Response In Young Rats Research Articles

Specific inhibitor of Wnt/beta-catenin pathway can alter behavioral responses in young rats with malformed cortices

The Wnt/beta-catenin pathway plays a crucial role in regulating cellular processes and has been implicated in neural activity-dependent learning as well as anxiety. However, the role of this pathway in young children with abnormal cortical development is unknown. Cortical malformations at early development, behavioral abnormalities, and a susceptibility to seizures have been reported in rats prenatally exposed to methylazoxymethanol. In this study, we aimed to investigate whether we could improve the behavioral deficits in young rats with malformed cerebral cortices by modulation of the Wnt/beta-catenin pathway. We found a small molecule Wnt/beta-catenin inhibitor (CWP) that increased exploratory behavior in the open field test (P9, CWP 100 ug treatment, peripheral exploration, P = 0.011) and social behavior test (P12, CWP 250 ug treatment, distance traveled in center, P = 0.033) and decreased anxiety in fear conditioning. However, it did not reduce the susceptibility to seizures. After high dose (250 ug) CWP treatment at P12, phosphocreatine and glutathione (GSH) were decreased in the cortex at P15 (P = 0.021). These findings suggest that the role of Wnt/beta-catenin signaling in exploratory behavior and anxiety during early development warrants further investigation.

Attenuation of Aging-Induced Vascular Dysfunction by Inhibition of Ca2+/Calmodulin Protein Kinase II (CaMKII) in Isolated Renal and Carotid Rat Arteries

An increased prevalence of cardiovascular problems is recorded due to aging. The importance of aging as a potential risk factor for cardiovascular diseases has been increasing in most of the developing countries since populations continue to become older. Age-associated unusual structural changes that develop in blood vessels have been reported such as stiffening of the vasculature and fibrosis. CaMKII is a protein kinase that is present all-over in the body. In this study, it is suggested that acute inhibition of CaMKII-mediated signaling may be an effective method to prevent agingassociated detrimental changes in isolated blood vessels in SD male rats. The inhibitory effect of CaMKII in aging-induced renal/carotid vascular dysfunction was studied using the selective inhibitor KN-93. Isolated ring segments of the renal or carotid arteries were suspended in organ-bath chambers for measurement of isometric tension. Responses to Phenylephrine (PE), Endothelin-1 (ET-1), carbachol and Sodium Nitroprusside (SNP) were determined by measurement of changes in isometric tension. Results from this study showed abnormal vascular responses to vasoactive agonists in the vessels obtained from aged rats. Vasoconstrictor responses to phenylephrine were potentiated, while vasodilator responses to carbachol were reduced in blood vessels obtained from aged rats, in comparison to responses in young rats. Acute incubation of the blood vessels with KN-93 (10-5 M), an inhibitor of CaMKII, resulted in significant improvement in vascular function to both vasoactive agonists. Our results indicated that activation of CaMKII pathway contributes to aging-induced vascular dysfunction. Therefore, development of novel therapies that inhibit CaMKII pathway may prevent or reduce development of vascular abnormalities induced by aging.

Thermal and cytokine responses to endotoxin challenge during early life.

Sudden infant death syndrome (SIDS) remains the leading cause of infant mortality beyond the neonatal period. An increase in body temperature as a result of high environmental temperature, overwrapping of infants, and (or) infection are associated with SIDS. Endotoxins such as lipopolysaccharide (LPS) and heat stress may perturb cardiorespiratory function and thermoregulation. Although LPS-mediated body temperature and cytokine responses are well documented in older animals, the capacity of LPS to induce fever and cytokine response in young rats remains unclear. Therefore, we sought to investigate the acute effects of LPS on body temperature and cytokine concentrations in rat pups. Postnatal day 7 rat pups were divided into 3 groups: Group 1, rats were administered LPS intraperitoneally (200 μg/kg); Group 2, rats received saline at volume equal to that administered in the LPS group; Group 3, rats received no treatment. Pups were placed in custom-made chambers maintained at ambient temperature of 33 °C. Body surface temperature was continuously monitored for 4 h. Thereafter, the rats were euthanized and serum was collected for cytokine analysis. We demonstrate that LPS treatment increased MIP-1α, IL-10, MCP-1, IP-10, fractalkine, and TNF-α with no concurrent rise in body surface temperature. Although neonatal rats produced an array of cytokines in response to LPS, there was no evidence of fever.

