Hippocampal remodeling and damage by corticosteroids: implications for mood disorders.

Mood disorders are common, recurrent and disabling illnesses which are frequently associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and memory loss. The hippocampus provides negative feedback to the HPA axis and has an important role in key aspects of spatial and declarative memory. Thus, hippocampal dysfunction could account for both the memory impairment and neuroendocrine abnormalities found in mood disorders. The critical role of the hippocampus in declarative memory, emotional processing, and vulnerability to stress has been demonstrated in both animal and human studies. Cellular processes in the hippocampus including long-term potentiation, neurogenesis, and dendritic remodeling are currently areas of intense study. Human studies report cognitive impairment consistent with hippocampal dysfunction in depression, bipolar disorder, Cushing's disease, and in those individuals receiving exogenous corticosteroids. This review examines data on the role of corticosteroids in hippocampal remodeling and atrophy in patients with mood disorders. Interventions to prevent or reverse the damaging effects of corticosteroids on the hippocampus are discussed.     

Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI

Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100 mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11–19 min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.     

Chotosan,a Kampo Formula,Ameliorates Hippocampal LTD and Cognitive Deficits in Juvenile-Onset Diabetes Rats

Childhood-onset type 1 diabetes is associated with modest impairments in cognition and has an elevated risk of cognitive decline. Our previous study showed that working memory and hippocampal long-term depression (LTD) were impaired in juvenile-onset diabetes mellitus (JDM) rats. In this study, we investigated the effect of chotosan (CTS), a traditional herbal formula called a Kampo medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on JDM rats. The repeated treatment with CTS (1 g/kg per day) for 3 – 7 days restored spatial working memory and hippocampal LTD in JDM rats. The expression level of NR2B glutamate receptor subunits, but not other glutamate receptor subunits was enhanced in the hippocampus of JDM rats, and repeated treatment with CTS reversed these changes. These results suggest that CTS improves diabetes-induced cognitive deficits by modulating NMDA-receptor subunit expression.     

Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy

Hypoxic-ischaemic (HI) encephalopathy is a severe complication of perinatal asphyxia and remains a frequent cause of a variety of brain disorders with long-term effects on the patients' life. The associated brain damage is strongly related to the toxic action of excitatory amino acids, especially glutamate and aspartate. Lamotrigine is an anti-epileptic drug that blocks the voltage-gated sodium channels of the presynaptic neuron and inhibits the release of glutamate. In the present study a well-established model of perinatal asphyxia in 7-d-old rats was used to investigate the effect of lamotrigine on HI-induced damage to different hippocampal brain structures, since disruption of this brain area is thought to play a key role in schizophrenia and epilepsy. Therefore, a combination of ischaemia, induced by unilateral occlusion of the left common carotid artery, followed by exposure to a 1-h period of hypoxia, was carried out in neonatal 7-d-old rats. Immediately after the insult, lamotrigine was given i.p. The histological outcome in the hippocampus was conducted and the tissue levels of glutamate, aspartate, GABA, and glutamine in the same area were determined. A remarkable reduction of HI-evoked damaged neurons in most of the investigated hippocampal regions was noted after lamotrigine administration. Furthermore, lamotrigine decreased the asphyxia-induced hippocampal tissue levels of glutamate and aspartate. Immediately after perinatal asphyxia GABA levels were enhanced, while levels of glutamine were decreased. Lamotrigine administration did not affect either GABA or glutamine levels. These results suggest a neuroprotective effect of lamotrigine in this particular animal model of neonatal HI encephalopathy.     

The role of hippocampus in the pathophysiology of bipolar disorder

Bipolar disorder (BD) is thought to be associated with abnormalities within discrete brain regions associated with emotional regulation, particularly in fronto-limbic-subcortical circuits. Several reviews have addressed the involvement of the prefrontal cortex in the pathophysiology of BD, whereas little attention has been given to the role of the hippocampus. This study critically reviews data from brain imaging, postmortem, neuropsychological, and preclinical studies, which suggested hippocampal abnormalities in BD. Most of the structural brain imaging studies did not find changes in hippocampal volume in BD, although a few studies suggested that anatomical changes might be restricted to the psychotic, pediatric, or unmedicated BD subgroups. Functional imaging studies showed abnormal brain activation in the hippocampus and its closely related regions during emotional, attentional, and memory tasks. This is consistent with neuropsychological findings that revealed a wide range of cognitive disturbances during acute mood episodes and a significant impairment in declarative memory during remission. Postmortem studies indicate abnormal glutamate and GABA transmission in the hippocampus of BD patients, whereas data from preclinical studies suggest that the regulation of hippocampal plasticity and survival might be associated with the therapeutic effects of mood stabilizers. In conclusion, the available evidence suggests that the hippocampus plays an important role in the pathophysiology of BD.     

