RESUMO
The principal raw material of modern U.S. agriculture is fossil fuel, whereas the labor input is relatively small (about 9 hours per crop acre). As agriculture is dependent upon fossil energy, crop production costs will also soar when fuel costs increase two- to fivefold. A return of 2.8 kcal of corn per 1 kcal of fuel input may then be uneconomical. Green revolution agriculture also uses high energy crop production technology, especially with respect to fertilizers and pesticides. While one may not doubt the sincerity of the U.S. effort to share its agricultural technology so that the rest of the world can live and eat as it does, one must be realistic about the resources available to accomplish this mission. In the United States we are currently using an equivalent of 80 gallons of gasoline to produce an acre of corn. With fuel shortages and high prices to come, we wonder if many developing nations will be able to afford the technology of U.S. agriculture. Problems have already occurred with green revolution crops, particularly problems related to pests (57). More critical problems are expected when there is a world energy crisis. A careful assessment should be made of the benefits, costs, and risks of high energy-demand green revolution agriculture in order to be certain that this program will not aggravate the already serious world food situation (58). To reduce energy inputs, green revolution and U.S. agriculture might employ such alternatives as rotations and green manures to reduce the high energy demand of chemical fertilizers and pesticides. U.S. agriculture might also reduce energy expenditures by substituting some manpower currently displaced by mechanization. While no one knows for certain what changes will have to be made, we can be sure that when conventional energy resources become scarce and expensive, the impact on agriculture as an industry and a way of life will be significant. This analysis is but a preliminary investigation of a significant agricultural problem that deserves careful attention and greater study before the energy situation becomes more critical.
RESUMO
The matrix protein p17gag (MA) is a product of proteolytic cleavage of the gag gene encoded polyprotein (pr55gag) and is formed when HIV particles undergo the process of maturation. The MA protein is associated with the inner surface of the viral membrane and determines the overall shape of the virion. Previous studies have shown the existence of trimers of MA in solution and in the crystalline state. Here, we used molecular modelling methods to identify feasible interactions between pairs of MA trimers and have related this to structural data from electron microscopy. A systematic search docking procedure was able to identify many energetically favourable conformations for a pair of trimers, including some which have been previously reported. These conformations were used to generate several networks of MA trimers, which were then evaluated against structural observations of the MA network. The model suggested here provides a good match with experimental data such as the spacing between gag protein rings, the number and disposition of glycoprotein (gp41-gp120) knobs and the number of copies of MA in a virus particle. It also rationalizes the observed distribution of sizes of virus particles and is consistent with the presence of icosahedral organisation in mature HIV. Energy minimisation performed with explicit water and counter ions, was used to identify residues participating in inter-trimer interactions. The nature of these interactions is discussed in relation to the conservation of these residues in reported variants of the HIV and SIV MA protein sequences.
Assuntos
Simulação por Computador , Produtos do Gene gag/química , Produtos do Gene gag/ultraestrutura , Antígenos HIV/química , Antígenos HIV/ultraestrutura , HIV/química , Modelos Moleculares , Proteínas Virais , Cristalografia por Raios X , Produtos do Gene gag/genética , Produtos do Gene gag/metabolismo , HIV/genética , HIV/crescimento & desenvolvimento , HIV/fisiologia , Antígenos HIV/genética , Antígenos HIV/metabolismo , Ligação de Hidrogênio , Microscopia Eletrônica , Ligação Proteica , Estrutura Quaternária de Proteína , Solventes , Eletricidade Estática , Termodinâmica , Montagem de Vírus , Produtos do Gene gag do Vírus da Imunodeficiência HumanaRESUMO
It is suggested that the immune system may play a role in the etiology of age-associated cognitive decline and/or Alzheimer's disease. The relationship between brain-reactive antibodies (BRA) and age-associated cognitive dysfunction is reviewed and discussed. A parallel relationship between BRA increases with age and decline of avoidance learning capacity is described in mouse models. Transfer of immunity from old to young mice was found to accelerate both age-related formation of brain-reactive antibodies and age-related decline of avoidance learning capacity. Short-lived mouse genotypes with accelerated autoimmunity were found to show accelerated age-related declines in their ability to acquire an avoidance response when compared with nonautoimmune mice. Overall, these findings suggest that the immune system could be an important target for development of intervention strategies aimed at extending the intellectually competent period of life. Mice in which autoimmunity is accelerated may be useful as models for the development of such interventions.