Protective Effect of N-Acetyl-Cysteine (NAC) in Lipopolysaccharide (LPS)-Associated Inflammatory Response in Rat Neonates.

ObjectiveIncreased inflammatory response may be associated with adverse clinical outcomes, especially in the neonatal period. The aims of this study were to determine whether N-acetyl-cysteine (NAC), an anti-inflammatory agent, attenuates the inflammatory response in young rats and to determine the most effective route of administration.MethodsFour groups of Sprague-Dawley rats (in each group four rats) were studied at 30 days of age. One hour following intraperitoneal (IP) injection of lipopolysaccharide 50 μg/kg, the rats were randomized to subcutaneous (SC), per os (PO), or intraperitoneal (IP) injection of NAC 300 mg/kg, or saline. The control group received saline injection (IP). Three hours following the N-acetyl-cysteine injection the rats were sacrificed, then serum tumor necrosis factor-α (TNF-α) and IL-6 levels were determined by ELISA.ResultsLipopolysaccharide significantly increased the neonatal serum IL-6 and TNF-α (2051.0±349 and 147.0±25.8 pg/mL, respectively; P<0.01) levels compared to 10 pg/mL in the controls. N-acetyl-cysteine administered one hour following lipopolysaccharide injection significantly attenuated the inflammatory response. Intraperitoneal administration of NAC decreased IL-6 and TNF-α concentration to 294.6 and 17.1 pg/mL, respectively, and was more effective than SC or PO administration.ConclusionsN-acetyl-cysteine attenuated the inflammatory response in the neonatal rats, and IP was the most effective administration route.

Age Is Associated with Reduced Sharp-Wave Ripple Frequency and Altered Patterns of Neuronal Variability.

Spatial and episodic memory performance declines with age, and the neural basis for this decline is not well understood. Sharp-wave ripples are brief (∼70 ms) high-frequency oscillatory events generated in the hippocampus and are associated with the consolidation of spatial memories. Given the connection between ripple oscillations and memory consolidation, we investigated whether the structure of ripple oscillations and ripple-triggered patterns of single-unit activity are altered in aged rats. Local field and single-unit activity surrounding sharp-wave ripple events were examined in the CA1 region of the hippocampus of old (n = 5) and young (n = 6) F344 rats during periods of rest preceding and following performance on a place-dependent eyeblink-conditioning task. Neural responses in aged rats differed from responses in young rats in several ways. First, compared with young rats, the rate of ripple occurrence (ripple density) is reduced in aged rats during postbehavior rest. Second, mean ripple frequency during prebehavior and postbehavior rest is lower in aged animals (aged: 132 Hz; young: 146 Hz). Third, single neurons in aged animals responded more consistently from ripple to ripple. Fourth, variability in interspike intervals was greater in aged rats. Finally, neurons were tuned to a narrower range of phases of the ripple oscillation relative to young animals. Together, these results suggest that the CA1 network in aged animals has a reduced "vocabulary" of available representational states. The hippocampus is a structure that is critical for the formation of episodic memories. Sharp-wave ripple events generated in the hippocampus have been implicated in memory consolidation processes critical to memory stabilization. We examine here whether these ripple oscillations are altered over the course of the life span, which could contribute to hippocampus-dependent memory deficits that occur during aging. This experiment used young and aged memory-impaired rats to examine age-related changes in ripple architecture, ripple-triggered spike variance, and spike-phase coherence. We found that there are, indeed, significant changes in characteristics of ripples in older animals that could impact consolidation processes and memory stabilization in the aged brain.

Effects of tityustoxin on cerebral inflammatory response in young rats

Accidents caused by scorpion stings, mainly affecting children, are considered an important cause of morbidity and mortality in tropical countries. Clinical studies demonstrate the relevant role of systemic inflammatory events in scorpion envenoming. However, remains poorly understood whether the major lethal component in Tityus serrulatus venom, tityustoxin (TsTX), is able to induce inflammatory responses in the cerebral microcirculation. In this study, we systematically examined leukocyte recruitment into the CNS in response to TsTX injection. Accordingly, developing rats were subjected to a subcutaneous (s.c.) injection of TsTX (0.75mg/kg), and leukocyte recruitment (i.e., 4, 8 and 12h after injection) and TNF-α levels were evaluated. Rats injected with TsTX presented a significant increase in leukocyte rolling and adhesion and higher levels of TNF-α at all time points studied, compared to the control group. Altogether, this work demonstrates the triggering of neuroimmunological mechanisms induced by TsTX injection in young rats.

