Benzodiazepine Receptor System Research Articles

Altered cerebral benzodiazepine receptor binding in post-traumatic stress disorder

Agonists of the γ-aminobutyric acid (GABA) type A benzodiazepine (BZD) receptor exert anxiolytic effects in anxiety disorders, raising the possibility that altered GABA-ergic function may play a role in the pathophysiology of anxiety disorders, such as post-traumatic stress disorder (PTSD). However, few neuroimaging studies have assessed the function or binding potential of the central GABAA BZD receptor system in PTSD. Therefore, our aim was to compare the BZD receptor binding potential between PTSD patients and healthy controls. Twelve medication-free participants with a current diagnosis of PTSD and 15 matched healthy controls underwent positron emission tomography (PET) imaging using [11C] flumazenil. Structural magnetic resonance imaging (MRI) scans were obtained and co-registered to the PET images to permit co-location of neuroanatomical structures in the lower resolution PET image data. Compared to healthy controls, PTSD patients exhibited increased BZD binding in the caudal anterior cingulate cortex and precuneus (p’s < 0.05). Severity of PTSD symptoms positively correlated with BZD binding in the left mid- and anterior insular cortices. This study extends previous findings by suggesting that central BZD receptor system involvement in PTSD includes portions of the default mode and salience networks, along with insular regions that support interoception and autonomic arousal.

Anxiolytic and antidepressant activities of Pelargonium roseum essential oil on Swiss albino mice: Possible involvement of serotonergic transmission.

The anxiolytic and antidepressant activities of the Reunion Geranium (Pelargonium roseum Willd) essential oil (EO) were evaluated in male Swiss albino mice by intraperitoneal administration of 10, 20, and 50mg/kg bw using elevated plus maze (EPM), open-field test (OFT), and forced swimming test (FST). Moreover, we evaluated whether the 5-HT1A and GABAA -benzodiazepine receptor systems are involved in the anxiolytic effects through the coadministration of WAY-100635 (a selective 5-HT1A receptor antagonist) and flumazenil (an antagonist of benzodiazepine). GC-MS revealed the monoterpene alcohols citronellol (35.9%) and geraniol (18.5%) as the main components of the P.roseum EO. EO was effective in increasing the total number of entries and time spent in the open arms of EPM whereas number of rearing in OFT was significantly decreased in comparison with the control. In the FST, immobility time decreased in EO treated mice. Pretreatment with WAY-100635, but not Flumazenil, was able to reverse the effects of the EO in the EPM and FST, indicating that the EO activity occurs via the serotonergic but not GABAergic transmission. Overall, results of this work showed significant anxiolytic and antidepressant activity of P.roseum EO and confirmed the traditional uses of Pelargonium species as calming agents.

The Effect of Chronic Alcohol Abuse on the Benzodiazepine Receptor System in Various Areas of the Human Brain

Objective: Alcohol abuse induces neuroadaptive changes in the functioning of neurotransmitter systems in the brain. Decrease of GABAergic neurotransmission found in alcoholics and persons with a high risk of alcohol dependence. Benzodiazepine receptor (BzDR) is allosterical modulatory site on GABA type A receptor complex (GABAAR), that modulate GABAergic function and may be important in mechanisms regulating the excitability of the brain processes involved in the alcohol addiction. The purpose of this study was to investigate the effects of chronic alcohol abuse on the BzDR in various areas of the human brain. Materials and Methods: Investigation of BzDR properties were studied in synaptosomal and mitochondrial membrane fractions from different brain areas of alcohol abused patients and non-alcoholic persons by radioreceptor assay with using selective ligands: [3H] flunitrazepam and [3H] PK-11195. Brain samples obtained at autopsy urgent. In total 126 samples of human brain areas were obtained to study radioreceptor binding, including a study group and control group. Results: Comparative study of kinetic parameters (Kd, Bmax) of [3H] flunitrazepam and [3H] PK-11195 binding with membrane fractions in studding brain samples was showed that affinity of BzDR was decreased and capacity increased in different areas of human brain under influence of alcohol abuse. More alters of synaptic BzDR “central” type (CBR) appeared in prefrontal cortex, mitochondrial BzDR “peripheral” type (PBR) – in n.caudatus and cerebella cortex. These results showed that alcohol addiction induce more expressive alterations in PBR than CBR in the brain structures that agree with maintaining function of glial cells in CNS under influence of different toxic factors. Conclusion: Chronic exposure to ethanol results in harmful effects on the human brain: causing nonuniform adaptive changes of BzDR in various areas of the brain, which can modulate GABAAR and reduce neuromediation GABA in various areas of the brain which can cause alcohol addiction. Graphical Abstract: Alcohol abuse induces neuroadaptive alters of benzodiazepine receptor system in various areas of the brain in patients with alcoholism that can modulate GABAAR and mediation of GABA in the brain, which can cause alcohol addiction.

