Brain and peripheral angiotensin II play a major role in stress

Angiotensin II (Ang II), the active principle of the renin-angiotensin system (RAS), was discovered as a vasoconstrictive, fluid retentive circulating hormone. It was revealed later that there are local RAS in many organs, including the brain. The physiological receptor for Ang II, the AT(1) receptor type, was found to be highly expressed in many tissues and brain areas involved in the hypothalamic-pituitary-adrenal axis response to stress and in the sympathoadrenal system. The production of circulating and local Ang II, and the expression of AT(1) receptors increase during stress. Blockade of peripheral and brain AT(1) receptors with receptor antagonists administered peripherally prevented the hormonal and sympathoadrenal response to isolation stress, the stress-related alterations in cortical CRF(1) and benzodiazepine receptors, part of the GABA(A) complex, and reduced anxiety in rodents. AT(1) receptor blockade prevented the ulcerations of the gastric mucosa produced by cold-restraint stress, by preservation of the gastric blood flow, prevention of the stress-induced inflammatory response of the gastric mucosa, and partial blockade of the sympathoadrenal response to the stress. Our observations demonstrate that Ang II is an important stress hormone, and that blockade of AT(1) receptors could be proposed as a potentially useful therapy for stress-induced disorders.     

Modifications in basal and stress-induced hypothalamic AMP-activated protein kinase (AMPK) activity in rats chronically treated with an angiotensin II receptor blocker

5' adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor. The role of hypothalamic AMPK in response to restraint and surgical stress has not been previously investigated. It has been recently suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating metabolic pathways including the regulation of the AMPK system. This study was thus aimed to evaluate the effects of candesartan, an angiotensin II AT1 receptor blocker drug, on hypothalamic AMPK activity under basal conditions and after restraint in conscious rats or after surgical stress under general anesthesia. Male Wistar rats were treated with 5 mg/kg/day candesartan in the drinking water for 2 weeks. The hypothalamic AMPK activity was determined under basal and stress conditions, using a kinase activity assay. Chronic administration of candesartan significantly increased hypothalamic AMPK activity. Hypothalamic AMPK activity was also increased by restraint stress whereas no change was observed during surgical stress under anesthesia. The high levels of hypothalamic AMPK activation observed in candesartan-treated rats were not changed by restraint stress but were reduced to control levels by anesthesia and surgery. In conclusion, chronic candesartan treatment and restraint stress in conscious rats stimulate the hypothalamic AMPK activity, whereas surgical stress under anesthesia inhibits pathways regulating the AMPK activity even in candesartan-treated rats.     

Delta-sleep inducing peptide (DSIP) and ACTH (4-10) analogue influence fos-induction in the limbic structures of the rat brain under emotional stress

The effects of the ACTH (4-10) analogue, ACTH (4-7)-Pro-Gly-Pro, and delta-sleep inducing peptide (DSIP) on the induction of Fos immunoreactivity in the hypothalamic parvocellular paraventricular nucleus (pPVN) and limbic brain regions were studied in Wistar rats with high (resistant) or low (predisposed) resistance to emotional stress, predicted from differences in their open-field behaviour. Fos-immunoreactive (Fos-IR) cells were counted in brain sections automatically with a computer-based image analyser. Under basal conditions, Fos-IR cell numbers were greater in the pPVN in the predisposed rats, but were lower than in the resistant rats in the basolateral amygdala and medial and lateral septum. Intraperitoneal DSIP injection (30 μg/kg) increased basal Fos-IR cell number in the pPVN and lateral septum in resistant rats, with no effects in predisposed rats. ACTH (4-10) analogue (50 μg/kg)increased Fos expression in the pPVN in both resistant and predisposed rats, with essentially no effects in the basolateral amygdala or medial and lateral septum. Emotional stress (60 min restraint and intermittent subcutaneous electrical shocks) increased Fos expression in the pPVN and medial and lateral septum similarly in predisposed and resistant rats, but in the basolateral amygdala in only the predisposed rats. Intraperitoneal DSIP injection reduced the increases in Fos-IR cell number after emotional stress, particularly in predisposed rats. In predisposed rats DSIP decreased the number of Fos-IR cells in the pPVN and the medial and lateral septum, with no change in the basolateral amygdala. In resistant rats, DSIP decreased Fos expression only in the lateral septum. ACTH (4-10) analogue injection inhibited stress-induced Fos expression in the pPVN and the medial septum, but only in predisposed rats. The experiments indicate that DSIP and ACTH (4-10) analogue reduce pPVN and limbic neurone responses to emotional stress in the rats predisposed to emotional stress; the effects on Fos expression may play a role in the biological activities of these peptides.     

