1,720,988 research outputs found
Physiological and pharmacological bases for the diverse properties of benzodiazepines and their congeners.
No full textBenzodiazepines (BZs), which have been marketed by pharmaceutical companies since the sixties, are the most commonly prescribed psychotropic drugs. Diazepam, the prototype of this class of drugs, has a vast spectrum of therapeutic indications. It possesses, over a narrow dose-range, the well-known neuropsychopharmacological profile consisting of anxiolytic, anticonvulsant, sedative, and muscle relaxant effects, and CNS depression. Recently, BZ ligands that retain anxiolytic and antiepileptic properties at doses that are unable to produce a CNS depression have been developed. The pharmacological profiles of these drugs are discussed in light of: the heterogeneity of the structure of the GABAA receptor complex; intrinsic efficacy of the ligand; action of the BZ ligand on the mitochondrial BZ receptor
Alteration of behavioral and endocrinological reactivity induced by 3 brief social defeats in rats: Relevance to human psychopathology.
No full textIn the realm of animal models of psychopathology, social stress based procedures rely on robust theoretical prerequisites to meet construct validity criteria for the target syndromes. In order to further assess the relevance for human psychopathology of a social defeat based model in rats, known to elicit consistent behavioral and hormonal changes, we expanded its characterization on the basis of both behavioral parameters and peripheral biomarkers thought to be pertinent for clinical symptoms. Rats were subjected to 3 daily social defeat experiences that shortly thereafter led to the insurgence of defensive behaviors, anhedonia, and body weight loss. HPA axis showed an activated response when rats were sampled as early as after the first social defeat experience, while none of the peripheral immune, metabolic, and neurotrophic factors examined were concurrently affected. With the aim of determining the long-term bio-behavioral sequelae of the social defeat experience, rats were assessed also3 weeks after the social defeats. At this time, behavioral changes were still observed, including decreased general activity and sociality in a social avoidance test, increased immobility and decreased escape responses in a forced swim test. These alterations were not paralleled by alterations in anhedonia nor HPA axis responses from controls, nor where evident changes in the humoral component of the immune response nor in brain derived neurotrophic factor levels, whereas a substantial increase in leptin levels was observed in previously socially defeated rats compared to control. Overall these data depict a very complex set of alterations induced both acutely and long-term by social stress in endocrinological and behavioral reactivity of rats
Different susceptibility to social defeat stress of BalbC and C57BL6/J mice.
No full textSocial stress may precipitate psychopathological disorders in susceptible individuals. The present experiments were focused on the biology beyond the differential susceptibility to social stress. Social defeat, an ethologically relevant stressor known to elicit different coping strategies, was used in two mouse strains differing for baseline emotionality, such as C57BL6/J and BalbC. In separate experiments, in both strains a single social defeat decreased home-cage activity without altering social aversion; it diminished body weight only in defeated BalbC mice. In longitudinal experiments, mice experienced repeated social defeats that induced multiple long-term consequences. Defeated C57BL6/J increased their body weight and food intake; defeated BalbC mice diminished their metabolic efficiency. Only defeated BalbC subjects exhibited increased social avoidance levels; no differences from controls were seen on forced swim test response in defeated mice of either strain. No long-term effects of social defeat were detected in peripheral biomarkers of stress, metabolic, and immune responses, although the analysis of selected internal organs revealed decreases in abdominal fat and gonadal organs in all defeated subjects. These results demonstrated a strain-distinctive profile in the susceptibility to social defeat stress, either acutely or chronically, with metabolic consequences more consistently found in C57BL6/J while social aversion induced predominantly in BalbC subjects
Social defeat-induced contextual conditioning differentially imprints behavioral and adrenal reactivity: A time-course study in the rat
No full textThe present experiments were based on the rat resident-intruder paradigm and aimed at better understanding the long-term conditioning properties of this social stress model. Intruders were exposed to aggressive conspecifics residents. During 3 daily encounters, intruders were either defeated or threatened by residents, providing the defeated-threatened (DT) and threatened-threatened (TT) groups respectively, or exposed to a novel empty cage (EC). The effect of such exposures was assessed in 3 separate experiments 8, 14, or 21 days following the last session on both behavior and hypothalamus-pituitary-adrenal (HPA) axis parameters. A specific and persistent behavioral conditioning due to social defeat but also to the sole social threat experience was observed as defensive behaviors and anxiety-like behaviors were observed respectively in DT and TT rats, highlighting a lack of habituation for the conditioning properties of this social stressor. On the other hand, at the earlier time points examined a less specific activation of the HPA axis parameters was found, starting to show habituation at day 21 in EC but not in DT or TT rats. These data give further support to the lasting effects of this social stress model, bestowing a special emphasis upon the impact of its psychological component and upon the relevance of its development and maintenance over time. (C) 2007 Elsevier Inc. All rights reserved
Social defeat-induced contextual conditioning differentially imprints behavioral and adrenal reactivity: a time-course study in the rat.