Aggression and the Acoustic Startle Response in Young Rats Genetically Predisposed to Aggression and Nonaggressive Rats

The aim of the present work was to study the relationship between expression of the reflex startle reaction and fear-induced aggression. The extent of aggressive reactions towards humans and the amplitude of the acoustic startle response were studied in adult and 15-day-old Norway rats bred for 70 generations for a high level of fear-induced aggression towards humans and in animals without such aggression. Adult rats of the aggressive strain demonstrated a high level of aggression and a significantly greater reflex startle amplitude than rats bred for the absence of aggression. In contrast to 15-day-old rat pups of the nonaggressive strain, pups of the highly aggressive strain showed clear aggression directed towards humans, though these reactions were weaker than those of adults of this strain. There were no differences in the amplitudes of the acoustic startle reaction between aggressive and nonaggressive rat pups. Adult aggressive rats showed a significant decrease in the amplitude of the acoustic startle reaction on sequential presentations of the sound stimulus, while 15-day-old rat pups of the aggressive strain showed no change in the acoustic startle reflex. The amplitude of the acoustic startle reflex on sequential presentations of the sound stimulus decreased significantly in both adult and 15-day-old nonaggressive rats. Thus, protective-defensive aggression in rats genetically predisposed to fear-induced aggression appears quite early ‐ these animals displayed marked aggressive responses against humans by the moment of eye opening. The startle reflex is one of the elements of a complex behavior ‐ protective-defensive aggression ‐ an element which does not play a significant role in aggression in young rats but is involved in age-related increases in aggression.

Intestinal immune system of young rats influenced by cocoa-enriched diet

Gut-associated lymphoid tissue (GALT) maintains mucosal homeostasis by counteracting pathogens and inducing a state of nonresponsiveness when it receives signals from food antigens and commensal bacteria. We report for the first time the influence of continuous cocoa consumption on GALT function in rats postweaning. Weaned Wistar rats were fed cocoa-enriched diets (4% or 10% food intake) for 3 weeks. The function of the primary inductive sites of GALT, such as Peyer's patches (PP) and mesenteric lymph nodes (MLN), was evaluated through an analysis of IgA-secretory ability and lymphocyte composition (T, B and natural killer cells), activation (IL-2 secretion and IL-2 receptor α expression) and proliferation. T-helper effector cell balance was also established based on cytokine profile (interferon γ, IL-4 and IL-10) after mitogen activation. A 10% cocoa intake induced significant changes in PP and MLN lymphocyte composition and function, whereas a 4% cocoa diet did not cause significant modifications in either tissues. Cocoa diet strongly reduced secretory IgA (S-IgA) in the intestinal lumen, although IgA's secretory ability was only slightly decreased in PP. In addition, the 10% cocoa diet increased T-cell-antigen receptor γδ cell proportion in both lymphoid tissues. Thus, cocoa intake modulates intestinal immune responses in young rats, influencing γδ T-cells and S-IgA production.

Interactive Effects of Dietary Resistant Starch and Fish Oil on Short-Chain Fatty Acid Production and Agonist-Induced Contractility in Ileum of Young Rats

We have shown independently that dietary fiber and n-3 fatty acids can affect gut function. This study investigated the interactive effects of resistant starch (RS) (as high amylose maize starch [HAMS]) and tuna fish oil on ileal contractility. Four-week-old male Sprague Dawley rats were fed 4 diets that contained 100 g/kg fat as sunflower oil or tuna fish oil, with 10% fiber supplied as alpha -cellulose or HAMS for 6 weeks. Fish oil feeding led to higher ileal n-3 fatty acid levels (mainly as DHA) and higher agonist-induced maximal contractility with an RS effect noted for carbachol. HAMS-containing diets resulted in lower colonic pH and higher total short-chain fatty acids (SCFA), but not for butyrate with fish oil. Low prostanoid responses in young rats were enhanced by fish oil independent of RS. The order of muscarinic receptor subtype responses were different compared to older rats; fish oil feeding altered the sensitivity of the M(1) receptor subtype. Although little interactive effects were demonstrated, these data suggest developmental changes in ileal receptor systems with independent effects of RS and fish oil on some bowel properties in juvenile rats.

