Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat

One of the functions of group 11 metabotropic glutamate receptors (mGluR2/3) is to modulate glutamate release. Thus, targeting mGluR2/3s might be a novel treatment for several psychiatric disorders associated with inappropriate glutamatergic neurotransmission, such as schizophrenia. In an effort to evaluate the antipsychotic properties of LY379268; a potent and selective mGluR2/3 agonist, we examined its effect on ketamine-evoked hyperlocomotion and sensorimotor gating deficit (PPI) in rats, an animal model of schizophrenia. We also measured the ex vivo tissue level of glutamate (Glu), dopamine (DA) and serotonin (5-HT) as well as the DA metabolites DOPAC and the major 5-HT metabolite HIAA to determine the neurochemical effects of ketamine (12 mg/kg) and LY379268 (1 mg/kg) in the dentate gyrus (DG). While LY379268 (1-3 mg/kg) reduced ketamine-evoked hyperlocomotion (12 mg/kg), it could not restore ketamine-evoked PPI deficits (4-12 mg/kg). In the DG we found that ketamine decreased Glu and DA levels, as well as HIAA/5-HT turnover, and that LY379268 could prevent ketamine effects on Glu level but not on monoamine transmission. These results may indicate that the inability of LY379268 to reverse PPI deficits is attributable to its lack of effect on ketamine-induced changes in monoamine transmission, but that LY379268 can prevent ketamine-evoked changes in glutamate, which is sufficient to block hyperlocomotion. In addition to the partial effectiveness of LY379268 in the ketamine model of schizophrenia, we observed a dual effect of LY379268 on anxious states, whereby a low dose of this compound (1 mg/kg) produced anxiolytic effects, while a higher dose (3 mg/kg) appeared to be anxiogenic. Additional work is needed to address a possible role of LY379268 in schizophrenia and anxiety treatment. (c) 2006 Elsevier Inc. All rights reserved

Simultaneous Quantification of the Concentration and Carbon Isotopologue Distribution of Polar Metabolites in a Single Analysis by Gas Chromatography and Mass Spectrometry

13C-isotope tracing is a frequently employed approach to study metabolic pathway activity. When combined with the subsequent quantification of absolute metabolite concentrations, this enables detailed characterization of the metabolome in biological specimens and facilitates computational time-resolved flux quantification. Classically, a 13C-isotopically labeled sample is required to quantify 13C-isotope enrichments and a second unlabeled sample for the quantification of metabolite concentrations. The rationale for a second unlabeled sample is that the current methods for metabolite quantification rely mostly on isotope dilution mass spectrometry (IDMS) and thus isotopically labeled internal standards are added to the unlabeled sample. This excludes the absolute quantification of metabolite concentrations in 13C-isotopically labeled samples. To address this issue, we have developed and validated a new strategy using an unlabeled internal standard to simultaneously quantify metabolite concentrations and 13C-isotope enrichments in a single 13C-labeled sample based on gas chromatography-mass spectrometry (GC/MS). The method was optimized for amino acids and citric acid cycle intermediates and was shown to have high analytical precision and accuracy. Metabolite concentrations could be quantified in small tissue samples (≥20 mg). Also, we applied the method on 13C-isotopically labeled mammalian cells treated with and without a metabolic inhibitor. We proved that we can quantify absolute metabolite concentrations and 13C-isotope enrichments in a single 13C-isotopically labeled sample. BT/Industrial Microbiolog

Advanced glycation end-products, a pathophysiological pathway in the cardiorenal syndrome

The prevalence of heart failure (HF) is increasing. A distinction is made between diastolic HF (preserved left ventricular ejection fraction (LVEF)) and systolic HF (reduced LVEF). Advanced glycation end-products (AGEs) are crystallized proteins that accumulate during ageing, but are particularly increased in patients with diabetes mellitus and in patients with renal failure. Through the formation of collagen crosslinks, and by interaction with the AGE-receptor, which impairs calcium handling and increases fibrosis, AGE-accumulation has pathophysiologically been associated with the development of diastolic and renal dysfunction. Interestingly, diastolic dysfunction is a frequent finding in elderly patients, diabetic patients and in patients with renal failure. Taken together, this suggests that AGEs are related to the development and progression of diastolic HF and renal failure. In this review, the role of AGEs as a possible pathophysiological factor that link the development and progression of heart and renal failure, is discussed. Finally, the role of AGE intervention as a possible treatment in HF patients will be discussed

Acute and Conditioned Blood Pressure Changes in Relation to Social and Psychosocial Stimuli in Rats

The naturally occurring tendency to compete with other rats for territorial space has been used to study individual behavior characteristics and blood pressure reactivity to social stimuli in adult male TMD-S3 rats. The competitive characteristics of the individual rats are consistent in two different social situations (victory and defeat). Blood pressure responses during the victory of home territory rats over intruders was more pronounced in the more competitive animals. In addition to defeat by a trained fighter rat, the experimentals were also psychosocially stimulated by the fighter while it was confined in a small wire mesh cage. The blood pressure response to this event was enhanced by the prior defeat of the test animal by the one now confined to the small cage. This response was more pronounced in competitive rats. This approach has potential as an animal model of etiological processes in socially induced hypertension.

Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats

Acute treatment with LY354740 {1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate}, a potent and selective agonist for group 11 metabotropic glutamate receptors (mGlu2/3), has previously been shown to block some schizophrenia-like effects of N-methyl-D-aspartate (NMDA) receptor antagonists, suggesting a novel therapeutic strategy for schizophrenia. The present study examined the effects of subchronic pretreatment with LY354740 (0.3, 3 and 10 mg/kg i.p.) on ketamine-evoked (12 mg/kg s.c.) prepulse inhibition deficits, hyperlocomotion and c-fos expression. At all doses, LY354740 failed to reverse both behavioral and neuronal effects of the ketamine. These results therefore do not support the putative antipsychotic role of LY354740. (c) 2006 Elsevier B.V All rights reserved

Individual Characteristics of Behavior, Blood Pressure, and Adrenal Hormones in Colony Rats

Previous experiments suggested that rats with an active behavioral strategy and high endocrine and blood pressure responses to social interactions would be at risk to get a high blood pressure. To test this hypothesis, a long-term study of social behavior was performed in laboratory colonies of rats. The more aggressive rats, as indicated by individual precolony resident-intruder tests, are more aggressive in the colony also. After colony aggregation, the aggressive rats appeared to have higher resting blood pressures. The dominant rat (although aggressive, too) and the nonaggressive rats have lower blood pressures. Plasma levels of catecholamines and corticosterone after colony experience do not show a relation with blood pressure but reflect the rat's original precolony aggressive characteristic. We conclude that the individual characteristic of an active social strategy is a risk factor that indeed predicts the development of high blood pressure, possibly by way of the associated higher physiological reactivity we found earlier. Chronic environmental factors that are hard to control for the animal, like involvement in social processes or possibly other continuous challenges, may stimulate the prone physiology to develop an elevation of blood pressure.

A Coherent Pattern Among Social Behavior, Blood Pressure, Corticosterone and Catecholamine Measures in Individual Male Rats

Behavioral and physiological responses of 18 chronically cannulated male TMD-S3 rats were assessed during various social interactions with conspecifics, both with and without the possibility for physical contact (social vs. psychosocial stimulation). Response magnitudes (behavior, blood pressure, plasma catecholamines) depend upon both the social environmental requirements (offense, defense, psychosocial stimulus following defense) and individual characteristics. The more competitive males generally reacted with higher responses of blood pressure and catecholamines than more passive rats. In addition, these competitive males had higher baseline levels of noradrenaline. The present experiment shows that male rats differ in the individual sympathetic tone and reactivity in relation to their behavior in a social environment.

A coherent pattern among social behavior, blood pressure, corticosterone and catecholamine measures in individual male rats

Behavioral and physiological responses of 18 chronically cannulated male TMD-S3 rats were assessed during various social interactions with conspecifics, both with and without the possibility for physical contact (social vs. psychosocial stimulation). Response magnitudes (behavior, blood pressure, plasma catecholamines) depend upon both the social environmental requirements (offense, defense, psychosocial stimulus following defense) and individual characteristics. The more competitive males generally reacted with higher responses of blood pressure and catecholamines than more passive rats. In addition, these competitive males had higher baseline levels of noradrenaline. The present experiment shows that male rats differ in the individual sympathetic tone and reactivity in relation to their behavior in a social environment

Social Stress Induced Pressure Breathing and Consequent Blood Pressure Oscillation

A large amplitude blood pressure oscillation occurs during social defeat in a territorial fight between male rats, and during the application of a psychosocial stimulus associated with this defeat. Synchronous recording of blood pressure, intrathoracic pressure and diaphragm activity shows that the blood pressure oscillation coincides with a typical respiratory pattern called 'pressure breathing', during which a strongly positive intrathoracic pressure with expiration can be observed. The expiration was relatively prolonged and accompanied by a rise in blood pressure and a decrease in heart frequency. These alterations outlast the applied social respectively psychosocial stimulations. The results of this study suggest that behaviorally induced pressure breathing is of importance to attentional processes during social stimulation. The contribution to the development of hypertension is discussed.