P.1.g.051 Benzodiazepine receptor system in the brains of rats with experimental alcoholism and treatment effect of a novel anticonvulsant

Purpose: Alcohol abuse induces neuroadaptive alterations in the benzodiazepine receptors (BDR) that modulate GABAAR and GABA mediation in brain regions associated with reward function, producing alcohol addiction. Studying the effects of drugs that have modulatory effects on neuronal receptors, in particular the GABAA-benzodiazepine receptors, can be the basis for understanding the formation of alcohol motivation and addiction, to develop new approaches to the treatment of this disease. Materials and Methods: Male Wistar rats (n = 250) were used in an experimental model of alcoholism. Properties of BDR ‘synaptosomal’ and ‘mitochondrial’ types were examined in respective membrane fractions obtained from brain cortex of rats with experimental alcoholism and treatment with the novel anticonvulsant meta-chlorobenzhydryl urea by radioreceptor assay (RRA) with [3H]flunitrazepam and [3H]Ro5-4864. Results: Based on their consumption of 15% alcohol and/or water, the rats were divided into 3 major groups. Group 1 consisted of rats drinking ethanol only − these ‘heavy drinking’ rats had chronic alcoholism (15% alcohol as the sole source of drinking for 10 months); the second group consisted of rats preferring ethanol − these ‘non-heavy drinking’ rats drank mostly ethanol; the third group − ‘non-preferring’ rats − drank water mostly. In each group, a number of animals were administered meta-chlorobenzhydryl urea (m-CIBHU) 100mg/kg for 14 days. Introduction of m-CIBHU caused a significant decrease in alcohol consumption in animals preferring alcohol (1st and 2nd groups), by 82.7% from baseline and 75% from baseline, respectively (p< 0.05). Alcohol consumption by rats preferring water was not affected by m-CIBHU. Reduction of alcohol consumption started on the 2−3rd day of m-CIBHU administration, and persisted while on the drug and for 2 weeks after drug discontinuation. Thus, the introduction of m-CIBHU resulted in a significant reduction of ethanol intake for animals preferring ethanol. Comparative study of the kinetic parameters (Kd and Bmax) of [3H]flunitrazepam and [3H]Ro5-4864 binding with synaptosomal and mitochondrial membranes showed different properties of BDR in membranes from the brain cortex of rats with different preferences for alcohol: the affinity of [3H]flunitrazepam and [3H]Ro5-4864 binding with membranes was decreased, but capacity of receptors was increased, in the brain cortex of ‘heavy drinking’ and ‘non-heavy drinking’ rats compared with ‘non-preferring’ rats. Administration of the anticonvulsant meta-chlorobenzhydryl urea increased the affinity of BDR in the brain cortex of ‘heavy drinking’ rats, which induced mediation of GABA in the brain of these rats and reduced alcohol consumption. Conclusions: Our study revealed that the novel anticonvulsant meta-chlorobenzhydryl urea had a normalizing effect on GABAAreceptor function in ‘heavy drinking’ rats, and reduced alcohol consumption in these animals. P.1.g.052 Cariprazine demonstrates greater potency than aripiprazole in animal models of psychosis, cognitive impairment, and negative symptoms

Effect of meta-chlorobenzhydryl urea (m-ClBHU) on benzodiazepine receptor system in rat brain during experimental alcoholism.

Chronic alcohol intake induces neuroadaptive changes in benzodiazepine receptors modulating GABAA receptors that promote alcohol addiction. Analysis of benzodiazepine receptors in the brain of Wistar rats differing by alcohol preference has demonstrated that affinity of [(3)H]flunitrazepam and [(3)H]Ro5-4864 binding with membrane fraction was reduced, while the density of specific binding sites in the brain cortex of heavy drinking and low drinking rats was increased in comparison with rats nonpreferring alcohol. Administration of anticonvulsant meta-chlorobenzhydryl urea increased affinity of benzodiazepine receptors in the brain cortex of heavy drinking rats, which improved GABA neurotransmission in the brain of these animals and reduced alcohol consumption.