Chronic administration of an angiotensin II receptor antagonist resets the hypothalamic-pituitary-adrenal (HPA) axis and improves the affect of patients with diabetes mellitus type 2: preliminary results

Diabetes mellitus type 2 (DM type 2) is associated with depressive symptomatology and intermittent hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis. DM type 2 is also accompanied by increased tissue levels of angiotensin II (Ang II), which stimulates the HPA axis through the Ang II type 1 receptors (AT1). We investigated the effect of candesartan, an angiotensin receptor blocker (ARB) that crosses the blood brain barrier, on the activity of the HPA axis and on the affect of 17 patients with DM type 2, aged 40-65 years, who were treated with 4 mg/day candesartan per os for at least 3 months. Before and after candesartan administration, a corticotropin-releasing hormone (CRH) stimulation test and psychological tests were performed. In response to hCRH, time-integrated secretion of ACTH was not altered by candesartan administration, however, the cortisol response was decreased significantly compared to baseline (mean +/- SEM, 2327 +/- 148.3 vs. 1943 +/- 131.9 microg/dl, P = 0.005) suggesting reduced sensitivity of the adrenals to ACTH. In parallel, there was a significant improvement in interpersonal sensitivity (0.91 +/- 0.16 vs. 0.70 +/- 0.15, P = 0.027) and depression scores (0.96 +/- 0.15 vs. 0.71 +/- 0.10, P = 0.026). We suggest that candesartan resets the HPA axis of patients with DM type 2 and improves their affect.     

Effects of acute, repeated and chronic variable stress on in vivo tyrosine hydroxylase activity and on alpha(2)-adrenoceptor sensitivity in the rat brain

We assessed the effects of a single tail pinch and two chronic stress regimes, repeated and variable, on in vivo tyrosine hydroxylase activity and on alpha2-adrenoceptor sensitivity in two brain regions. After administering a 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, tyrosine hydroxylase activity, measured as the accumulation of DOPA, and noradrenaline (NA) content were determined by using high-performance liquid chromatography. A single tail pinch for 5 min induced an enhancement of DOPA content in hippocampus (28%) and hypothalamus (67%) which was still present 24 h later. This increase could account for the lack of changes in NA content in both regions after the application of this stressor. However, tyrosine hydroxylase activity was unmodified 24 h after exposure to both repeated (5 min of tail pinch, twice daily, for 14 days) and chronic variable stress (one of 5 different stressors, once daily, for 14 days) although there was an enhancement of NA levels in hippocampus (45 and 54%, respectively) and hypothalamus (24.5 and 36%, respectively). The sensitivity of the alpha2-adrenoceptors which regulate [3H]-NA release in hippocampal and hypothalamic synaptosomes was not modified by the acute or chronic stress protocols assayed. The results show that both paradigms of chronic stress had similar effects on the noradrenergic indices evaluated.     

The role of the human thalamus in language and memory: evidence from electrophysiological studies

