Nobusuke Tan

Mild prenatal stress enhances learning performance in the non-adopted rat offspring.

The present study was designed to investigate whether mild stress during pregnancy affects offspring behaviors, including learning performance. Prenatal stress was induced by short-lasting, mild restraint stress, which had previously been shown to facilitate the morphological development of fetal brain neurons. Adult offspring whose dams had been restrained in a small cage for 30min daily from gestation day 15 to 17 showed enhanced active avoidance and radial maze learning performance. In addition, the prenatally stressed rats showed weaker emotional responses than unstressed control, as indicated by decreases both in ambulation upon initial exposure to an open field and in Fos expression in the amygdala induced by physical stress. The observed effects of prenatal stress on learning performance and emotional behavior were attenuated by foster rearing by unstressed dams. Fos expression in the hypothalamic paraventricular nucleus following physical stress and corticosterone secretion during physical and psychological stress did not differ between the prenatally stressed and unstressed control rats. From these results we suggest that mild prenatal stress facilitates learning performance in the adult offspring. The enhancement of learning performance appears to be accompanied by reduced emotionality, but not by any apparent alterations in hypothalamic-pituitary-adrenal responses. In addition, the observation of differential behaviors in the adopted and non-adopted animals supports the notion that the postnatal environment modifies the behavioral effects of prenatal stress.

The central role of corticotrophin-releasing factor (CRF-41) in psychological stress in rats.

1. We investigated the central role of corticotrophin‐releasing factor (CRF‐41) in psychological stress‐induced responses, including cardiovascular, thermoregulatory and locomotive activity in free‐moving rats. 2. Psychological stress was induced by cage‐switch stress. After rats were placed in the novel environment, blood pressure, heart rate, body temperature and locomotive activity significantly increased. The intracerebroventricular (I.C.V.) injection of alpha‐helical CRF(9‐41), a CRF‐41 receptor antagonist, significantly attenuated the stress‐induced hypertension, tachycardia, hyperthermia and increase in locomotive activity. However, in unstressed rats, the I.C.V. injection of alpha‐helical CRF(9‐41) had no effect on physiological parameters measured in this study. 3. In unstressed rats, the I.C.V. injection of CRF‐41 (1 microgram and 10 micrograms) increased blood pressure, heart rate, body temperature and locomotive activity in a dose‐dependent manner. The changes in these responses were quite similar to those observed during cage‐switch stress. 4. The results suggest that central CRF‐41 plays an important role in psychological stress‐induced hypertension, hyperthermia, tachycardia and increase in locomotive activity. However, it is likely that central CRF‐41 does not contribute to normal cardiovascular and body temperature regulation when rats are free from stress.

Sympatho-adrenal involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism.

We investigated the involvement of the sympatho-adrenal axis in the hyperthermia induced by methamphetamine by using a biotelemetric system. The intraperitoneal injection of methamphetamine (1 mg/kg) induced hyperthermia preceded by an increase in oxygen consumption in freely moving rats. The hyperthermic effect of methamphetamine was completely blocked by chemical sympathectomy with 6-hydroxydopamine (50 mg/kg, i.p.). Adrenalectomy, but not adrenal demedullation, prevented the hyperthermia. In adrenalectomized rats, dexamethasone supplementation (0.5 mg/kg, s.c.) restored the methamphetamine-induced hyperthermia. Furthermore, dantrolene (1 or 2 mg/kg, i.v.), which blocks Ca2+ release from the sarcoplasmic reticulum in skeletal muscle, attenuated the hyperthermia. These results suggest that methamphetamine stimulates norepinephrine release from sympathetic nerve terminals, which then enhances thermogenesis in skeletal muscle under the permissive action of glucocorticoids.

Modulating effects of prenatal stress on hyperthermia induced in adult rat offspring by restraint or LPS-induced stress.

The present study was carried out to investigate the effects of prenatal stress on stress-induced hyperthermia in adult rats. Prenatal stress was administered daily for 3 days (embryonic days 15-17) by restraining pregnant rats in a small cage either for 30 or 240 min. After birth, foster mothers raised the pups. Offspring were tested at 9-10-weeks-old. Changes in body temperature and in the plasma concentrations of corticosterone, norepinephrine (NE), and epinephrine (Epi) induced by restraint or lipopolysaccharide (LPS)-induced stress were examined. By comparison with the prenatally nonstressed control group, the 240-min stress group showed a significantly lower hyperthermia in response to restraint stress but a higher fever after injection of LPS. The 30-min stress group showed similar alterations in these hyperthermic responses but did not reach significance. Both the restraint stress and the injection of LPS evoked greater increases in the plasma level of corticosterone in the 240-min stress group than in the control group. Although restraint stress induced significant increases in NE and Epi in the control and 30-min stress groups, the plasma levels of these catecholamines did not increase in the 240-min stress group. These results demonstrate for the first time that prenatal stress has opposite effects on the hyperthermic responses to restraint and LPS injection, suggesting that different mechanisms underlie the modulating effects of prenatal stress on the responses to the two types of stressors.

