRESUMO
Benzodiazepines, mainly diazepam, are commonly used as anticonvulsants in the treatment of organophosphate casualties. Although very effective, diazepam usually is not used in prophylactic treatments because of its adverse effects on task performance and its abuse liability. Benzodiazepine (BZ) partial agonists are unique in that they are able to occupy all the population of a given receptor without eliciting the maximal physiological response. The BZ receptor agonistic occupancy was found to differ among the various physiological responses in the following order: antipanic > anticonvulsion > sedation > muscle relaxation. Thus, partial agonists, by the use of which controlled levels of agonistic activity can be achieved, might serve as effective anticonvulsants, with fewer side-effects. Bretazenil, a partial agonist, was found to counteract metrazol-induced convulsions in rats. At the anticonvulsive doses (125-250 microg x kg(-1), i.p.) bretazenil, in combination with pyridostigmine (100 microg x kg(-1), i.m.) and aprophen (4 mg x kg(-1), i.m.), conferred prophylactic protection against sarin and soman poisoning (protective ratios 2.6 and 2.1, respectively). Relevant doses of bretazenil (50-400 microg x kg(-1), i.p.) also were tested for general behavioural effects in the open field and for its anti-anxiety properties in the plus maze. The incapacitation was much lower compared with diazepam. Bretazenil should be considered as a candidate for incorporating into a prophylactic mixture as a central nervous system protectant, with significant advantages concerning incapacitation.