The Role of the Amygdala and Olfaction in Unconditioned Fear in Developing Rats

Early in ontogeny, young rats must be able to detect dangerous stimuli and to exhibit appropriate defensive behaviors. Different nuclei of the amygdala mediate unconditioned and conditioned fear responses to threat in adult rats. The aim of this study was to determine the role of the amygdala in unlearned fear behavior in young rats. When exposed to an unfamiliar adult male rat, preweaning rat pups freeze, with peak levels on postnatal day 14 and declining levels on day 18. Pups were made anosmic to block olfactory input to the amygdala, and amygdala activation was assessed by quantifying the neuronal marker c-fos. Anosmic pups did not freeze in the presence of the male rat and had decreased c-fos expression in the medial amygdala on day 14 and in the medial and lateral amygdala on day 18. However, the decrease in freezing between days 14 and 18 was not associated with a decrease in c-fos expression in the medial amygdala. The medial and lateral amygdala were then inactivated by local muscimol infusion on day 14. Muscimol infusion into the medial amygdala decreased freezing to the male rat but not to a loud noise, whereas infusion into the lateral amygdala blocked freezing to a loud noise but not to the male. These findings indicate that different nuclei of the amygdala process sensory information of different modalities, mediate unconditioned freezing, and may be involved in developmental changes in the fear response in young rats.

Enhanced behavioral response to repeated-dose cocaine in adolescent rats

Most lifelong drug addiction in humans originates during adolescence. Important structural and functional changes in the brain occur during adolescence, but there has been little direct study of how this impacts on drug abuse vulnerability. An emerging literature suggests that adolescents exhibit different behavioral responses to single doses of several addictive drugs, including ethanol, amphetamine, and cocaine. However, few studies have explored behavioral responses to the repeated dosing that is characteristic of human abuse of these substances. We have investigated age-related behavioral responses to acute "binge" cocaine treatment between adults and adolescents. Adolescent rats displayed an exaggerated behavioral response to cocaine administered in two different binge patterns. Total locomotion after cocaine administration was the same in adolescents and adults. However, adolescent rats engaged in more intense stereotypic behaviors, including paw treading, head weaving, and focused sniffing than adult rats. These differences were observable following a modest dose of cocaine and became more robust following subsequent doses within a binge. Cocaine [corrected] brain levels were not significantly different between age groups during any of the exposure sessions. These findings suggest that equivalent tissue concentrations of cocaine produce a greater behavioral response in young rats, and that adolescent animals display an apparent form of intrabinge sensitization.

Age-specific threats induce CRF expression in the paraventricular nucleus of the hypothalamus and hippocampus of young rats

Young animals respond to threatening stimuli in an age-specific way. Their endocrine and behavioral responses reflect the potential threat of the situation at a given age. The aim of the present study was to determine whether corticotropin-releasing factor (CRF) is involved in the endocrine and behavioral responses to threat and their developmental changes in young rats. Preweaning 14-day-old and postweaning 26-day-old rats were exposed to two age-specific threats, cat odor and an adult male rat. The acute behavioral response was determined during exposure. After exposure, the time courses of the corticosterone response and of CRF expression in the paraventricular nucleus of the hypothalamus (PVN) and in extrahypothalamic areas were assessed. Preweaning rats became immobile when exposed to cat odor or the male rat, whereas postweaning rats became immobile to cat odor only. Male exposure increased serum corticosterone levels in 14-day-old rats, but cat odor failed to increase levels at either age. Exposure induced elevation of CRF mRNA levels in the PVN that paralleled changes in corticosterone levels. CRF may thus play a role in endocrine regulation and its developmental changes during early life. Neither cat odor nor the adult male altered CRF mRNA levels in the bed nucleus of the stria terminalis (BNST) or the amygdala, but both stimuli increased levels in the hippocampus. Hippocampal CRF mRNA expression levels did not parallel cat odor or male-induced immobility, indicating that CRF is not involved in this response in young rats but may be involved in aspects of learning and memory.