EPA-0628 – Benzodiazepine receptor system of human brain in alcohol addiction

Background alcohol abuse induce neuroadaptive alters of benzodiazepine receptors (BDR) that modulate GABAAR, mediation of GABA and activity of dopaminergic neurons in brain regions, associated with reward function in the brain that serve alcohol addictions. Method properties of BDR’central’ (CBR) and’peripheral’ (PBR) types were studied in synaptosomal and mitochondrial membranes from different brain areas of alcohol abused patients and non-alcoholic persons (early postmortem material, less 5 hours after death) by radioreceptor assay with using selective ligands: [ 3 H]flunitrazepam and [ 3 H]PK-11195. Results comparative study of kinetic parameters (affinity and capacity) of [ 3 H]flunitrazepam and [ 3 H]PK-11195 binding with synaptosomal and mitochondrial membranes in autopsy samples from different areas of human brain was showed that affinity of BDR was decreased: CBR – in 1,2 times in prefrontal cortex and n.caudatus, less – in cerebella cortex; PBR – in 2,1 times in n.caudatus, 1,3 times – in prefrontal cortex and cerebella cortex in patients with alcohol addiction. Capacity of BDR was increased in different areas of human's brain under influence of alcohol abuse. More alters of CBR appeared in prefrontal cortex (179%) and cerebella cortex (176%), less – in n.caudatus (145%); PBR – in n.caudatus (262%); and cerebella cortex (205%), and less in prefrontal cortex (123%). These results showed that alcohol addiction induce more alterations in PBR (mitochondrial) than CBR (synaptic) that agree with maintaining function of glial cells in CNS under influence of different toxic factors. Conclusion our findings suggest hypothesis of difference in response BDR from various brain areas on alcohol influence.

Anxiolytic effects of Julibroside C1 isolated from Albizzia julibrissin in mice

Julibroside C1 is a saponin-containing compound isolated from Albizzia julibrissin Durazz. In this study, we investigated the putative anxiolytic effects of Julibroside C1 using the elevated plus maze (EPM) in mice. Julibroside C1 at doses of 0.5 and 1 mg/kg significantly increased the time spent in the open arms and the number of entries into the open arms of the EPM compared to the control group. Moreover, the anxiolytic-like effects of Julibroside C1 (0.5 mg/kg) were blocked by WAY-100635 (5-HT1A receptor antagonist), bicuculline (GABA(A) receptor antagonist), and flumazenil (antagonist of the GABA(A) receptor benzodiazepine site). However, Julibroside C1 did not change locomotor activity or induce myorelaxant effects. We used quantitative receptor autoradiography to investigate the effects of Julibroside C1 on alterations in mouse brain receptors. After acute treatment with Julibroside C1 (0.5 mg/kg), [(3)H]-8-OH-DPAT binding was significantly decreased in the CA1 region of the hippocampus and [(3)H]-flunitrazepam binding was decreased remarkably in the cingulate cortex region. However, [(3)H]-muscimol binding did not show a significant change in any brain region. Taken together, our findings suggest that Julibroside C1 shows anxiolytic-like effects, which might be mediated by the 5-HT1A and GABA(A)-benzodiazepine receptor systems.

Mu-opioid receptor knockout mice are more sensitive to chlordiazepoxide-induced anxiolytic behavior

We have previously demonstrated benzodiazepine binding in the cortex and hippocampus of mu-opioid receptor knockout (KO) mice. It is known that benzodiazepine receptors are involved in regulating anxiety-like behaviors. Thus, the present study was designed to examine whether there are changes in anxiety-like behavior in mice lacking mu-opioid receptors. To produce anxiolytic activity (less anxiety), the prototype benzodiazepine receptor agonist chlordiazepoxide (CDP, 5 mg/kg) was intraperitoneally administered in wild type (WT) and mu-opioid receptor KO mice. We found that compared to WT mice, mu-opioid receptor KO mice showed enhanced anxiolytic activity to CDP, including increased number of entries into open arm, increased percentage of the time spent in open arms, and decreased percentage of the time spent in enclosed arms in the elevated plus-maze test. We also assessed protein expression of the gamma-aminobutyric acid (GABA) synthetic enzyme (glutamic acid decarboxylase; GAD). Western blotting data indicated that neither the lack of mu-opioid receptors nor CDP treatment altered cortical or hippocampal GAD₆₅ or GAD₆₇ protein expression. These data indicate that compared with WT, mu-opioid receptor KO mice experienced less anxiety and exhibited enhanced anxiolytic activity to CDP treatment, and these effects were not dependent on GAD₆₅ or GAD₆₇ protein expression. Our previous and present data suggest that the anxiolytic activity displayed in mu-opioid receptor KO mice is associated with upregulation of the benzodiazepine receptor system.

