RESUMO
Body fat serves as a storage compartment for lipophilic pollutants and affects the pharmacokinetics of many toxic chemicals. Understanding how body fat varies with gender, strain, and age may be essential for development of experimental models to study mechanisms of toxicity. Nuclear magnetic resonance (NMR)-based analysis serves as a noninvasive means of assessing proportions of fat, lean, and fluid in rodents over their lifetime. The aim of this study was to track changes in body composition of male and female Long-Evans (LE), Sprague-Dawley (SD), Fischer (F334), and Brown Norway (BN) rats from postweaning over a >2-yr period. Percent fat of preweaned LE and SD rats was markedly higher compared to the other strains. LE and SD strains displayed marked increases in body fat from weaning to 8 mo of age. Postweaned F344 male and females showed relatively low levels of percent fat; however, at 2 yr of age percent fat of females was equal to that of SD and LE in females. BN rats showed the highest levels of lean tissue and lowest levels of fat. Percent fat of the BN strain rose at the slowest rate as they aged. Percent fluid was consistently higher in males for all strains. Females tended to have higher percent fat than males in LE, SD, and F344 strains. Assessing changes in body fat as well as lean and fluid of various strains of male and female rats over their lifetime may prove useful in many research endeavors, including pharmacokinetics of lipophilic toxicants, mechanisms underlying obesity, and metabolic disorders.
Assuntos
Composição Corporal/genética , Ratos/fisiologia , Fatores Etários , Animais , Feminino , Estudos Longitudinais , Masculino , Ratos/genética , Ratos Endogâmicos BN/genética , Ratos Endogâmicos BN/fisiologia , Ratos Endogâmicos F344/genética , Ratos Endogâmicos F344/fisiologia , Ratos Long-Evans/genética , Ratos Long-Evans/fisiologia , Ratos Sprague-Dawley/genética , Ratos Sprague-Dawley/fisiologia , Fatores Sexuais , Especificidade da EspécieRESUMO
NEW FINDINGS: What is the central question of this study? How do lean and obese rats respond physiologically to caloric restriction? What is the main finding and its importance? Obese rats show marked benefits compared with lean animals. Reduced body fat is associated with improved longevity with caloric restriction (CR) in rodents. Little is known regarding effects of CR in genetically lean versus obese strains. Long-Evans (LE) and Brown Norway (BN) rats make an ideal comparison for a CR study because the percentage body fat of young adult LE rats is double that of BN rats. Male LE and BN rats were either fed ad libitum (AL) or were calorically restricted to 80 or 90% of their AL weight. The percentages of fat, lean and fluid mass were measured non-invasively at 2- to 4-week intervals. Metabolic rate and respiratory quotient were measured after 3, 6, 9 and 12 months of CR. Overall health was scored monthly. The percentage of fat of the LE strain decreased with CR, whereas the percentage of fat of the BN strain remained above the AL group for several months. The percentage of lean mass increased above the AL for both strains subjected to CR. The percentage of fluid was unaffected by CR. The average metabolic rate over 22 h of the BN rats subjected to CR was reduced, whereas that of LE rats was increased slightly above the AL group. The respiratory quotient of BN rats was decreased with CR. Overall health of the CR LE group was significantly improved compared with that of the AL group, whereas health of the CR BN rats was impaired compared with the AL group. Overall, the lean BN and obese LE strains differ markedly in fat utilization and metabolic response to prolonged CR. There appears to be little benefit of CR in the lean strain.
Assuntos
Composição Corporal , Peso Corporal , Restrição Calórica , Obesidade/metabolismo , Animais , Metabolismo Basal , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Long-EvansRESUMO
Setting exposure standards for environmental pollutants may consider the aged as a susceptible population but the few published studies assessing susceptibility of the aged to air pollutants are inconsistent. Episodic ozone (O3) is more reflective of potential exposures occurring in human populations and could be more harmful to the aged. This study used radiotelemetry to monitor heart rate (HR), core temperature (T(c)) and motor activity (MA) in adult (9-12 months) and senescent (20-24 months) male, Brown Norway rats exposed to episodic O3 (6 h/day of 1 ppm O3 for 2 consecutive days/week for 13 weeks). Acute O3 initially led to marked drops in HR and T(c). As exposures progressed each week, there was diminution in the hypothermic and bradycardic effects of O3. Senescent rats were less affected than adults. Acute responses were exacerbated on the second day of O3 exposure with adults exhibiting greater sensitivity. During recovery following 2 d of O3, adult and senescent rats exhibited an elevated T(c) and HR during the day but not at night, an effect that persisted for at least 48 h after O3 exposure. MA was elevated in adults but not senescent rats during recovery from O3. Overall, acute effects of O3, including reductions in HR and T(c), were attenuated in senescent rats. Autonomic responses during recovery, included an elevation in T(c) with a pattern akin to that of a fever and rise in HR that were independent of age. An attenuated inflammatory response to O3 in senescent rats may explain the relatively heightened physiological response to O3 in younger rats.