Lack of involvement of μ1 opioid receptors in dermorphin-induced inhibition of hypoxic and hypercapnic ventilation in rat pups

The effects of dermorphin, a mu-selective opioid agonist, on respiratory responses to altered O(2) and CO(2) during postnatal development were investigated in conscious, unrestrained Wistar rats aged 2-21 days. Respiration was recorded by barometric plethysmography. Dermorphin (4 mg kg(-1)) was administered subcutaneously, and the ventilatory responses to hypoxia (11% O(2), 89% N(2)) in 2-21-day-old pups and hyperoxia (100% O(2)), and hypercapnia (8% CO(2), 92% O(2)) in 2-13-day-old pups were assessed in the presence and absence of the mu(1) receptor antagonist naloxonazine (10 mg kg(-1) s.c.) administered 1 day before testing. Six minutes of hypoxia increased ventilation in all age groups, largely via an increase in frequency. Dermorphin inhibited the ventilatory response to hypoxia, and this inhibition was insensitive to naloxonazine. After 5 min of hyperoxia, ventilation was the same as with air breathing except in the presence of dermorphin, when hyperoxic ventilation was depressed by a naloxonazine-insensitive decrease in frequency. Following this 5 min 100% O(2) exposure, pups were exposed to hypercapnia, and respiratory parameters were measured 5 min later. The ventilatory response to CO(2) was inhibited by dermorphin in a naloxonazine-insensitive manner. There was no evidence for endogenous mu(1) receptor modulation of the ventilatory responses to altered gases in rat pups of any age. Thus, mu opioid-induced inhibition of the hypoxic and hypercapnic responses in young rats does not occur via activation of mu(1) opioid receptors.

Age-related decline in emotional adaptability to short-term stressful situation: The participation of the monoaminergic nervous systems in the cerebral limbic system

The relationship between emotional stress adaptability and amine dynamics in serotonergic, noradrenergic or dopaminergic nervous systems in the cerebral limbic system was investigated in young (10 weeks old) and aged (110 weeks old) rats. The appearance of emotional stress responses such as struggling behavior and vocalization in both young and aged rats was caused by exposure to acute restraint stress. During exposure to acute restraint stress for 1 h, the appearance of these responses in young rats decreased time-dependently, but the struggling behavior of aged rats was constant throughout the exposure. After exposure to acute restraint stress, the serum corticosterone concentration in young and aged rats was significantly increased. Also, a significant increase in serotonin turnover (5-hydroxyindole-3-acetic acid/serotonin) was observed in the amygdala (AM), hippocampus (HC) and septum (SE) of the young rat brain, but this neurochemical change was not observed in these regions of the aged rat brain. Furthermore, in the AM, HC and SE of young rats, norepinephrine turnover (4-hydroxy-3-methoxyphenylglycol/norepinephrine) was significantly increased by exposure to acute restraint stress. Norepinephrine turnover in the AM and SE of aged rats was increased, but was unaltered in the HC. On the other hand, acute restraint stress had no effect on dopamine turnover (3,4-dihydroxyphenyl acetic acid/dopamine) in the AM, HC or SE of either young or aged rats. These findings suggest that emotional adaptability to acute restraint stress declines age-dependently. Also, the decreases in serotonergic nervous activities in the cerebral limbic system and noradrenergic activities in the HC may be related to the decline of emotional stress adaptability.

CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood–brain barrier breakdown

Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1–5]. Rodent models have demonstrated a ‘window of susceptibility’ in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6,7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1β (IL-1β) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys–X–Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1β. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1β-induced blood–brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood–brain barrier damage and represents a significant therapeutic possibility.

Age-related changes in sympathetic modulation of sensory nerve activity in rat skin.

