RESUMO
Mice were trained in a passive (foot shock)avoidance task. When administered after training, the stimulants caffeine or nicotine blocked amnesia for the task that had been produced by injections of the protein synthesis inhibitor anisomycin given prior to training. With foot shock at a higher intensity, anisomycin did not produce amnesia by itself, but the administration of the depressants chloral hydrate or sodium phenobarbital after training did cause amnesia. Stimulants and depressants did not have an appreciable influence on the overall degree of protein synthesis inhibition produced by anisomycin. The results support the hypothesis that arousal after training is an important factor in the conversion of short-term to long-term memory.
Assuntos
Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Memória/efeitos dos fármacos , Pirrolidinas/farmacologia , Animais , Cafeína/farmacologia , Hidrato de Cloral/farmacologia , Interações Medicamentosas , Masculino , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Nicotina/farmacologia , Fenobarbital/farmacologiaRESUMO
Inhibition of brain protein synthesis by anisomycin and acetoxycycloheximide was studied in mice for its biochemical and behavioral effects. By employing both drugs in low doses in a series of injections, we were able to maintain inhibition of protein synthesis of 80% or greater for up to 14 hr without causing detectable permanent physiological impairment. The drugs were employed as amnestic agents in mice trained to avoid footshock in a T-maze. As the duration of inhibition increased, the percentage of mice classed as amnesic increased. This amnesia could be reduced by increasing (a) the rate of acquisition, or (b) the number of training trials. Anisomycin was shown to cause a significant degree of amnesia for the escape component as well as the avoidance component of the learning. A single injection of anisomycin given 15 min prior to training did not cause significant changes in the acquisition or retention of avoidance conditioning, when comparison was made with saline-injected controls. Only additional injections given after training to prolong inhibition caused amnesia. Thus, those injections critical in obtaining amnesia were given at a time at which interference with acquisition could not have occurred, so the results bear clearly on memory processes.
Assuntos
Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Cicloeximida/análogos & derivados , Memória/efeitos dos fármacos , Pirrolidinas/farmacologia , Animais , Encéfalo/metabolismo , Cicloeximida/farmacologia , Depressão Química , Aprendizagem por Discriminação/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Masculino , Memória/fisiologia , Camundongos , Modelos Biológicos , Proteínas do Tecido Nervoso/biossínteseRESUMO
This study utilizes a pole jump active avoidance task to investigate the effects of protein synthesis on memory formation. An extinction training procedure for this task is also described. Amnesia for extinction is produced by inhibition of protein synthesis and is also demonstrated by active responding, so it is clear that there is no general impairment sufficient to disrupt motor skill, motivation, or retrieval of stored memories. It was found that while inhibition of protein synthesis in brain for 2 hr did not produce amnesia, inhibition for 6 to 8 hr did. These results demonstrate that for both shock-motivated learning and non-shock motivated extinction learning, the duration of inhibition of protein synthesis is important in determining whether amnesia occurs. We conclude that inhibition of cerebral protein synthesis can best account for amnesia induced by anisomycin, cycloheximide, and acetoxycycloheximide.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/metabolismo , Extinção Psicológica/efeitos dos fármacos , Memória/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Animais , Anisomicina/farmacologia , Encéfalo/efeitos dos fármacos , Cicloeximida/farmacologia , Depressão Química , Masculino , Camundongos , Retenção Psicológica/efeitos dos fármacos , Fatores de TempoRESUMO
The effects of peptides derived from ACTH on the formation of long-term memory have been investigated in male mice. Post-training administration of ACTH 4-10-L-Phe-7 (ACTH-L) improved retention for both passive and active avoidance tasks. Administration of ACTH 4-10-D-Phe-7 (ACTH-D) impaired retention for both tasks. The optimum dose for ACTH-L was about 0.3 mg/kg; the optimum dose for ACTH-D was in the range of 1.0-3.0 mg/kg. Using the passive avoidance task, it was shown that either drug had to be administered within 60 min of training to be highly effective. Amnesia produced by anisomycin (Ani), an inhibitor of protein synthesis, was lessened by ACTH-L and increased by ACTH-D, ACTH-D opposed the memory facilitating effects of ACTH-L. Using intact mice, ACTH-L or ACTH-D did not significantly change the incorporation of valine into protein, nor did these peptides influence the inhibition of protein synthesis caused by anisomycin. The results show that ACTH may play a major role in memory processing, perhaps by facilitating essential protein synthesis at sites specific for the memory being established.