Interactive effects of chronic cigarette smoking and age on hippocampal volumes

Background

Previous cross-sectional MRI studies with healthy, young-to-middle-aged adults reported no significant differences between smokers and non-smokers on total hippocampal volume. However, these studies did not specifically test for greater age-related volume loss in the total hippocampus or hippocampal subregions in smokers, and did they did not examine relationships between hippocampal and subfield volumes and episodic learning and memory performance.

Methods

Healthy, young-to-middle-aged (45 ± 12 years of age) smokers (n = 39) and non-smokers (n = 43) were compared on total hippocampal and subfield volumes derived from high-resolution 4 Tesla MRI, emphasizing testing for greater age-related volume losses in smokers. Associations between hippocampal volumes and measures of episodic learning and memory were examined.

Results

Smokers showed significantly smaller volumes, as well as greater volume loss with increasing age than non-smokers in the bilateral total hippocampus and multiple subfields. In smokers, greater pack-years were associated with smaller volumes of the total hippocampus, presubiculum, and subiculum. In the entire cohort, performance on measures of learning and memory was related to larger total hippocampal and several subfield volumes, predominately in the left hemisphere.

Conclusions

Chronic cigarette smoking in this young-to-middle aged cohort was associated with smaller total hippocampal and subfield volumes, which were exacerbated by advancing age. Findings also indicated an adverse smoking dose/duration response (i.e., pack-years) with total hippocampal and select subfield volumes. These hippocampal volume abnormalities in smokers may be related to the deficiencies in episodic learning and memory in young-to-middle-aged smokers reported in previous studies.     

NMDA receptor-mediated pilocarpine-induced seizures: characterization in freely moving rats by microdialysis

1. Pilocarpine administration has been used as an animal model for temporal lobe epilepsy since it produces several morphological and synaptic features in common with human complex partial seizures. Little is known about changes in extracellular neurotransmitter concentrations during the seizures provoked by pilocarpine, a non-selective muscarinic agonist.
2. Focally evoked pilocarpine-induced seizures in freely moving rats were provoked by intrahippocampal pilocarpine (10 mM for 40 min at a flow rate of 2 μl min⁻¹) administration via a microdialysis probe. Concomitant changes in extracellular hippocampal glutamate, γ-aminobutyric acid (GABA) and dopamine levels were monitored and simultaneous electrocorticography was performed. The animal model was characterized by intrahippocampal perfusion with the muscarinic receptor antagonist atropine (20 mM), the sodium channel blocker tetrodotoxin (1 μM) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine maleate, 100 μM). The effectiveness of locally (600 μM) or systemically (10 mg kg⁻¹ day⁻¹) applied lamotrigine against the pilocarpine-induced convulsions was evaluated.
3. Pilocarpine initially decreased extracellular hippocampal glutamate and GABA levels. During the subsequent pilocarpine-induced limbic convulsions extracellular glutamate, GABA and dopamine concentrations in hippocampus were significantly increased. Atropine blocked all changes in extracellular transmitter levels during and after co-administration of pilocarpine. All pilocarpine-induced increases were completely prevented by simultaneous tetrodotoxin perfusion. Intrahippocampal administration of MK-801 and lamotrigine resulted in an elevation of hippocampal dopamine levels and protected the rats from the pilocarpine-induced seizures. Pilocarpine-induced convulsions developed in the rats which received lamotrigine perorally.
4. Pilocarpine-induced seizures are initiated via muscarinic receptors and further mediated via NMDA receptors. Sustained increases in extracellular glutamate levels after pilocarpine perfusion are related to the limbic seizures. These are arguments in favour of earlier described NMDA receptor-mediated excitotoxicity. Hippocampal dopamine release may be functionally important in epileptogenesis and may participate in the anticonvulsant effects of MK-801 and lamotrigine. The pilocarpine-stimulated hippocampal GABA, glutamate and dopamine levels reflect neuronal vesicular release.