No full textThe present experiments were based on the rat resident–intruder paradigm and aimed at better understanding the long-term conditioning properties of this social stress model. Intruders were exposed to aggressive conspecifics residents. During 3 daily encounters, intruders were either defeated or threatened by residents, providing the defeated–threatened (DT) and threatened–threatened (TT) groups respectively, or exposed to a novel empty cage (EC). The effect of such exposures was assessed in 3 separate experiments 8, 14, or 21 days following the last session on both behavior and hypothalamus–pituitary–adrenal (HPA) axis parameters. A specific and persistent behavioral conditioning due to social defeat but also to the sole social threat experience was observed as defensive behaviors and anxiety-like behaviors were observed respectively in DT and TT rats, highlighting a lack of habituation for the conditioning properties of this social stressor. On the other hand, at the earlier time points examined a less specific activation of the HPA axis parameters was found, starting to show habituation at day 21 in EC but not in DT or TT rats. These data give further support to the lasting effects of this social stress model, bestowing a special emphasis upon the impact of its psychological component and upon the relevance of its development and maintenance over time
Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.
No full textAnxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Characterization of [3H]-imidazenil binding to rat brain membranes.
No full text1. The binding of [3H]-imidazenil, an imidazobenzodiazepine carboxamide, to rat cerebellar membranes was characterized at different temperatures. 2. Specific binding was linear with tissue concentrations and reached maximum after 90, 30 and 5 min incubation at 0, 21 and 37 degrees C, respectively. The binding was of high affinity, specific and saturable; non linear regression and Scatchard analysis of the data was compatible with the presence of a single population of receptor sites with Bmax of 0.74 +/- 0.020, 0.90 +/- 0.011 and 1.0 +/- 0.036 pmol mg-1 protein at 0, 21 and 27 degrees C, respectively. Binding affinity decreased with increasing temperature: Kd were 0.29 +/- 0.051 nM (0 degrees C), 1.0 +/- 0.080 nM (21 degrees C) and 2.4 +/- 0.38 nM (37 degrees C). 3. At all tested temperatures, [3H]-imidazenil binding was reversible and the Kd calculated from the dissociation and association rate constants approximated the equilibrium Kd. 4. In the presence of gamma-aminobutyric acid (GABA), Kd increased 4 fold at 0 degrees C, whereas Bmax increased, albeit slightly, at all temperatures. 5. Benzodiazepines (BZDs), imidazopyridines and methyl-beta-carboline-3-carboxylate (beta CCM) were effective inhibitors of [3H]-imidazenil binding. Conversely, GABAA antagonists, barbiturates, picrotoxin and peripheral BZD receptor ligands were devoid of any activity. 6. Comparing [3H]-imidazenil to [3H]-flumazenil binding in various brain areas, similar densities of recognition sites as well as like regional differences in the distribution of binding sites for both radioligands were observed (cortex = striatum > cerebellum > spinal cord). 7. The present results indicate that [3H]-imidazenil specifically binds to the BZD sites of GABAA receptors. Furthermore, the effects of GABA and temperature differentiate imidazenil from classicalBZDs. It is suggested that the characteristics of imidazenil binding may be relevant to the in vivo pharmacology of the drug
A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress.
No full textAccumulating evidences underlie the importance of the
interplay between environmental and genetic factors
in contributing to the risk to develop mental illness.
Brain-derived neurotrophic factor (BDNF) and its Tyrosine
receptor kinase B (TrkB) receptor play a fundamental
contribution to brain development and plastic
adaptations to life events. In the present study, the
potential for the BDNF/TrkB contribution in increasing
vulnerability to negative social experiences was
assessed by subjecting TrkB.T1 overexpressing mice
to a chronic social defeat model. TrkB.T1 mice overexpress
the dominant-negative truncated splice variant
of TrkB receptor leading to decreased BDNF signaling.
After repeated social defeat, mice were assessed in a longitudinal
study for behavioral, physiological, endocrine
and immune responses potentially related to psychiatric
endophenotypes. TrkB.T1 overexpression corresponded
to smaller changes in metabolic parameters such as
body weight, food intake, feed efficiency and peripheral
ghrelin levels compared with wild-type (wt) littermates
following social defeat. Interestingly, 4 weeks after the
last defeat, TrkB.T1 overexpressing mice exhibited more
consistent social avoidance effects than what observed
in wt subjects. Finally, previously unreported effects of
TrkB mutations could be observed on lymphoid organ
weight and on peripheral immune biomarker levels, such
as interleukin-1α and regulated on activation, normal,
T-cell expressed, and secreted (RANTES), thus suggesting
a systemic role of BDNF signaling in immune
function. In conclusion, the present data support a contribution
of TrkB to stress vulnerability that, given the
established role of TrkB in the response to antidepressant
treatment, calls for further studies addressing the
link between stress susceptibility and variability in drug
efficacy
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