Sensory nerves play an important role in mediating neurogenic inflammation and subsequent tissue healing. A decrease in sensory nerve function with increasing age has been reported to correlate with poor tissue healing. Sympathetic nerves are known to modulate sensory nerve function, and changes in this modulation could also have important implications with ageing. The aims of this study were to examine the effect of different frequency electrical stimulation (ES) on the microvascular responses obtained to sensory nerve activation in young, aged and capsaicin-pretreated rats and modulation of these responses by sympathetic efferents. Using laser Doppler flowmetry, vascular responses to antidromic ES of the sciatic nerve were monitored in the base of vacuum-induced blisters in the hind footpad. The non-selective alpha-adrenoceptor antagonist phentolamine (3 mg/kg, i.v.) was administered 20 min prior to ES. At high frequency ES (20V, 2ms, 15Hz for 1 min), the vascular response in old rats was significantly reduced (46 percent decrease, p < 0.05) compared to young control. At low frequency ES (20 V, 2 ms, 5 Hz for 1 min) however, older rats produced similar vascular responses to the young. Capsaicin-pretreated rats showed significantly reduced vascular responses to both high and low frequency ES, regardless of age. Pretreatment with phentolamine significantly increased the microvascular response in young rats at high (87 percent) and low (36 percent) frequency ES. In contrast, phentolamine significantly increased the ES-induced response in old rats at high frequency only (147 percent increase). The results suggest that the aged sensory nerve responds preferentially to low frequency ES and that sympathetic efferents exert an inhibitory modulatory effect on the vascular response evoked by sensory nerve stimulation. There are age-related changes in sympathetic modulation of sensory nerve-mediated responses which is dependent on stimulation frequency.

Thermoregulation with age: role of beta-adrenergic signal transduction.

The predominance of the evidence from our studies indicates that beta 3-adrenergic-mediated thermogenesis in interscapular BAT is impaired with age. Moreover, upon exposure to cold, beta-adrenergic responsiveness in BAT is restored. However, the exact nature of the beta 3-adrenergic upregulation is unknown. When senescent rats are exposed to cold for as a little as 1 h, the increase in GDP binding is equal to the response in young rats. This indicates that any cold-induced upregulation of the beta-adrenergic signal transduction pathway must respond within this time frame. The senescent rats employed in our studies have been reared throughout their life at or near thermoneutrality. We hypothesize that under such conditions, beta 3-adrenergic signal transduction atrophies with age, whereas the induction pathways for the components of this signal transduction system remain intact. For example, the beta 3-adrenergic stimulation of UCP mRNA in BAT from senescent rats maintained at thermoneutrality is 54% of that of young rats. Upon exposure to the cold, possibly through a combination of enhanced beta 3AR-adenylyl cyclase coupling or enhanced gene expression of components in the signal transduction pathway or both, beta 3-adrenergic responsiveness is restored in the senescent rat.

Alterations in the cardiovascular control by the chemoreflex and the baroreflex in old rats.

The aging process is associated with alterations in the autonomic control of cardiovascular function. In the present study, we observed that reflex bradycardia and tachycardia produced by pressor and depressor agents were attenuated in old (24 mo) rats [70 and 56% of responses in young rats (4 mo), respectively]. In contrast, the bradycardia induced by chemoreflex activation with increasing doses of KCN (60, 100, 140, and 180 micrograms/kg) was greater in old [-30 +/- 19, -155 +/- 32, -198 +/- 15, and -204 +/- 24 beats/ min (bpm)] than in young rats [-13 +/- 6, -75 +/- 20 (P < 0.05), -99 +/- 26 (P < 0.05), and -103 +/- 20 (P < 0.05) bpm]. The chemoreflex-pressor responses tended to be greater in old (12 +/- 6, 47 +/- 6, 54 +/- 7, and 55 +/- 5 mmHg) than in young rats (4 +/- 2, 32 +/- 8, 42 +/- 6, and 44 +/- 4 mmHg), but the differences between both groups were not statistically significant. However, pressor responses were higher in old rats after the chemoreflex-activated bradycardia was attenuated by atropine (4 mg/kg iv) [old (17 +/- 9(1) P < 0.05; 57 +/- 4, P < 0.05; 61 +/- 4; and 64 +/- 5 mmHg) vs. young (3 +/- 2, 29 +/- 9(1) 50 +/- 5, and 58 +/- 7 mmHg)]. Administration of the alpha 1-blocker prazosin (1 mg/kg iv) blunted pressor responses but did not change the bradycardia induced by chemoreflex in both groups. In conclusion, our data indicate that the bradycardia and pressor responses to chemoreflex activation were exaggerated, whereas the heart rate responses (bradycardia and tachycardia) to baroreflex were depressed in old rats.

Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats.