     

Regulation of Hippocampal Cannabinoid CB1 Receptor Actions by Adenosine A1 Receptors and Chronic Caffeine Administration: Implications for the Effects of ��9-Tetrahydrocannabinol on Spatial Memory

The cannabinoid CB₁ receptor-mediated modulation of γ-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A₁ receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A₁ receptors localized in GABAergic cells do not directly influence GABA release. CB₁ and A₁ receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Δ⁹-tetrahydrocannabinol (THC, a CB₁ receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A₁–CB₁ interaction influences GABA and glutamate release in the hippocampus. We found that A₁ receptor activation attenuated the CB₁-mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine–cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, >12 h before trials) led to an A₁-mediated enhancement of the CB₁-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB₁ receptor number and an attenuation of CB₁ coupling with G protein. A₁ receptor levels were increased following chronic caffeine administration. This study shows that A₁ receptors exert a negative modulatory effect on CB₁-mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory.     

Effects of high frequency electrical stimulation and R-verapamil on seizure susceptibility and glutamate and GABA release in a model of phenytoin-resistant seizures

The present study was focused to characterize the effects of intrahippocampal application of R-verapamil, a P-glycoprotein blocker, and High Frequency Electrical Stimulation (HFS) at 130 Hz, on seizure susceptibility and extracellular concentrations of glutamate and γ-aminobutyric acid (GABA) in hippocampus of kindled rats with drug-resistant seizures. Fully kindled rats classified in responsive and non-responsive to phenytoin were used for this purpose. In contrast with responsive animals, non-responsive rats showed lower afterdischarge threshold (ADT) values in pre-kindling conditions and required less number of kindling trials to achieve the kindled state. Once the animals attained the kindled state, both epileptic groups presented high glutamate and low GABA interictal release, effect more evident in non-responsive rats. In hippocampus of responsive animals, GABA levels demonstrated two increases at 120 and 240 min after the ictal event, a situation no detected for non-responsive rats. Kindled animals receiving hippocampal HFS showed augmented ADT, an effect associated with enhanced GABA release in responsive rats. Intrahippocampal perfusion of R-verapamil (5 mM) decreased the seizure susceptibility (high ADT values), enhanced the interictal GABA release and the postictal levels of glutamate and GABA in responsive and non-responsive rats. It is conclude that alterations of glutamate and GABA release in the epileptic hippocampus of non-responsive animals resemble those found in hippocampus of patients with refractory TLE. In addition, intrahippocampal application of HFS and R-verapamil modifies the amino acid release and reduces the seizure susceptibility of both, responsive and non-responsive rats.     

Omega-3 polyunsaturated fatty acids and cognition in a college-aged population

The cognitive influences of omega-3 polyunsaturated fatty acids (n-3 PUFA) remain unclear throughout the life span. Dietary n-3 PUFA appear cognitively beneficial prenatally and neuroprotective at later age; however, researchers using supplementation designs have reported disparate findings across age groups. Few studies have examined the cognitive impact of n-3 PUFA during young adulthood. This study assessed the cognitive effects of fish oil supplementation at college age, hypothesizing benefits on affect, executive control, inhibition, and verbal learning and memory. College-aged participants were assigned to active (n = 20, 5 men; age = 19.9, sage = 1.8) or placebo (n = 21, 7 men; age = 20.4, sage = 1.6) treatments, receiving fish oil (480 mg DHA/720 mg EPA) or coconut oil, respectively. Both groups completed four weeks of supplementation. At baseline and posttreatment, the researchers administered the Rey Auditory Verbal Learning Test (RAVLT; Lezak, 1995), Stroop Color and Word Test (SCWT; Golden & Freshwater, 2002), Trail Making Test (TMT; Corrigan & Hinkeldey, 1987; Gaudino, Geisler, & Squires, 1995; Lezak, 1995), and Positive and Negative Affect Schedule (PANAS; Watson, Clark, & Tellegen, 1988). Repeated-measures ANOVAs indicated no benefits of fish oil on the SCWT, RAVLT Stages 1 to 5, or PANAS. An interaction occurred between condition and time of measurement (i.e., baseline and posttreatment) on RAVLT Stages 6 and 7, and placebo significantly improved TMT performance over fish oil. The benefits of n-3 PUFA on RAVLT performance derived more from depreciated placebo performance than improved performance due to fish oil. The placebo gain on TMT performance likely derived from a learning effect. Together, these results present limited cognitive benefits of n-3 PUFA at college age; however, the treatment may have been subtherapeutic, with a larger sample needed to generalize these results.     