The data reviewed here indicate that electrical stimulation of the dominant ventrolateral thalamus can produce deficits in language processing that are not seen after similar stimulation of the nondominant ventrolateral thalamus. The nature of the language deficit produced varies, depending upon the rostrocaudal location of the stimulation site. Stimulation of the anterior left ventrolateral thalamus in right-handed patients resulted in production of a repeated erroneous word, stimulation of the medial ventrolateral thalamus evoked perseveration, and stimulation of the posterior ventrolateral thalamus and anterior pulvinar resulted in misnaming and omissions. Additional studies have examined the effect of electrical thalamic stimulation on verbal and nonverbal short-term memory. Left (but not right) ventrolateral thalamic stimulation during verbal memory input greatly decreased subsequent recall errors, while stimulation during verbal memory retrieval increased recall errors. This finding contrasted with those obtained from studies on nonverbal memory, in which right ventrolateral stimulation during memory input decreased recall errors, while left thalamic stimulation at the same stage increased recall errors. Left pulvinar stimulation disrupted verbal memory processing, while right pulvinar stimulation disrupted nonverbal memory processing. Limited evidence suggests that the effects of thalamic electrical stimulation on verbal memory may persist for several days after the stimulation has ended. The lateralization of thalamic functions also affects the motoric aspects of speech production. Left (but not right) ventrolateral thalamic stimulation disrupted speech articulation and increased the expiratory phase of respiration. The fact that these motor effects were evoked from the same general area of the thalamus that produced the language deficits discussed above raises the possibility that the thalamus is involved in coordinating the cognitive and motoric aspects of language production. A model of thalamic function is discussed in which defined regions of the thalamus operate as a "specific alerting response," increasing the input to memory of category-specific material while simultaneously inhibiting retrieval from memory.     

Short- and long-term effects of juvenile stressor exposure on the expression of GABAA receptor subunits in rats

During the juvenile period rodents are particularly sensitive to stressors. Aversive events encountered during this period may have enduring effects that are not evident among animals initially stressed as adults. Interestingly, experiencing stressor during juvenile period was found to elicit a biphasic behavioral pattern over the course of development. During the juvenile period, the expression of several GABAA receptor subunits is subject to elevated plasticity, rendering the GABAergic system sensitive to stressors. In the present investigation, animals were exposed to a juvenile variable stressor regimen (JUV-S) at 27-29 postnatal days (PND): 27 PND-acute swim stress (10 min), 28 PND-elevated platform stress (3 sessions×30 min each), and 29 PND-restraint (2 h). One hour following the last exposure to stressor or in adulthood (60 PND), anxiety-related behaviors were assessed in a 5-min elevated plus maze test. The western blotting technique was used to evaluate whether the juvenile stress induced behavioral pattern will be accompanied by respective changes in GABAA α1, α2, and α3 protein expression in male rats. Our findings further established that juvenile stressor elicits hyper-reactivity when rats were tested as juveniles, whereas rats exhibited reduced activity and increased anxiety when tested as adults. Additionally, the effects of juvenile stressor on α1, α2, and α3 were more pronounced among juvenile stressed rats that were challenged as adults compared with rats that were only challenged as juveniles. Interestingly, the stress-induced modulation of the subunits was particularly evident in the amygdala, a brain region closely associated with anxiety. Thus, age- and region-specific alterations of the α subunits may contribute to the age-specific behavioral alterations observed following juvenile stress exposure.     

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.     

Stress-induced progesterone secretion and progesterone receptor immunoreactivity in the paraventricular nucleus are modulated by pubertal development in male rats

Male rats show a differential adrenocortical response to stress before and after pubertal development, such that prepubertal animals have a more prolonged stress-induced corticosterone response compared to adults. Whether pubertal maturation affects other adrenocortical responses to stress is currently unknown. To address this question, we assessed stress-induced progesterone secretion in both intact and gonadectomized prepubertal (28 days of age) and adult (77 days of age) male rats either before or after exposure to a 30 min session of restraint stress. We found that prepubertal males show a greater and more prolonged stress-induced progesterone response compared to adults. We also found a similar effect in castrated prepubertal and adult males, indicating the differential stress-induced progesterone response is not gonadal in origin. We also examined progesterone receptor (PR) levels by immunohistochemistry in the paraventricular nucleus (PVN) of the hypothalamus, a key regulatory nucleus of the hypothalamic-pituitary-adrenal (HPA) axis, and found lower PR protein expression in the PVN of prepubertal compared to adult males. These data indicate that in addition to corticosterone, stress-induced adrenocortical progesterone levels are differentially affected by pubertal maturation. Furthermore, these data raise the possibility of different progesterone sensitivity of the PVN before and after puberty. The significance of this differential response is presently unknown. However, given the pleiotropic effects of progesterone on male physiology and behaviour, it is likely that the disparate post-stress exposure to progesterone affects the prepubertal and adult male differently.     