Assuntos
Envelhecimento , Poluentes Atmosféricos/toxicidade , Bradicardia/induzido quimicamente , Hipotermia/induzido quimicamente , Exposição por Inalação/efeitos adversos , Síndromes Neurotóxicas/fisiopatologia , Ozônio/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Oxidantes Fotoquímicos/toxicidade , Ratos Endogâmicos BN , Índice de Gravidade de Doença , Taquifilaxia , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica , ToxicocinéticaRESUMO
Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.
Assuntos
Intolerância à Glucose/patologia , Doenças Metabólicas/patologia , Ozônio/toxicidade , Adiponectina/sangue , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Fatores Etários , Animais , Biomarcadores/metabolismo , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Intolerância à Glucose/induzido quimicamente , Teste de Tolerância a Glucose , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Leptina/sangue , Lipoproteínas HDL/sangue , Lipoproteínas IDL/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Doenças Metabólicas/induzido quimicamente , Osteopontina/sangue , Fosforilação , Ratos , Ratos Endogâmicos BN , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Triglicerídeos/sangue , alfa-Macroglobulinas/metabolismoRESUMO
Ozone (O3) is a pervasive air pollutant that produces pulmonary and cardiovascular dysfunction and possible neurological dysfunction. Young and old individuals are recognized as being susceptible to O3; however, remarkably little is known about susceptibility with senescence. This study explored the pulmonary, cardiovascular and neurological effects of O3 exposure in adult (4 m) and senescent (20 m) Brown Norway rats exposed to 0 or 0.8 ppm O3 for 6 h, 1 d/week, for 17 weeks. Ventilatory function was assessed 1 and 7 d after each exposure (Buxco). Heart rate, blood pressure (tail cuff) and motor activity were measured biweekly. Blood, aorta and bronchoalveolar lavage fluid (BALF) were analyzed 24 h after the last exposure for pulmonary inflammation, serum biomarkers and aorta mRNA markers of vascular disease. Measures of normal ventilatory function declined following each O3 exposure in both adult and senescent rats, however, senescent rats took weeks to exhibit a decline. Evidence for residual respiratory effects of O3 7 d after exposure in both age groups was observed. O3 had no effect on either heart rate or blood pressure, but decreased motor activity in both age groups. BALF indicated mild neutrophilic inflammation and protein leakage in adults. Age affected 17/58 serum analytes, O3 affected 6/58; 2/58 showed an age-O3 interaction. Leptin, adiponectin, lipocalin and insulin were increased in senescent rats. Overall, adult rats exhibited more immediate effects of episodic O3 than senescent rats. Residual effects were, however, obtained in both ages of rat, especially for ventilatory endpoints.
Assuntos
Comportamento Animal/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Coração/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Oxidantes Fotoquímicos/toxicidade , Ozônio/toxicidade , Adiponectina/metabolismo , Fatores Etários , Envelhecimento , Animais , Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Suscetibilidade a Doenças , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Insulina/metabolismo , Leptina/metabolismo , Lipocalinas/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos BN , Testes de Função RespiratóriaRESUMO
Life stage is an important risk factor for toxicity. Children and aging adults, for example, are more susceptible to certain chemicals than are young adults. In comparison to children, relatively little is known about susceptibility in older adults. Additionally, few studies have compared toxicant susceptibility across a broad range of life stages. Results are presented for behavioral evaluations of male Brown Norway rats obtained as adolescents (1 month), or young (4 months), middle-age (12 months) and senescent (24 months) adults. Motor activity was evaluated in photocell devices during 30-min sessions. Age-related baseline characteristics and sensitivity to toluene (0, 300, 650, or 1000mg/kg, p.o.) were determined. In Experiment 1, young-adult, middle-age and senescent rats were treated with corn-oil vehicle before five weekly test sessions. Baselines of horizontal and vertical activity decreased with age, but each age-group's averages remained stable across weeks of testing. Baseline activity of older rats was more variable than that of the young adults; older rats were also more variable individually from week to week. Toluene (1000mg/kg) increased horizontal activity proportionately more in senescent rats (ca. 300% of control) than in middle-age or young-adult rats (ca.145-175% of control). Experiment 2 established toluene dose-effect functions in individual adolescent, young-adult, middle-age and senescent rats; each rat received all treatments, counterbalanced across four weekly sessions. Toluene produced dose-related increases in horizontal activity that increased proportionately with age. Experiment 3 replicated the effects of toluene (1000mg/kg) in Experiment 1, showing that toluene-induced increases in horizontal activity were greatest in the oldest rats. Collectively, the results show that aging increased susceptibility to toluene and also increased variability in toluene response. Given the rapid growth of the aged population, further research is needed on aging-related susceptibility to environmental contaminants.