Hydrocortisone impairs working memory in healthy humans, but not in patients with major depressive disorder

Objective

Several studies have shown that stress or the administration of glucocorticoids can impair hippocampus-based declarative memory retrieval and prefrontal dependent working memory performance in healthy subjects. Major Depressive Disorder (MDD) is often characterized by memory impairment and increased cortisol secretion. Studies indicate that the impairing effects of glucocorticoids on declarative memory performance are missing in patients with MDD. The purpose of our study was to investigate whether the finding of missing effects of acute cortisol administration on memory performance in MDD is also seen when examining prefrontal-based working memory.

Methods

In a placebo-controlled study, 57 patients with MDD and 56 sex- and age-matched healthy control subjects received either placebo or 10?mg of hydrocortisone orally before memory testing. To test the verbal modality of working memory, the Word Suppression Test was applied with one negative and one neutral test part.

Results

After hydrocortisone intake, healthy subjects showed a significantly poorer working memory performance compared to placebo treatment when negative interference words were administered. In contrast, memory performance of MDD patients was not affected by hydrocortisone treatment.

Conclusions

The missing effects of glucocorticoid administration on working memory in MDD might be interpreted in the context of reduced central glucocorticoid receptor function.     

A placebo-controlled,cross-over trial of lamotrigine in depersonalization disorder

There is evidence to support the view that glutamate hyperactivity might be relevant to the neurobiology of depersonalization. We tested the efficacy of lamotrigine, which reduces glutamate release, as a treatment for patients with depersonalization disorder. A double-blind, placebo-controlled, cross-over design was used to evaluate 12 weeks of treatment of lamotrigine. Subjects comprised nine patients with DSM-IV depersonalization disorder. Changes on the Cambridge Depersonalization Scale and the Present State Examination depersonalization/derealization items were compared across the two cross-over periods. Lamotrigine was not significantly superior to placebo. None of the nine patients was deemed a responder to the lamotrigine arm of the cross-over. Lamotrigine does not seem to be useful as a sole medication in the treatment of depersonalization disorder.     

Memory ability and hippocampal volume in adolescents with prenatal drug exposure

The objective of the present study was to examine the influence of prenatal drug exposure (PDE) on memory performance and supporting brain structures (i.e., hippocampus) during adolescence. To achieve this goal, declarative memory ability and hippocampal volume were examined in a well-characterized sample of 138 adolescents (76 with a history of PDE and 62 from a non-exposed comparison group recruited from the same community, mean age=14 years). Analyses were adjusted for: age at time of the assessments, gender, IQ, prenatal exposure to alcohol and tobacco, and indices of early childhood environment (i.e., caregiver depression, potential for child abuse, and number of caregiver changes through 7 years of age). Results revealed that adolescents with a history of PDE performed worse on the California Verbal Learning Test-Child Version (CVLT-C), and story recall from the Children's Memory Scale (CMS), and had larger hippocampal volumes, even after covariate adjustment. Hippocampal volume was negatively correlated with memory performance on the CVLT-C, with lower memory scores associated with larger volumes. These findings provide support for long-term effects of PDE on memory function and point to neural mechanisms that may underlie these outcomes.     