Why Dexamethasone Poorly Penetrates in Brain

Dexamethasone poorly penetrates in brain. A tracer amount of [3H]-dexamethasone administered to adrenalectomized rats or mice is poorly retained by glucocorticoid receptors in brain, while pituitary corticotrophs containing equivalent amounts of these receptors accumulate and retain large amounts of this synthetic steroid. However, adrenalectomized mice with a genetic disruption of the multiple drug resistance (mrd1a) gene have a tenfold increase of [3H]-dexamethasone uptake in brain glucocorticoid target sites reaching levels observed in the pituitary. These data demonstrate that dexamethasone is extruded from brain by the mrd1a-encoded P-glycoproteins. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release, which implies that chronic dexamethasone treatment does not replace the endogenous corticosteroids depleted from brain mineralocorticoid (MRs) and glucocorticoid receptors (GRs). Dexamethasone, therefore, causes a profound disturbance in the balance of these two receptor types in hippocampus, which is an unfavourable condition threatening the neuronal integrity of this brain structure through the expression of noxious genes.     

中枢N-甲基-D-天冬氨酸受体在应激所致行为改变中的作用

应激所致行为效应的脑机制研究是目前生理心理学研究的热点领域。近年来,对于参与应激所致行为效应的神经递质研究从5-HT、多巴胺和去甲肾上腺素的范畴,逐渐发展到关注脑内含量最为丰富的谷氨酸能神经元所产生的兴奋性递质,包括谷氨酸、天冬氨酸及其相应受体NMDAR可能在应激性行为效应的中枢机制中的作用。近十年来的研究表明,中枢NMDAR是学习记忆的关键物质,在兴奋性突触传递、突触可塑性和脑发育过程中扮演重要的角色。不同类型的应激能导致动物的与行为密切相关脑区如杏仁核,海马的兴奋性氨基酸及NMDAR数量增多,活性增高。突触间隙增多的兴奋性氨基酸与NMDAR结合后,通过激活NMDAR促进糖皮质激素的相关性释放,共同产生的兴奋毒性作用引起上述脑区的神经元细胞缺失和变性;或干扰其他中枢神经递质在动物行为的脑内奖赏机制中的正常功能;或通过持续激活NMDAR,导致细胞内Ca2＋超载,损害其信号传导途径下游的蛋白激酶级联反应,使其底物蛋白的磷酸化或去磷酸化作用发生改变,影响突触可塑性和神经细胞间的信号传递,导致动物出现相应的行为障碍。应激前给动物的上述脑区注射NMDAR阻滞剂,可以减轻动物的应激性焦虑和抑郁行为。而NMDAR依赖性LTP下游途径的新信号分子,神经颗粒素,参与了脑内多种蛋白信号传导,可能是应激性行为效应的另一重要中枢机制。     

Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.     

Angiotensin-(1-7)/Mas axis integrity is required for the expression of object recognition memory

It has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1-7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1-7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1-7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1-7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1-7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1-7)/Mas axis is essential for normal ORM processing.     

Inhibition of the LH Surge by Restraint Stress in Cyclic Rats: Studies on the Role of GABAA and GABAB Receptors

There is evidence that stress can alter the activity in the brain of gamma-aminobutyricacid (GABA), a neurotransmitter that has been implicated in the regulation of LH secretion. In the present study the role of GABA in the restraint stress-induced inhibition of the LH surge was investigated in the intact cyclic rat. Intracerebroventricular (icv) administration of the GABAA receptor agonist muscimol (0.1, 0.5 or 1 μg) 5 min before the presumed onset of the pro-oestrous LH surge (at 0900 h) caused a dose dependent suppression of the surge. A single dose of the GABAB receptor agonist baclofen (1 μg; icv) injected at 0855 h postponed the onset of the LH surge, and repeated injections at 0855 and 1130 h suppressed the surge. These data indicate that GABA-ergic activity in the brain can inhibit the LH surge in the cyclic rat via GABAA and GABAB receptors. Pro-oestrous rats were subjected to 5 hrs of restraint starting at 0855 h. Pretreatment with the GABAA receptor antagonist bicuculine (1 μg; icv) at 0840, 0940 and 1040 h or pretreatment with the GABAB receptor antagonist phaclofen (10 μg; icv) at 0840 h were ineffective in preventing the restraint-induced inhibition of the LH surge. The results suggest that GABAA and GABAB receptors are not involved in the inhibitory effect of restraint stress on the LH surge.     