A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system

The binding of two radiolabelled analogues (N-(5-[125I]Iodo-2-phenoxyphenyl)-N-(2,5-dimethoxybenzyl)acetamide ([125I]desfluoro-DAA1106) and N-(5-[125I]Fluoro-2-phenoxyphenyl)-N-(2-[125I]Iodo-5-methoxybenzyl)acetamide ([125I]desmethoxy-DAA1106) of the peripheral benzodiazepine receptor (PBR) (or TSPO, 18 kDa translocator protein) ligand DAA1106 was examined by in vitro autoradiography on human post mortem whole hemisphere brain slices obtained from Alzheimer's disease (AD) patients and age-matched controls. Both [ 125I]desfluoro-IDAA1106 and [ 125I]desmethoxy-IDAA1106 were effectively binding to various brain structures. The binding could be blocked by the unlabelled ligand as well as by other PBR specific ligands. With both radiolabelled compounds, the binding showed regional inhomogeneity and the specific binding values proved to be the highest in the hippocampus, temporal and parietal cortex, the basal ganglia and thalamus in the AD brains. Compared with age-matched control brains, specific binding in several brain structures (temporal and parietal lobes, thalamus and white matter) in Alzheimer brains was significantly higher, indicating that the radioligands can effectively label-activated microglia and the up-regulated PBR/TSPO system in AD. Complementary immunohistochemical studies demonstrated reactive microglia activation in the AD brain tissue and indicated that increased ligand binding coincides with increased regional microglia activation due to neuroinflammation. These investigations yield further support to the PBR/TSPO binding capacity of DAA1106 in human brain tissue, demonstrate the effective usefulness of its radio-iodinated analogues as imaging biomarkers in post mortem human studies, and indicate that its radiolabelled analogues, labelled with short half-time bioisotopes, can serve as prospective in vivo imaging biomarkers of activated microglia and the up-regulated PBR/TSPO system in the human brain.

Altered Cerebral γ-Aminobutyric Acid Type A–Benzodiazepine Receptor Binding in Panic Disorder Determined by [11C]Flumazenil Positron Emission Tomography

The benzodiazepine (BZD) receptor system has been implicated in the pathophysiologic mechanism of panic disorder (PD) by indirect evidence from pharmacological challenge studies and by direct evidence from single-photon emission computed tomography and positron emission tomography neuroimaging studies. However, the results of previous neuroimaging studies are in disagreement, possibly because of experimental design limitations related to sample size, matching between patients and controls, and confounding medication effects. To compare BZD receptor binding between subjects with PD and healthy control subjects. Cross-sectional study for association. Psychiatric outpatient clinic of the National Institute of Mental Health. Fifteen subjects with PD who were naïve to BZD drug exposure and were not receiving other drug treatment, and 18 healthy controls. Images of BZD receptor binding were acquired using positron emission tomography and flumazenil tagged with carbon 11. The BZD receptor binding potential was assessed by a simplified reference tissue-tracer kinetic model. The BZD receptor binding potential was decreased in multiple areas of the frontal, temporal, and parietal cortices and was increased in the hippocampus/parahippocampal region in subjects with PD vs controls. The most significant decrease was located in the dorsal anterolateral prefrontal cortex (DALPFC); the most significant increase, in the hippocampus/parahippocampal gyrus. These abnormalities were not accounted for by comorbid depression. In subjects with PD, the severity of panic and anxiety symptoms correlated positively with BZD receptor binding in the DALPFC but negatively with binding in the hippocampus/parahippocampal gyrus. These data provide evidence of abnormal BZD-gamma-aminobutyric acid type A receptor binding in PD, suggesting that basal and/or compensatory changes in inhibitory neurotransmission play roles in the pathophysiologic mechanism of PD. They also provide evidence of an impairment of frontal-limbic interaction in the modulation of anxiety responses, consistent with previous functional and structural neuroimaging studies in PD.