Riluzole Partially Rescues Age-Associated, but not LPS-Induced, Loss of Glutamate Transporters and Spatial Memory

Impaired memory may result from synaptic glutamatergic dysregulation related to chronic neuroinflammation. GLT1 is the primary excitatory amino acid transporter responsible for regulating extracellular glutamate levels in the hippocampus. We tested the hypothesis that if impaired spatial memory results from increased extracellular glutamate due to age or experimentally induced chronic neuroinflammation in the hippocampus, then pharmacological augmentation of the glutamate transporter GLT1 will attenuate deficits in a hippocampal-dependent spatial memory task. The profile of inflammation-related genes and proteins associated with normal aging, or chronic neuroinflammation experimentally-induced via a four-week LPS infusion into the IV^th ventricle, were correlated with performance in the Morris water maze following treatment with Riluzole, a drug that can enhance glutamate clearance by increasing GLT1 expression. Age-associated inflammation was qualitatively different from LPS-induced neuro-inflammation in young rats. LPS produced a pro-inflammatory phenotype characterized by increased IL-1ß expression in the hippocampus, whereas aging was not associated with a strong central pro-inflammatory response but with a mixed peripheral immune phenotype. Riluzole attenuated the spatial memory impairment, the elevation of serum cytokines and the decrease in GLT1 gene expression in Aged rats, but had no effect on young rats infused with LPS. Our findings highlight the therapeutic potential of reducing glutamatergic function upon memory impairment in neurodegenerative diseases associated with aging.     

Resting-state functional connectivity after hydrocortisone administration in patients with post-traumatic stress disorder and borderline personality disorder

In a previous study, we found that - in contrast to healthy individuals - patients with borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) showed better memory retrieval performance after hydrocortisone administration compared to placebo. As these results suggest an altered function of corticosteroid receptors in the brain in PTSD and BPD, we examined the effect of hydrocortisone on brain activation in both disorders. We recruited 40 female healthy controls, 20 female unmedicated patients with PTSD and 18 female unmedicated patients with BPD. We conducted a placebo-controlled cross-over study, in which all participants underwent two resting state MRI measurements after they received either a placebo or 10 mg hydrocortisone orally and in randomized order. There was a time interval of one week between the measurements. We analysed resting state functional connectivity (RSFC) with the hippocampus and the amygdala as seed regions. Compared to healthy controls, both patient groups showed reduced hippocampus RSFC to dorsomedial prefrontal cortex (dmPFC). Positive hippocampus dmPFC RSFC correlated negatively with childhood trauma (r = -0.47) and with severity of clinical symptoms, measured with the Borderline Symptom List (r = -0.44) and the Posttraumatic Stress Diagnostic Scale (r = -0.45). We found neither differences in amygdala RSFC nor an effect of hydrocortisone administration. Childhood trauma might lead to decreased positive hippocampus dmPFC RSFC. This might explain symptoms of PTSD and BPD that are characterized by dysfunctional fear regulation.     

Dopamine D<Subscript>2</Subscript> receptor plays a role in memory function: implications of dopamine–acetylcholine interaction in the ventral hippocampus

Rationale The role of the hippocampal dopaminergic system in mnemonic function has not been clarified yet. Objective We previously reported that the dopamine D₂ receptor (D₂R) is involved in the regulation of acethylcholin (ACh) release in the hippocampus. In this study, we further investigated ACh–dopamine (DA) interaction in the hippocampus and its involvement in mnemonic function. Methods For experiment 1, rats fed with Cholin (Ch)-deficient chow were used. We examined the effects of D₂R antagonist, raclopride, on cognitive performance using a passive avoidance task. We further carried out in vivo microdialysis to assess the effect of infusion of D₂R agonist, quinpirole, into the ventral hippocampus on its capacity to release ACh. For experiment 2, rats fed with normal chow were used. The performance of a radial arm maze task was assessed to examine the effects of hippocampal injection of D₂R agonist, quinpirole, on memory impairment induced by scopolamine, a muscarinic ACh antagonist. Results In experiment 1, rats fed with Ch-deficient chow showed impaired performances indicated by prolonged latency on retention trials of a passive avoidance task following the hippocampal injection of D₂R antagonist, and showed reduced capacity to release ACh following the injection of D₂R agonist compared with rats fed with normal chow. In experiment 2, memory impairment induced by the intraperitoneal injection of scopolamine was ameliorated by the injection of D₂R agonist into the ventral hippocampus. Conclusion These results indicate the possible involvement of hippocampal ACh–DA interaction in mnemonic processing.     