Assuntos
Envelhecimento/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Solventes/farmacologia , Tolueno/farmacologia , Fatores Etários , Análise de Variância , Animais , Masculino , Ratos , Ratos Endogâmicos BNRESUMO
This study examined the effects of acute and weekly administration of anatoxin-a and nicotine on operant performance. Anatoxin-a is a potent nicotinic receptor agonist produced by cyanobacteria, which are found in fresh waters throughout the world. Anatoxin-a is a potential human health hazard and has been responsible for numerous deaths of wildlife, livestock and domestic animals. Remarkably little is known, however, about the effects of anatoxin-a on behavior. Nicotine, the psychomotor stimulant in tobacco, has many well-documented behavioral effects, which often diminish (i.e. tolerance develops) when it is given daily. Male Long Evans rats initially were trained to respond under a multiple variable-ratio 30-response variable-interval 60-s (mult VR-30 VI 60-s) schedule of food reinforcement. They were then divided into 12 groups of 8 that received four weekly subcutaneous injections of anatoxin-a (0.05-0.2 mg/kg), nicotine (0.125-1.8 mg/kg), or vehicle 5-min prior to testing. When initially administered, each compound decreased response rates and reinforcement rates in both components of the multiple schedule. Substantial tolerance developed to the disruptive effects of nicotine with weekly administration. Tolerance also developed to the effects of anatoxin-a, although to a lesser degree; the highest dose severely decreased performance with little evidence of recovery. In conjunction with prior findings, these results suggest the behavioral effects of anatoxin-a and nicotine are similar, but not identical, and that relatively infrequent (episodic) administration can produce tolerance.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Desempenho Psicomotor/efeitos dos fármacos , Tropanos/toxicidade , Animais , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Masculino , Ratos , Esquema de ReforçoRESUMO
Anatoxin-a is a naturally occurring nicotinic agonist produced by cyanobacterial blooms; exposures are likely to occur episodically when the blooms repeatedly form and dissipate. Tolerance and sensitization to nicotine's effects on the motor activity of rats can occur when administered episodically at weekly intervals. It was therefore of interest to compare the effects of anatoxin-a and nicotine when given weekly. Adult male Long Evans rats were tested daily (M-F) in a photocell device, that recorded both horizontal and vertical motor activity, during 30-min sessions. Anatoxin-a and nicotine were given s.c. once a week for 4 weeks, just prior to a test session. Anatoxin-a was given as the (+) isomer and as the racemate. Dose ranges were: (+)anatoxin-a, 0.075-0.225 mg/kg; (+/-)anatoxin-a, 0.2-0.95 mg/kg; and (-)-nicotine, 0.3-1.8 mg/kg. Each experiment also included a saline-control group. Nicotine initially decreased both horizontal activity and, to a greater extent, vertical activity. Tolerance developed to nicotine's effects with weekly administration. Both forms of anatoxin-a also initially decreased horizontal and vertical activity, and to roughly equivalent degrees. Neither form of anatoxin-a, however, induced tolerance with weekly administration. Thus, anatoxin-a and nicotine can be distinguished by their effects on motor activity with episodic treatment, suggesting different sites of action for the compounds in the nervous system.
Assuntos
Atividade Motora/efeitos dos fármacos , Nicotina/toxicidade , Tropanos/toxicidade , Animais , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Estimulantes Ganglionares/toxicidade , Injeções Subcutâneas , Masculino , Agonistas Nicotínicos/toxicidade , Ratos , Ratos Long-Evans , Estereoisomerismo , Fatores de Tempo , Tropanos/químicaRESUMO
Nicotine's effects on motor activity have been studied extensively. Sensitization or tolerance can develop to nicotine's acute effects with daily exposure. Limited data indicate that sensitization can also develop when nicotine is given less frequently than daily. The present experiments were designed to extend this finding and to more fully characterize the effects of nicotine on motor activity when given at weekly intervals. In both experiments, the horizontal and vertical activity of adult female Long-Evans (LE) rats was recorded in photocell chambers. In Experiment 1, either saline or nicotine hydrogen tartrate (0.3, 0.6, 1.2 or 1.8 mg of salt/kg BW, s.c.) was administered once each week to rats that were tested daily (M-F). Acute nicotine administration produced no significant effect on horizontal activity at lower doses, while the highest dose produced a decrease (ca. 30%). Substantial and significant dose-related decreases in vertical activity were also obtained initially. Weekly dosing produced tolerance to nicotine's decreasing effects on vertical activity and increases (i.e., sensitization) in horizontal activity at all doses, and these effects persisted for at least 3 weeks. Experiment 2 partially replicated the results of Experiment 1 and indicated further that small sequential dose variations generally had little influence on nicotine tolerance and sensitization. The present results on horizontal activity extend prior findings of sensitization to weekly nicotine to include a broad range of doses. Results also showed that tolerance, but not sensitization, occurred to nicotine's effects on vertical activity over a comparable dose range. Further research is warranted on the importance of episodic, or recurring intermittent exposures in determining nicotine's effects, and those of other nicotinic agents, on behavior.