Cardiovascular responses induced in free-moving rats by immune cytokines.

1. We investigated the effect of intraperitoneal (I.P.) injections of the immune cytokines, interleukin‐1 beta (IL‐1 beta) and tumour necrosis factor (TNF) on cardiovascular responses in free‐moving rats, using a biotelemetry system. 2. The I.P. injection of a small dose of IL‐1 beta (1 microgram/kg) induced a monophasic increase in the heart rate, and that of a large dose (10 micrograms/kg) induced biphasic increases in the blood pressure and heart rate. However, the I.P. injection of any of several doses of TNF (1, 10 and 50 micrograms/kg) had no effect on cardiovascular responses in rats. 3. Pre‐treatment with I.P. injection of indomethacin (10 mg/kg), an inhibitor of cyclo‐oxygenase, significantly suppressed the cardiovascular responses and the increase in the plasma noradrenaline (NA) concentration induced by I.P. injection of IL‐1 beta. 4. Microinjection of IL‐1 beta (1 and 10 ng) into the preoptic and anterior hypothalamic (PO‐AH) region induced dose‐dependent increases in the blood pressure and heart rate in rats. These responses were also suppressed by pretreatment with I.P. indomethacin (10 mg/kg). In addition, microinjection of prostaglandin E2 (20 and 100 ng) into the PO‐AH region increased blood pressure and heart rate, but that of prostaglandin D2 (100 ng) had no effect. 5. The present results suggest that IL‐1 beta stimulates the release of prostaglandins, presumably E series, near regions of the hypothalamus, which act on the hypothalamus to induce activation of the sympathetic nervous system. Subsequently, the blood pressure, heart rate and the plasma level of NA increase.

ACTH response induced in capsaicin-desensitized rats by intravenous injection of interleukin-1 or prostaglandin E.

1. We investigated whether afferent nerves are involved in the development of adrenocorticotrophic hormone (ACTH) responses induced either by systemic administration of interleukin‐1 beta (IL‐1 beta) and prostaglandin E2, or by psychological stress. The capsaicin desensitization method was used to impair afferent C fibres and we compared the ACTH responses between capsaicin desensitized and vehicle pretreated control rats. 2. The present results showed that the capsaicin desensitized rats had significantly smaller increases in plasma ACTH than the control rats in response to intravenous injection of IL‐1 beta or prostaglandin E2. 3. There were no significant differences between the capsaicin desensitized and control rats in the ACTH responses induced by cage switch stress. 4. The capsaicin desensitized rats responded to intravenous injection of corticotrophin releasing factor (CRF) with a greater increase in the plasma level of ACTH than the control rats, indicating that capsaicin pretreatment resulted in augmentation of pituitary gland sensitivity to CRF. 5. These results suggest that afferent neurons play an important role in the ACTH responses induced by systemic injection of IL‐1 beta or prostaglandin E2.

Spontaneous wheel running attenuates cardiovascular responses to stress in rats

We investigated the effect of chronic, 10-week spontaneous wheel running (SWR) exercise on stress-induced cardiovascular responses in free-moving male rats, using a biotelemetry system. During cage-switch stress or immobilization stress, blood pressure and heart rate were significantly increased in both the SWR (P<0.001 for each stress) and control groups (P<0.001 for each stress). However the blood pressure response was attenuated significantly in the SWR group (P<0.001) during cage-switch stress, and the blood pressure and heart rate responses were attenuated significantly in the SWR group (P<0.0001 and 0.01, respectively) during immobilization stress. The plasma norepinephrine (NE) response induced by immobilization stress tended to be attenuated in the SWR group, but the groups showed no significant differences in the plasma NE and epinephrine (E) responses to both stresses. These results suggest that daily SWR in rats has beneficial effects in suppressing excessive blood pressure and heart rate responses induced by two different types of stress. The mechanisms responsible for the greater resistance to these stresses in the SWR rats should be investigated further.