Aging is frequently associated with changes in physiological and cognitive processes. Among these changes is a distinct dysregulation of the hypothalamic-pituitary-adrenal axis. In the current experiments, aspects of hypothalamic-pituitary-adrenal axis function were compared in young (3- to 4-month-old) and aged (21- to 24-month-old) Fisher 344/N male rats. Basal ACTH and corticosterone levels during the circadian trough were elevated in aged compared to young rats. During the evening peak of the circadian cycle, plasma ACTH levels in the young and aged rats were comparable; however, aged rats had significantly lower corticosterone levels than young rats. Stimulus-induced secretion of pituitary-adrenal hormones was attenuated in aged rats. The ACTH response to hemorrhage in the aged group was only 45 +/- 3% of the hemorrhage response in young rats. Pituitary responsiveness to an iv CRF challenge was 58 +/- 6% of that in the young population. These changes were associated with a 38 +/- 5% loss of anterior pituitary CRF receptor number in the aged population. Changes in the hypothalamic regulation of pituitary-adrenal function were also evident in the aged rats. Hypophysial-portal blood concentrations of CRF were significantly greater in aged (56 +/- 6 pM) compared to young rats (37 +/- 4 pM; P < 0.02, by two-tailed unpaired t test; n = 8/group), whereas portal levels of arginine vasopressin were significantly reduced in aged (0.56 +/- 0.01 nM) compared to young rats (0.89 +/- 0.01 nM; P < 0.01, by two-tailed unpaired t test; mean +/- SEM; n = 8/group). Portal CRF responses to hemorrhage were significantly (P < 0.01) greater in aged rats, whereas hemorrhage-stimulated increases in portal AVP levels were significantly (P < 0.01) reduced in the aged group compared to those in the young rats. Finally, regional assay of CRF content demonstrated significant reductions in the median eminence and frontal cortex of aged rats compared to young rats, whereas in situ hybridization analysis failed to reveal age-related differences in paraventricular CRF mRNA levels. Overall, these observations are consonant with the hypothesis that senescence is associated with hypothalamic CRF hypersecretion and a consequent down-regulation of corticotrope CRF receptor.

Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats

Aging is frequently associated with changes in physiological and cognitive processes. Among these changes is a distinct dysregulation of the hypothalamic-pituitary-adrenal axis. In the current experiments, aspects of hypothalamic-pituitary-adrenal axis function were compared in young (3- to 4-month-old) and aged (21- to 24-month-old) Fisher 344/N male rats. Basal ACTH and corticosterone levels during the circadian trough were elevated in aged compared to young rats. During the evening peak of the circadian cycle, plasma ACTH levels in the young and aged rats were comparable; however, aged rats had significantly lower corticosterone levels than young rats. Stimulus-induced secretion of pituitary-adrenal hormones was attenuated in aged rats. The ACTH response to hemorrhage in the aged group was only 45 +/- 3% of the hemorrhage response in young rats. Pituitary responsiveness to an iv CRF challenge was 58 +/- 6% of that in the young population. These changes were associated with a 38 +/- 5% loss of anterior pituitary CRF receptor number in the aged population. Changes in the hypothalamic regulation of pituitary-adrenal function were also evident in the aged rats. Hypophysial-portal blood concentrations of CRF were significantly greater in aged (56 +/- 6 pM) compared to young rats (37 +/- 4 pM; P < 0.02, by two-tailed unpaired t test; n = 8/group), whereas portal levels of arginine vasopressin were significantly reduced in aged (0.56 +/- 0.01 nM) compared to young rats (0.89 +/- 0.01 nM; P < 0.01, by two-tailed unpaired t test; mean +/- SEM; n = 8/group). Portal CRF responses to hemorrhage were significantly (P < 0.01) greater in aged rats, whereas hemorrhage-stimulated increases in portal AVP levels were significantly (P < 0.01) reduced in the aged group compared to those in the young rats. Finally, regional assay of CRF content demonstrated significant reductions in the median eminence and frontal cortex of aged rats compared to young rats, whereas in situ hybridization analysis failed to reveal age-related differences in paraventricular CRF mRNA levels. Overall, these observations are consonant with the hypothesis that senescence is associated with hypothalamic CRF hypersecretion and a consequent down-regulation of corticotrope CRF receptor.