Assuntos
Envelhecimento/imunologia , Doenças Autoimunes/complicações , Deficiências da Aprendizagem/imunologia , Envelhecimento/fisiologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/fisiopatologia , Animais , Autoanticorpos/metabolismo , Humanos , Deficiências da Aprendizagem/fisiopatologia , Macaca , RatosRESUMO
This article presents a discussion of some key considerations in the measurement of age-related changes in psychomotor function of mice. We illustrate that "standard" measures of psychomotor performance, such as running speed on a rotorod task, are highly sensitive to practice effects. Examples are cited in which failure to assess practice effects can influence conclusions regarding the magnitude and rate of change in psychomotor capacity as a function of age. A second set of examples is focused on estimating the effect of an experimental intervention, caloric restriction, on age-related changes in psychomotor performance. These examples show that psychomotor performance at a given age may vary directly, and reversibly, with the level of caloric intake. Independent of such reversible effects, the level of caloric intake can also modulate the rate of change in capacity as a function of age. It is concluded that reversible, short-term effects must be considered in estimating the effect of an experimental intervention on the rate of age-associated change in psychomotor function.
Assuntos
Envelhecimento/fisiologia , Ingestão de Energia/fisiologia , Camundongos Endogâmicos/genética , Desempenho Psicomotor/fisiologia , Envelhecimento/genética , Animais , Fatores de Confusão Epidemiológicos , Genótipo , Aprendizagem/fisiologia , Camundongos , Atividade Motora/fisiologia , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Old F-344 rats were given endurance training over a 10-week period on a motorized treadmill. This treatment resulted in substantial heart-to-body weight ratio increases, indicative of effective training. To determine whether endurance training might alter some of the known immune system and cognitive changes observed during aging, exercised old rats were compared to nonexercised old and young controls on three variables: in vivo antigen-specific immune activity, brain-reactive antibody formation, and spatial memory. The exercise training did not influence any of these measures in the old rats. Both groups of old rats showed poorer antibody response to a specific antigen, more brain-reactive antibody formation, and poorer spatial memory than the young controls. There was, however, a significant relationship between brain-reactive antibody formation and spatial memory performance, regardless of training condition.
Assuntos
Envelhecimento/fisiologia , Formação de Anticorpos , Autoimunidade/fisiologia , Encéfalo/imunologia , Memória/fisiologia , Condicionamento Físico Animal , Envelhecimento/imunologia , Animais , Antígenos/imunologia , Hemocianinas/imunologia , Imunoglobulina G/biossíntese , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
Coenzyme Q (CoQ) was previously demonstrated in vitro to indirectly act as an antioxidant in respiring mitochondria by regenerating alpha-tocopherol from its phenoxyl radical. The objective of this study was to determine whether CoQ has a similar sparing effect on alpha-tocopherol in vivo. Mice were administered CoQ10 (123 mg/kg/day) alone, or alpha-tocopherol (200 mg/kg/day) alone, or both, for 13 weeks, after which the amounts of CoQ10, CoQ9 and alpha-tocopherol were determined by HPLC in the serum as well as homogenates and mitochondria of liver, kidney, heart, upper hindlimb skeletal muscle and brain. Administration of CoQ10 and alpha-tocopherol, alone or together, increased the corresponding levels of CoQ10 and alpha-tocopherol in the serum. Supplementation with CoQ10 also elevated the amounts of the predominant homologue CoQ9 in the serum and the mitochondria. A notable effect of CoQ10 intake was the enhancement of alpha-tocopherol in mitochondria. alpha-Tocopherol administration resulted in an elevation of alpha-tocopherol content in the homogenates of nearly all tissues and their mitochondria. Results of this study thus indicate that relatively long-term administration of CoQ10 or alpha-tocopherol can result in an elevation of their concentrations in the tissues of the mouse. More importantly, CoQ10 intake has a sparing effect on alpha-tocopherol in mitochondria in vivo.