Therapeutic implications of HPA axis abnormalities in Alzheimer's disease: review and update

The adaptive and maladaptive roles of the hypothalamic-pituitary-adrenal (HPA) axis in stressful conditions and in disorders such as major depression, posttraumatic stress disorder, and Cushing's syndrome, have been the subject of substantial, ongoing study. In particular, HPA disturbances have been associated with memory impairments, and hypercortisolemic conditions with atrophy of the hippocampus, a limbic structure closely associated with declarative memory. Recent discoveries support a more complicated picture of HPA axis function and pathology in acquiring, retrieving, and consolidating new memories. These findings include: the existence of an 'inverted U-shaped relationship" between stimulation of brain glucocorticoid receptors and memory performance; that distinct areas of the hippocampus have been found to respond differently to cortisol stimulation; and that hippocampal atrophy has been found to be potentially reversible in some conditions, although whether such atrophy is a cause or effect of these pathological conditions is currently unclear. More longitudinal studies of HPA axis function in aging normal individuals, those with mild cognitive impairment,and individuals with Alzheimer' disease, examining pertinent variables such as APOEe-4 status, are needed to help clarify these new findings. Antiglucocorticoid agents appear to have therapeutic value in particular conditions. These results are relevant for understanding and treating memory dysfunction in individuals with Alzheimer's disease, a disorder prominently and invariably characterized by early hippocampal lesions and memory impairment. Given the burden of this disease, we feel it timely to encourage controlled trials of antiglucocorticoid agents in the treatment of mild cognitive impairment and Alzheimers disease.     

Effects of chronic prenatal ethanol exposure on cGMP content and glutamate release in the hippocampus of the neonatal guinea pig

The glutamate-N-methyl-D-aspartate (NMDA) receptor-nitric oxide synthase (NOS)-cGMP signal transduction system plays key neurotrophic and intercellular communication roles in the hippocampus. In the guinea pig, chronic prenatal ethanol exposure (CPEE), via maternal ethanol administration, suppresses the hippocampal glutamate-NMDA receptor-NOS pathway in the near-term fetus and decreases stimulated glutamate release in the hippocampus of young postnatal offspring, with no effect on NMDA receptor number or NOS activity. At present, the effect of CPEE on cGMP, a key second messenger of the glutamate signal transduction system, in the hippocampus is not known. The objective of this study was to test the hypothesis that CPEE suppresses the hippocampal glutamate signal transduction system in the neonatal guinea pig at the levels of cGMP content and glutamate release. Timed pregnant guinea pigs received chronic oral administration of 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose/pair-feeding, or water treatment throughout gestation. CPEE decreased brain and hippocampal weights at postnatal day (PD) 1 and PD 5 (P<.05). CPEE did not affect basal, NMDA (1, 10, or 100 microM)-stimulated, or K(+) (15 or 30 mM)-stimulated cGMP content in transverse hippocampal slices at PD 1 or 5. At 60 mM K(+), however, CPEE decreased stimulated hippocampal cGMP content at PD 1 (P<.05) and increased stimulated cGMP content at PD 5 (P<.05). In transverse hippocampal slices, CPEE did not affect basal or K(+) (40 or 45 mM)-stimulated glutamate release at PD 1 or 5, or NMDA (50 microM)-stimulated glutamate release at PD 1, but did decrease NMDA (50 microM)-stimulated glutamate release at PD 5 (P<.05). The data demonstrate that the effects of CPEE on stimulated cGMP content and glutamate release in the hippocampus of the neonatal guinea pig are stimulating agent- and age-dependent.     

Effects of hydrocortisone administration on cognitive function in the elderly

Previous studies have found adverse effects of both acute and chronic elevations of corticosteroids on cognitive function in humans and that cortisol levels may predict cognitive decline in elderly subjects. However, no previous studies have directly investigated the effects of hydrocortisone on cognitive functioning in the healthy elderly. Sixteen healthy elderly subjects took part in a placebo-controlled, double-blind, cross-over trial. Hydrocortisone 20 mg or placebo was administered twice, 12 h and 1 h before cognitive testing. On each occasion, a battery of neuropsychological tests was performed which included tests of attention, working memory, declarative memory and executive function. Salivary cortisol levels at the time of testing were elevated approximately 10-fold following hydrocortisone compared with placebo. No significant effects were found on memory or a range of other cognitive functions. The lack of effect of this regime of hydrocortisone is in contrast to studies in younger subjects. The elderly may be less sensitive to cognitive effects of short-term increases in cortisol levels, possibly due to an age-related downregulation of hippocampal glucocorticoid receptors.