Effects of running training on the blood glucose and lactate in rats during rest and swimming

The purpose of this study was to examine the effect of physical training on the concentrations of glucose and lactate in the blood of rats during rest and after an acute bout of exercise. We used the following types and periods of training; (i) swimming for 4 weeks, (ii) running for 4 weeks, and (iii) running for 10 weeks. The results clearly show that the resting levels of blood glucose was significantly lower in groups trained by either swimming or running than untrained groups. In addition, after the acute exercise of swimming, animals trained by either running or swimming showed a lower increase in the blood lactate than untrained animals. Furthermore, the increases in the blood glucose after swimming were significantly lower in the group trained by swimming for 4 weeks and by running for 10 weeks than in untrained groups. These results suggest that after physical training by running, animals show an adaptation in the changes in the blood glucose and the blood lactate that are induced by a different type of physical stress, swimming.

Possible involvement of glucocorticoids in the modulation of interleukin-1-induced cardiovascular responses in rats.

1. In freely moving rats, we investigated whether glucocorticoids modulate the cardiovascular responses to intraperitoneal (I.P.) injection of interleukin‐1 beta (IL‐1 beta). 2. A lower dose of IL‐1 beta (1 microgram kg‐1, I.P.) induced monophasic increases, and a higher dose (10 micrograms kg‐1, I.P.) induced biphasic increases in both blood pressure and heart rate. Plasma concentration of corticosterone increased significantly after injection of IL‐1 beta (10 micrograms kg‐1). 3. Systemic pretreatment with an exogenous glucocorticoid, dexamethasone (DEX; 0.5 mg kg‐1) reduced the monophasic pressor response, the first phase of the biphasic pressor response and also the initial tachycardia. By contrast, the second phase of the biphasic pressor response was enhanced. 4. After bilateral adrenalectomy, the IL‐1 beta (10 micrograms kg‐1)‐induced pressor effect was reduced; it was restored by treatment with DEX (0.5 mg kg‐1). The heart rate response was enhanced in adrenalectomized (ADX) rats; this enhancement was attenuated by DEX. 5. IL‐1 beta (10 micrograms kg‐1)‐induced increases in plasma noradrenaline (NA) were suppressed in intact rats pretreated with DEX (0.5 mg kg‐1). The IL‐1 beta‐induced NA response was greater in ADX rats than in sham‐ADX rats. 6. We suggest that glucocorticoids are an important modulator of cardiovascular responses induced in rats by systemically administered IL‐1 beta.

Febrile responses induced in adrenalectomized rats by administration of interleukin‐1 beta or prostaglandin E2.

1. The present study was carried out to investigate the effect of bilateral adrenalectomy on fevers induced in rats by systemic injection of interleukin‐1 beta (IL‐1 beta) or by central injection of prostaglandin E2 (PGE2). 2. Intraperitoneal (I.P.) injections of two doses of IL‐1 beta (0.5 and 1.0 microgram kg‐1) induced biphasic fevers in normal control rats in a dose‐dependent manner. Adrenalectomized (ADX) rats showed higher fevers than sham‐ADX rats after I.P. injection of small doses of IL‐1 beta (0.5 micrograms kg‐1). This fever enhancement was inhibited by acute or chronic glucocorticoid, dexamethasone (DEX), treatment. In contrast, there was no significant difference between fevers induced in ADX and sham‐ADX rats by I.P. injection of large doses of IL‐1 beta (1.0 g kg‐1). 3. Dose‐dependent fevers were observed in normal control rats after injections of several doses of PGE2 (5, 25 and 100 ng) into the preoptic hypothalamic area (POA). The injection of a large dose of PGE2 (100 ng) into the POA led to a lower fever in ADX rats, compared with that in sham‐ADX rats. This fever in ADX rats was increased by acute or chronic treatment with DEX. On the other hand, adrenalectomy had no effect on fevers induced by the injections of small doses of PGE2 (5 and 25 ng) 4. The injections of PGE2 (100 ng) into the POA induced increases in oxygen consumptions in ADX rats that were significantly smaller than those in sham‐ADX rats, suggesting that the lower PGE2 fever was, at least in part, due to attenuated thermogenesis in ADX rats. 5. There was no significant difference in plasma osmolality between the ADX and the sham‐ADX rats. The ADX rats were given 0.9% salt water instead of tap water. 6. These results suggest that endogenous glucocorticoid is one of the important modulators of the IL‐1‐induced and the PGE2‐induced fevers in rats.