Assuntos
Dieta , Mitocôndrias/efeitos dos fármacos , Ubiquinona/farmacologia , Vitamina E/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Distribuição Tecidual , Ubiquinona/farmacocinética , Vitamina E/metabolismo , Vitamina E/farmacocinéticaRESUMO
The objective of this study was to test the hypothesis that the widely observed age-associated increase in the amounts of macromolecular oxidative damage is due to an elevation in the availability of redox-active iron, that is believed to catalyze the scission of H2O2 to generate the highly reactive hydroxyl radical. Concentrations of bleomycin-chelatable iron and nonheme iron were measured in various tissues and different regions of the brain of mice fed on ad libitum (AL) or a calorically restricted (to 60% of AL) diet at different ages. The concentrations of these two pools of iron varied markedly as a function of tissue, age, and caloric intake. There was no consistent ratio between the amounts of nonheme and the bleomycin-chelatable iron pools across these conditions. Nonheme iron concentration increased with age in the liver, kidney, heart, striatum, hippocampus, midbrain and cerebellum of AL animals, whereas bleomycin-chelatable iron increased significantly with age only in the liver. Amounts of both nonheme and bleomycin-chelatable iron remained unaltered during aging in the cerebral cortex and hindbrain of AL mice. Caloric restriction had no effect on iron concentration in the brain or heart, but caused a marked increase in the concentration of both bleomycin-chelatable and nonheme iron in the liver and the kidney. The results do not support the hypothesis that accumulation of oxidative damage with age, or its attenuation by CR, are associated with corresponding variations in redox-active iron.
Assuntos
Envelhecimento/metabolismo , Bleomicina/farmacologia , Quelantes de Ferro/farmacologia , Ferroproteínas não Heme/metabolismo , Animais , Encéfalo/metabolismo , Ingestão de Energia , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Especificidade de ÓrgãosRESUMO
The purpose of this study was to understand the nature of the causes underlying the senescence-related decline in skeletal muscle mass and performance. Protein and lipid oxidative damage to upper hindlimb skeletal muscle mitochondria was compared between mice fed ad libitum and those restricted to 40% fewer calories--a regimen that increases life span by approximately 30-40% and attenuates the senescence-associated decrement in skeletal muscle mass and function. Oxidative damage to mitochondrial proteins, measured as amounts of protein carbonyls and loss of protein sulfhydryl content, and to mitochondrial lipids, determined as concentration of thiobarbituric acid reactive substances, significantly increased with age in the ad libitum-fed (AL) C57BL/6 mice. The rate of superoxide anion radical generation by submitochondrial particles increased whereas the activities of antioxidative enzymes superoxide dismutase, catalase, and glutathione peroxidase in muscle homogenates remained unaltered with age in the AL group. In calorically-restricted (CR) mice there was no age-associated increase in mitochondrial protein or lipid oxidative damage, or in superoxide anion radical generation. Crossover studies, involving the transfer of 18- to 22-month-old mice fed on the AL regimen to the CR regimen, and vice versa, indicated that the mitochondrial oxidative damage could not be reversed by CR or induced by AL feeding within a time frame of 6 weeks. Results of this study indicate that mitochondria in skeletal muscles accumulate significant amounts of oxidative damage during aging. Although such damage is largely irreversible, it can be prevented by restriction of caloric intake.
Assuntos
Envelhecimento , Ingestão de Energia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Fatores Etários , Animais , Peso Corporal , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Compostos de Sulfidrila/análise , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
This prospective study defines the clinical and biochemical features of acromegaly in a large cohort of patients. There was no difference in sex distribution, and for men and women the mean ages at diagnosis (40 +/- 12 and 40 +/- 14 yr, respectively) were similar. Nearly three-quarters of patients were overweight and some 12% severely overweight; the frequency and severity of obesity also was not different between the sexes. Half of patients were hypertensive or were taking anti-hypertensive drugs. Neither GH nor insulin levels were significantly different between normotensive and hypertensive patients. Acral growth and facial coarsening, soft tissue swelling, and excessive perspiration were present in the majority (98%) of patients. Mean serum GH, Sm-C, and PRL levels did not differ between the sexes. Sm-C levels correlated with mean GH concentration (r = 0.31, p < 0.001), both variables inversely related to age. With each decade of life, mean GH and Sm-C levels declined by 7.6 +/- 0.2 ng/mL and 0.5 +/- 0.2 U/mL, respectively. Impaired glucose tolerance was diagnosed in 36% and frank diabetes mellitus in 30% of patients. Hyperprolactinemia was noted in 18% of patients. Galactorrhea was noted in 43 (9%) patients, most of whom were female; the mean GH levels of patients with galactorrhea (60.1 +/- 13 ng/mL) were higher than those of patients without (35.4 +/- 2.6 ng/mL, p = 0.02). Acromegaly appears to afflict men and women equally with a preponderance of presentation in the fourth decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Acromegalia/fisiopatologia , Acromegalia/sangue , Acromegalia/complicações , Acromegalia/etiologia , Adenoma/complicações , Adolescente , Adulto , Idoso , Estatura , Peso Corporal , Estudos de Coortes , Feminino , Teste de Tolerância a Glucose , Hormônio do Crescimento/sangue , Humanos , Hiperprolactinemia/etiologia , Hipertensão/etiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicaçõesRESUMO
This study was conducted in order to test the concept that oxidative damage is associated with aging and may be a factor in the modulation of life span in response to variations in caloric intake. Mice fed a diet that was 40% lower in calories (DR) than the ad libitum fed (AL) animals exhibited a 43% extension in average life span and a 61% prolongation in mortality rate doubling time. A comparison of AL and DR mice at 9, 17 and 23 months of age indicated that the protein carbonyl content in the brain, heart and kidney increased with age and was significantly greater in the AL than DR group in each organ at each of the three ages. Mitochondrial state 4 or resting respiratory rate increased with age in the AL, but not the DR group, and was also relatively higher in the former. The rates of mitochondrial superoxide and hydrogen peroxide generation increased with age and were higher in the AL than DR mice in all the three organs at each age. In contrast, there was no clear-cut overall pattern of age-related or dietary-related changes in antioxidant defenses provided by superoxide dismutase, catalase and glutathione peroxidase. Results suggest that mechanisms of aging and life span shortening by enhanced caloric intake are associated with oxidative damage arising from corresponding changes in mitochondrial oxidant production. Protein carbonyl content, and mitochondrial O2.- and H2O2 generation may act as indices of aging.
Assuntos
Envelhecimento/metabolismo , Antioxidantes/metabolismo , Mitocôndrias/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/fisiologia , Animais , Peso Corporal/fisiologia , Ingestão de Energia , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Consumo de Oxigênio/fisiologia , Proteínas/metabolismoRESUMO
The objective of this study was to explore the role of molecular oxidative damage and caloric intake in the aging process. The concentration of 8-hydroxydeoxyguanosine (8-OHdG), a product of DNA oxidation, was compared in five different tissues of mice (skeletal muscle, brain, heart, liver and kidney) as a function of age and in response to dietary restriction. A comparison of 8- and 27-month-old mice indicated that the age-related increase in 8-OHdG concentration was greater in skeletal muscle, brain and heart, which are primarily composed of long-lived, post-mitotic cells, than in liver and kidney, which consist of slow-dividing cells. Dietary restricted (DR) mice kept on 60% caloric intake as compared to the ad libitum-fed (AL) mice showed a lower concentration in 8-OHdG content in all the tissues compared to AL mice. The DR-related amelioration of DNA oxidative damage was greater in the post-mitotic tissues compared to those undergoing slow mitoses. Results support the hypothesis that oxidative damage to long-lived post-mitotic cells may be a key factor in the aging process.
Assuntos
Envelhecimento/metabolismo , Dano ao DNA , Privação de Alimentos/fisiologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Encéfalo/metabolismo , DNA/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Ingestão de Energia , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous "benzodiazepine-like" endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Azidas/farmacologia , Benzodiazepinas/farmacologia , Flumazenil/farmacologia , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Amnésia/induzido quimicamente , Amnésia/prevenção & controle , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Escopolamina , Estimulação QuímicaRESUMO
The NZB/BlNJ (NZB) mice are an autoimmune-prone strain, known to develop brain-reactive antibodies in serum at much earlier chronological ages than normal mice. Measurement of locomotor activity in 8-10 month old C57BL/6 (C57) mice following the administration of either oxotremorine or physostigmine, revealed a biphasic response consisting of inhibition at small doses, but increased motor activity at large doses. In contrast, age-matched NZB mice exhibited little inhibition at the smaller doses, but had much greater increases in activity after the larger doses. Similarly, when compared to C57 mice, NZB mice were less sensitive to oxotremorine-induced salivation, diarrhea and visible tremors. Moreover, oxotremorine-induced hypothermia occurred at smaller doses in C57 mice than in NZB mice and was of a greater magnitude. Thus, at an age when NZB mice possess high levels of brain-reactive antibodies, and exhibit impairment in tests of learning/memory, these mice also show diminished responses in several tests of cholinomimetic-induced behavior and physiological alterations.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Oxotremorina/farmacologia , Fisostigmina/farmacologia , Envelhecimento/fisiologia , Animais , Encéfalo/fisiologia , Fibras Colinérgicas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Especificidade da EspécieRESUMO
RATIONALE: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. OBJECTIVES: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4"- and 4',4"-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. METHODS: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. RESULTS: All of the compounds displaced [3H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [3H]pirenzepine binding to muscarinic M1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs. CONCLUSIONS: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.