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Memória/efeitos dos fármacos , Amnésia/induzido quimicamente , Amnésia/metabolismo , Animais , Anisomicina , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Fragmentos de Peptídeos/farmacologia , Estereoisomerismo , Fatores de Tempo , Valina/metabolismoRESUMO
A series of biochemical and behavioral experiments tested the hypothesis that anisomycin (ANI), a protein synthesis inhibitor, produced decrements in long-term memory by raising free tyrosine levels and by the accumulation of catecholamines (CAs) rather than by its primary effect on protein synthesis. We compared the effects of ANI and three catecholamine synthesis inhibitors (CAIs)--diethyldithiocarbamic acid, alpha-methyl-p-tyrosine, and tetrabenazine--on cerebral concentrations of tyrosine and CAs and on the rate of accumulation of CAs. ANI had a relatively small effect, whereas the CAIs resulted in large reductions. When ANI and a CAI were used in combination, effects on CA levels were determined mainly by the CAI. The amnestic effects of ANI and the CAIs were also compared across seven experimental paradigms. Pretraining administration of any of the four drugs could result in amnesia for passive avoidance training, but only when training was weak. With an increase in training strength, a series of three injections of ANI (one pre- and two post-training) caused amnesia, but a similar series of CAI injections did not. Substituting one CAI injection for the second of three successive ANI injections did not cause amnesia, but substituting cycloheximide, another protein synthesis inhibitor, resulted in amnesia. With an active avoidance test, ANI caused amnesia while AMPT did not; d-amphetamine blocked the amnestic effect of ANI but caused amnesia in AMPT injected mice. Whereas ANI lengthened the temporal gradient over which electroconvulsive shock produced amnesia, AMPT or DDC did not. DDC caused only transient amnesia for passive avoidance training, while the amnestic effect of ANI remained constant at 24-hr and 1-week retention tests. We conclude that ANI and CAIs have distinctly different abilities to produce amnesia. These experiments provide additional support for the hypothesis that protein synthesis is required for formation of long-term memory.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Catecolaminas/biossíntese , Biossíntese de Proteínas , Amnésia/induzido quimicamente , Animais , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Cicloeximida/farmacologia , Dextroanfetamina/farmacologia , Dopamina/biossíntese , Eletrochoque , Masculino , Camundongos , Norepinefrina/biossíntese , Espectrometria de Fluorescência , Fatores de Tempo , Tirosina/metabolismoAssuntos
Amnésia/induzido quimicamente , Aprendizagem da Esquiva/efeitos dos fármacos , Cicloeximida/farmacologia , Memória/efeitos dos fármacos , Sobreaprendizagem/efeitos dos fármacos , Animais , Química Encefálica/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Depressão Química , Eletrochoque , Reação de Fuga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/biossíntese , Tempo de Reação/efeitos dos fármacos , Fatores de TempoAssuntos
Antibacterianos/farmacologia , Encéfalo/metabolismo , Cicloeximida/farmacologia , Memória/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Amnésia/metabolismo , Animais , Aprendizagem da Esquiva , Compostos de Benzil/farmacologia , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletrochoque , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pirrolidinas/farmacologiaAssuntos
Corticosteroides/farmacologia , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Retenção Psicológica/efeitos dos fármacos , Animais , Anisomicina/antagonistas & inibidores , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/metabolismo , Corticosterona/sangue , Corticosterona/farmacologia , Cicloeximida/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Hidrocortisona/farmacologia , Masculino , Camundongos , Proteínas do Tecido Nervoso/biossínteseRESUMO
Antibody immunoconjugates were made with native and recombinant forms of the type-I ribosome inactivating protein from barley (BRIP) and with three recombinant BRIP (rBRIP) analogs engineered to contain a unique cysteine residue near the C terminus (at amino acid 256, 270, or 277). rBRIP and all three cysteine analogs (rBRIPc256, rBRIPc270, and rBRIPc277) were produced in E. coli, with yields of soluble protein as high as 1 g/L, and were as active as native BRIP in inhibiting protein synthesis in vitro. Interestingly, the position of the engineered cysteine influenced not only the efficiency of conjugation to antibody but also the efficacy and disulfide bond stability of the immunoconjugates. Anti-CD5 antibody conjugates prepared with native and rBRIP were relatively inactive against antigen-positive target cells, while the conjugate made with rBRIPc277 was 5-fold more cytotoxic. Anti-CD7 antibody conjugates made with rBRIPc277 or rBRIPc270 also exhibited improved potency and stability compared to the conjugate with native BRIP. These results indicate that engineering a cysteine residue into selected positions near the C-terminus of a type-IRIP such as BRIP can improve immunoconjugate yield, disulfide bond stability, and potency.