Assuntos
Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Feminino , Ratos , Ratos Long-EvansRESUMO
While there is a long-standing tradition of using behavioral methods to study the effects of manufactured drugs and environmental chemicals, comparatively little attention has focused until recently on the behavioral effects of marine or freshwater toxins. A vast array of microorganisms, found in a variety of waters, are known to occasionally "bloom" and produce toxins that can cause either blatant toxicity (i.e., lethality) or damage to a number of organ systems. The nervous system is a known target for many of the toxins. Considerable research has in the past been carried out to determine toxin effects on the survivability of laboratory rodents (typically mice) following acute exposures. Newer research has shown, however, prominent toxin-induced alterations in motor, sensory, autonomic and cognitive functions at sublethal exposure concentrations. Future toxin research can capitalize upon a wealth of behavioral paradigms already available in toxicology, pharmacology and neuroscience.
Assuntos
Comportamento Animal/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Neurotoxinas/toxicidade , Animais , Água Doce , Humanos , CamundongosRESUMO
Anatoxin-a is a nicotinic agonist produced by several genera of cyanobacteria, and has caused numerous deaths of wildlife, livestock and domestic animals world-wide. Several studies in the literature have shown that exposure of mice and rats to nicotine early in development alters its effects when the rodents are subsequently challenged with nicotine. We therefore determined the effect of nicotine on the motor activity of adult mice that had been exposed prenatally to anatoxin-a. Pregnant CD-1 mice received either saline vehicle or one of two doses of (+/-) anatoxin-a (125, 200 microg/kg), i.p., on GD13-17. As adults (8 months), control mice of both genders were used to determine the effect of nicotine (0, 0.1, 0.3, 1.0 or 3.0 mg/kg, s.c.) on motor activity measured for 30-min in a photocell device. Under these conditions, nicotine produced dose-related decreases in both horizontal and vertical activity, with an ED50 estimated to be 0.65 mg/kg. Next, additional control mice and mice exposed prenatally to anatoxin-a received the nicotine ED50 and saline vehicle, in a counterbalanced fashion, with one week separating treatments. Nicotine decreased both horizontal and vertical activity in all mice, regardless of prenatal anatoxin-a treatment. Thus, no enduring effects of prenatal anatoxin-a were obtained in adult mice following nicotine challenge.
Assuntos
Toxinas Bacterianas/toxicidade , Toxinas Marinhas/toxicidade , Atividade Motora/efeitos dos fármacos , Neurotoxinas/toxicidade , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Masculino , Camundongos , Microcistinas , Gravidez , TropanosRESUMO
The present study examined the effects of morphine in pigeons responding under a progressive-ratio 25 schedule of food delivery. Morphine initially reduced response rates and breaking points. With chronic exposure, tolerance developed to these effects. The magnitude of the observed tolerance was not obviously different from that previously reported under a PR 5 schedule of food delivery. In addition, when drug effects were compared under the fixed-ratio 25 and fixed-ratio 100 components comprised by the progressive-ratio schedule, comparable tolerance was observed. Although prior studies using other procedures have shown that ratio size modulates the development of tolerance to morphine and other drugs, the present data suggest that this relation is constrained, and is not easily observed under progressive-ratio schedules.
Assuntos
Analgésicos Opioides/administração & dosagem , Interações Alimento-Droga , Morfina/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Columbidae , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Morfina/farmacologiaRESUMO
Previous studies have found that defecation increases in rats exposed to fixed-time schedules of dry food delivery. The purpose of the present study was to examine whether increases in defecation could be induced in rats exposed to fixed-time schedules of liquid food delivery. Eight rats were exposed to fixed-time 30-, 60-, and 120-s schedules of liquid food delivery. None of the subjects excreted significantly more fecal boli under the fixed-time schedules than during massed-food control sessions in which an equivalent amount of food was presented at the beginning of the sessions. Thus, the present findings identify a previously unknown constraint on schedule-induced defecation in rats.
Assuntos
Comportamento Animal/fisiologia , Defecação/fisiologia , Ingestão de Alimentos/fisiologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Previous studies have found that defecation increases in rats exposed to intermittent schedules of food delivery. In the present study, food-deprived pigeons were exposed to fixed-time 30-, 60-, 120-, and 240-s schedules of food delivery. For the subjects as a group, significantly more defecation (indexed by fecal weight) occurred under the fixed-time 60-s schedule than during massed-food control sessions in which an equivalent amount of food was presented. Thus, the present findings suggest that schedule-induced defecation occurs in pigeons.