Assuntos
Antiparkinsonianos/metabolismo , Benzotropina/análogos & derivados , Benzotropina/metabolismo , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Cocaína/metabolismo , Inibidores da Captação de Dopamina/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Simportadores , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Benzotropina/química , Benzotropina/farmacologia , Cocaína/química , Cocaína/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptor Muscarínico M1 , Receptores Muscarínicos/metabolismo , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
The present study compared cocaine-induced hyperlocomotion and cocaine i.v. self-administration in DBA/2J and C57BL/6J mice. In the locomotor activity experiment, these strains were tested for hyperlocomotion after i.p. cocaine injection (0-60.0 mg/kg), using a Digiscan Animal Activity Monitoring System. In the cocaine i.v. self-administration experiment, they were compared for their ability to acquire and maintain cocaine self-administration in operant chambers with levers as the manipulanda. Animals were first trained to respond for food as a reinforcer (condensed milk solution); they were then submitted to surgical i.v. insertion of an in-dwelling catheter, and required to respond for i.v. cocaine (0.25-4.0 mg/kg per injection) as a reinforcer. DBA/2J mice showed significantly higher maximal cocaine-induced hyperlocomotion, more rapid acquisition of cocaine self-administration, and significantly lower rates of cocaine self-administration. Cocaine concentration in the brains of DBA/2J and C57BL/6J mice failed to differ following i.p. injection, suggesting that distribution factors were not involved in the differential responses to cocaine. Although not conclusive, this pattern of effects may suggest that cocaine has greater reinforcing efficacy in DBA/2J mice, confirming genetic make-up as a determinant factor in cocaine taking behavior.
Assuntos
Encéfalo/metabolismo , Cocaína/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Cocaína/metabolismo , Condicionamento Operante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , AutoadministraçãoRESUMO
The age-associated increase in oxidative damage in ad libitum-fed mice is attenuated in mice fed calorically restricted (CR) diets. The objective of this study was to determine if this effect results from a slowing of age-related accumulation of oxidative damage, or from a reversible decrease of oxidative damage by caloric restriction. To address these possibilities, crossover studies were conducted in C57BL/6 mice aged 15 to 22 months that had been maintained, after 4 months of age, on ad libitum (AL) or a 60% of AL caloric regimen. One half of the mice in these groups were switched to the opposite regimen of caloric intake for periods up to 6 weeks, and protein oxidative damage (measured as carbonyl concentration and loss of sulfhydryl content) was measured in homogenates of brain and heart. In AL-fed mice, the protein carbonyl content increased with age, whereas the sulfhydryl content decreased. Old mice maintained continuously under CR had reduced levels of protein oxidative damage when compared with the old mice fed AL. The effects of chronic CR on the carbonyl content of the whole brain and the sulfhydryl content of the heart were fully reversible within 3-6 weeks following reinstatement of AL feeding. The effect of chronic CR on the sulfhydryl content of the brain cortex was only partially reversible. The introduction of CR for 6 weeks in the old mice resulted in a reduction of protein oxidative damage (as indicated by whole brain carbonyl content and cortex sulfhydryl), although this effect was not equivalent to that of CR from 4 months of age. The introduction of CR did not affect the sulfhydryl content of the heart. Overall, the current findings indicate that changes in the level of caloric intake may reversibly affect the concentration of oxidized proteins and sufhydryl content. In addition, chronic restriction of caloric intake also retards the age-associated accumulation of oxidative damage. The magnitude of the reversible and chronic effects appears to be dependent upon the tissue examined and the nature of the oxidative alteration.