Opiate receptor binding in the brain of rat during stress

Two types of opioid receptors were studied in the brain of rats: Delta (for endogenous opiate) and mu (for exogenous opiates).³H derivates: D-Ala²-enkephalin and Naloxone were used as labeled ligands. The results obtained were calculated by computer program for automatic estimation of the data using approximation equations. An increase of binding delta receptors is observed in both types of stress (2–8 times), while to the mu receptors the binding is less effective mainly after irradiation. These data suggest that a close interaction exists between sympathoadrenal system and opioid mechanisms during stress.     

Microinjections of the dopamine D2 receptor antagonist sulpiride into the medial prefrontal cortex attenuate glucocorticoid-induced impairment of long-term memory retrieval in rats

We recently reported that blockade of dopamine (DA) D2 receptors attenuated deficits in long-term memory retrieval induced by a systemic injection of corticosterone, but the anatomical sites of such interaction were not known. In this study, we investigated whether the DA D2 receptors located in the medial prefrontal cortex (mPFC) may play a role in the impairing effects of glucocorticoids on the memory retrieval process. Young adult male rats were trained in a one trial inhibitory avoidance task (0.5 mA, 3s footshock). On the retention test given 48 h after training, the latency to re-enter the dark compartment and the time spent in light compartment of the apparatus were recorded. Systemically administered corticosterone (1mg/kg) given to rats 30 min before retention testing impaired their memory retrieval. Bilateral microinjections of the DA D2 receptor antagonist sulpiride (10 or 100 ng/0.5 microl per side) into the mPFC 30 min before corticosterone administration attenuated the glucocorticoid-induced impairment of memory retrieval. Furthermore, applied doses of sulpiride alone were ineffective in modulating memory retrieval. These findings indicate that D2 receptors located in the mPFC play an important role in mediating the impairing effects of glucocorticoids on memory retrieval.     

Correlation between Changes in Stress-Induced Corticosterone Secretion and GR mRNA Levels

The current study was conducted to determine the potential relationship between stress-induced corticosterone secretion and corticosteroid receptor mRNA levels after 5 days of intermittent stress. In particular, we were interested in the rate at which animals terminate a stress response, and how this termination may be altered by repeated stress. Adult male Sprague-Dawley rats were subjected to either 5 days of restraint stress or 5 days of an unpredictable stress paradigm. Restraint-stress induced corticosterone secretion was measured on Days 1 and 5 in both groups, and animals were killed on Day 6. Glucocorticoid receptor (GR), and mineralocorticoid (MR) mRNA levels were determined using in-situ hybridization techniques. Five days of restraint stress caused an habituation of the plasma corticosterone response to stress measured 60 and 90 min post-stress initiation; this pattern of corticosterone secretion was not observed in the animals subjected to unpredictable stress. Five days of either stress paradigm did not alter MR mRNA levels measured within the hippocampus or GR mRNA levels within the hippocampus or the medial parvocellular division of the paraventricular nucleus of the hypothalamus (mpPVN). However, an individual's GR mRNA levels measured within the CA1/2 region of the hippocampus and the mpPVN were significantly correlated with the degree of habituation of the corticosterone response to stress measured on Day 5. This suggests that an increase in the rate of termination of the stress response and levels of GR within the hippocampus and mpPVN may be functionally related.     