Assuntos
Envelhecimento/metabolismo , Ingestão de Energia , Proteínas/metabolismo , Animais , Peso Corporal , Encéfalo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Oxirredução , Compostos de Sulfidrila/análiseRESUMO
Effects of MK-801 and ketamine, N-methyl-D-aspartate (NMDA) receptor blockers, on cocaine-stimulated locomotor activity were investigated in male Swiss-Webster mice. MK-801 (0.25, 0.5, 1.0 and 2.5 mg/kg), ketamine (10, 25 and 50 mg/kg) or saline was injected 20 min before cocaine (5, 10 and 20 mg/kg i.p.). Locomotor activity was measured for 30 min immediately following cocaine treatment. All doses of the drugs were also tested for ability to depress or stimulate locomotor activity in the naive (no cocaine-treated) mice. Cocaine produced a dose-dependent increase in locomotor activity that was blocked dose-dependently by MK-801 or ketamine. The blockade by MK-801 was more prominent than by ketamine. Our results may suggest that cocaine-induced locomotor stimulation in mice is modulated via NMDA receptor mediated mechanisms.
Assuntos
Cocaína/antagonistas & inibidores , Inibidores da Captação de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Maleato de Dizocilpina/farmacologia , Ketamina/farmacologia , Masculino , Camundongos , Atividade Motora/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
Mice pretreated with the benzodiazepine antagonist, CGS 8216 (2.5, 10, or 40 mg/kg, i.p.) learned a T-maze discrimination to a fixed performance criterion more rapidly than vehicle-treated mice. In retention tests conducted one week later, the drug-treated groups had better first-trial recall and greater difficulty reversing the previously trained maze habit when compared with controls, suggesting improved memory for the previously trained maze habit. The enhanced acquisition and retention following CGS 8216 was similar to that observed previously with another benzodiazepine antagonist, flumazenil (Ro 15-1788). It is postulated that CGS 8216 and flumazenil could act at benzodiazepine receptors to antagonize a tonic inhibitory influence of endogenous, diazepam-like, benzodiazepine receptor ligands on memory processes.
Assuntos
Benzodiazepinas/antagonistas & inibidores , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Pirazóis/farmacologia , Animais , Reação de Fuga/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Valores de ReferênciaRESUMO
Separate age groups of autoimmune NZB/BINJ and non-autoimmune C57BL/BNNia mice were compared for habituation of locomotor activity and its retention over four separate testing sessions spaced at 24-hr intervals. A decline in locomotion (distance in cm) or in the time spent in the center zone as a function of sessions was taken to indicate retention for habituation to stimuli within the test apparatus. The time spent in the center zone decreased as a function of sessions in young and mature C57BL/6NNia mice but failed to show reliable between-session decreases in old (24-26-months) C57BL/6NNia mice. When compared with the old C57BL/6NNia mice, young NZB/BINJ mice showed similar impairments. Habituation of locomotion was present in all age groups of C57BL/6NNia mice, but absent in NZB/BINJ mice regardless of age. The retention impairments of 2-4 month old NZB/BINJ mice were attenuated when i.p. injections of 0.04-0.16 mg physostigmine/kg were given just following each habituation session. The effectiveness of physostigmine was substantially reduced when injections were delayed by 20 min or longer following each habituation session. The time-dependent reversal of the aged-like retention deficits by the cholinesterase inhibitor, physostigmine, suggests that cholinergic modulation of memory storage processes may be impaired in NZB/BINJ mice.
Assuntos
Envelhecimento/fisiologia , Autoimunidade/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Retenção Psicológica/fisiologia , Animais , Genótipo , Habituação Psicofisiológica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Fisostigmina/farmacologia , Retenção Psicológica/efeitos dos fármacos , Fatores de TempoRESUMO
The development of strategies for treatment of Alzheimer's disease and other age-associated dementias is an important goal of research in the neurosciences. It is suggested that advances in understanding of the etiology of those disorders would provide the most obvious avenues to development of preventative treatments. Research findings from both clinical investigations and studies of animal models are presented which suggest a neuroimmunologic component in age-associated dementia. Clinical studies suggest an association between dementia and brain-reactive autoantibodies in subsets of patients with Alzheimer's disease. Studies of mice suggest that: 1) when compared with normal genotypes, mutant mice with accelerated autoimmunity show learning and memory impairments at earlier chronological ages; 2) the learning and memory deficits of autoimmune and normal mice are qualitatively similar; 3) the behavioral deficits of normal aged and autoimmune mice are sensitive to similar pharmacologic interventions. Overall, these findings suggest that intervention strategies targeting the immune system might be useful in the treatment or prevention of aging-associated dementia. Autoimmune mice would be useful as models for the development and testing of such immune-based interventions.