Blockade of NMDA receptors in the amygdala prevents latent inhibition of fear-conditioning

The association between a conditioned stimulus (CS) and an unconditioned stimulus (US) in fear-conditioning depends on N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala complex (BLA). Latent inhibition (LI) is the retardation in learning due to nonreinforced presentation of the prospective CS before conditioning. Disruption of LI in rats is an animal model of schizophrenia, reflecting the deficits of schizophrenic patients in neglecting irrelevant information. We investigated whether the BLA is involved in LI of fear-potentiated startle. Infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5; 12.5 nmoles) into the BLA before preexposure of rats to the neutral stimulus prevent LI of fear-conditioning. We also demonstrated by the same method that a complex of thalamic nuclei, comprising the medial part of the medial geniculate nucleus, the posterior intralaminar nucleus, and the suprageniculate nucleus, is involved in fear-conditioning, but not in LI. This suggests that the presentation of an innocuous stimulus during preexposure leads to an NMDA receptor-dependent change of neurotransmission in the BLA, but not in the thalamus. Our data show that the BLA but not the thalamus regulates in LI of fear-potentiated startle. Furthermore, it supports the hypothesis that the inability of schizophrenic patients to ignore irrelevant stimuli may be caused by hypofunction of the glutamatergic transmission in the brain and suggests an involvement of the amygdala in the neuropathology of schizophrenia.     

Effect of chronic intermittent immobilization stress on Fos-like immunoreactivity in rat brain and adrenal medulla

The present study examined the influence of short- and long-term chronic intermittent immobilization stress throughout the brain and on the adrenal medulla of intact rats using Fos-like immunoreactivity (Fos-LI) as a marker of cellular activation. The effect of adreno-medullectomy on the central nervous system (CNS) response to chronic immobilization stress was also examined. It was found that control unoperated, unstressed rats had no Fos-LI cells in the brain or in the adrenal medulla. In intact rats, neither short term (1 week) nor long term (4 weeks) chronic intermittent immobilization stress produced significant increases in Fos-LI in the CNS compared with control animals. However, marked increase in the number of Fos-LI cells was observed in the adrenal medulla of animals stressed for 4 weeks compared with control, unstressed animals or those stressed for 1 or 2 weeks. In adreno-medullectomised rats, 4 weeks, but not 1 week, chronic immobilization stress produced significant increases in numbers of Fos-LI neurons in the paraventricular hypothalamic and supraoptic nuclei and the medial amygdala compared with intact animals stressed for a similar period of time. It is concluded that long term stress produces chronic Fos-LI in the adrenal medulla and that adreno-medullectomy increases the Fos response of the PVN, supraoptic nucleus and medial amygdala to long term stress.     

Hippocampal infusions of glucose reverse memory deficits produced by co-infusions of a GABA receptor agonist

Although septal infusions of glucose typically have positive effects on memory, we have shown repeatedly that this treatment exacerbates memory deficits produced by co-infusions of gamma-aminobutyric acid (GABA) receptor agonists. The present experiments tested whether this negative interaction between glucose and GABA in the medial septum would be observed in the hippocampus, a brain region where glucose typically has positive effects on memory. Specifically, we determined whether hippocampal infusions of glucose would reverse or exacerbate memory deficits produced by hippocampal co-infusions of the GABA receptor agonist muscimol. Fifteen minutes prior to either assessing spontaneous alternation (SA) or continuous multiple trial inhibitory avoidance (CMIA) training, male Sprague-Dawley-derived rats were given bilateral hippocampal infusions of vehicle (phosphate-buffered saline [PBS], 1 microl/2 min), glucose (33 or 50 nmol), muscimol (0.3 or 0.4 microg, SA or 3 microg, CMIA) or muscimol and glucose combined in one solution. The results indicated that hippocampal infusions of muscimol alone decreased SA scores and CMIA retention latencies. More importantly, hippocampal infusions of glucose, at doses that had no effect when infused alone, attenuated (33 nmol) or reversed (50 nmol) the muscimol-induced memory deficits. Thus, although co-infusions of glucose with muscimol into the medial septum impair memory, the present findings show that an opposite effect is observed in the hippocampus. Collectively, these findings suggest that the memory-impairing interaction between glucose and GABA in the medial septum is not a general property of the brain, but rather is brain region-dependent.