Periictal Dynamic Changes in Benzodiazepine Receptors

Seizure-related Short-term Plasticity of Benzodiazepine Receptors in Partial Epilepsy: An [11C]Flumazenil-PET Study Bouvard S, Costes N, Bonnefoi F, Lavenne F, Mauguiere F, Delforge J, Ryvlin P Brain 2005;128:1330–1343 We have undertaken a test–retest [11C]flumazenil (FMZ) positron emission tomography (PET) study in 10 drug-resistant epilepsy patients, including six with a mesiotemporal epilepsy (MTE), and 10 normal controls, to investigate seizure-related short-term plasticity of benzodiazepine (BZD) receptors. All subjects underwent two FMZ-PET scans at a 1-week interval. Patients benefited from a concurrent video-EEG monitoring, which allowed determination of the duration of the interictal period (IP) preceding each PET study. Test–retest whole-brain B′max variations, evaluated with a partial-saturation injection protocol, were similarly observed in patients and controls, suggesting a physiologic modulation of BZD receptors. Five (50%) patients, but no controls, also demonstrated clinically significant test–retest FMZ-PET variations in the mesial temporal region. This was observed in all three patients with MTE and no hippocampal atrophy, in whom only the PET study associated with the shortest IP correctly identified the epileptogenic zone. Statistical analysis revealed a significant effect of IP duration on BZD receptor B′max in MTE patients, suggesting that the shorter the IP, the lower the B′max in the epileptogenic hippocampus. FMZ-PET appears to be an interesting tool for investigating both normal and abnormal short-term modulations of the BZD receptor system and should ideally be performed within a few days after a seizure in patients with MTE and a normal MRI.

Seizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: a [11C]flumazenil-PET study

We have undertaken a test-re-test [11C]flumazenil (FMZ) PET study in 10 drug-resistant epileptic patients, including six with a mesiotemporal epilepsy (MTE), and 10 normal controls, in order to investigate seizure-related short-term plasticity of benzodiazepine (BZD) receptors. All subjects underwent two FMZ-PET scans at a 1 week interval. Patients benefited from a concurrent video-EEG monitoring which allowed determination of the duration of the interictal period (IP) preceding each PET. Test-re-test whole brain B'(max) variations, evaluated with a partial-saturation injection protocol, were similarly observed in patients and controls, suggesting a physiological modulation of BZD receptors. Five patients (50%), but no controls, also demonstrated clinically significant test-re-test FMZ-PET variations in the mesial temporal region. This was observed in all three patients with MTE and no hippocampal atrophy in whom only the PET study associated with the shortest IP correctly identified the epileptogenic zone. Statistical analysis revealed a significant effect of IP duration on BZD receptor B'(max) in MTE patients, suggesting that the shorter the IP, the lower the B'(max) in the epileptogenic hippocampus. FMZ-PET appears to be an interesting tool for investigating both normal and abnormal short-term modulations of the BZD receptor system, and should ideally be performed within a few days following a seizure in patients with MTE and a normal MRI.

Peripheral benzodiazepine receptors reflect trait (early handling) but not state (avoidance learning)

Behavioral animal paradigms and experimental neuroendocrinological and neurochemical studies have shown that early environmental manipulations have profound effects on the late response to stress. The aim of the present study was to investigate the interactive effects of environmental manipulation (early handling) and experimentally induced behavioral differences on the peripheral benzodiazepine receptor (PBR) system, which is known to be involved in the response to stressors. Adult early-handled (EH) and nonhandled (NH; control) Wistar rats were placed in a two-way active avoidance/latent inhibition (LI) paradigm, and PBR densities in the adrenal glands, kidneys, and gonads were assessed. In line with previous studies, overall avoidance learning improved in the EH group, and LI was disrupted in the NH group (primarily in males). PBR densities were up-regulated in EH subjects, and more so in females than males. However, PBR densities did not correlate with any of the behavioral measures. These findings strengthen the hypothesis that differences in PBR densities between EH and NH rats are a reflection of trait rather than state, and they suggest that the PBR system is characterized by a highly stressor-specific response.

The 5-HT(1A) receptor knockout mouse and anxiety.

The 5-HT(1A) receptor has been implicated in the modulation of anxiety processes, mainly via pharmacological experiments. The recent production, in three independent research groups, of 5-HT(1A) receptor knockout (R KO) mice in three different genetic backgrounds (C57BL/6J, 129/Sv, Swiss-Webster) led to the intriguing finding that all mice, independent from the genetic background strain from which the null mutants were made, showed an "anxious" phenotype compared to corresponding wild-type mice. The present paper reviews the behavioral findings in these three KO lines and focuses on new findings in the 129/Sv-KO mice. These mice were more anxious or stress-prone only under specific conditions (high stress) and not as broadly as suggested from the initial studies. The 5-HT(1A) R KO made in the Swiss-Webster background displays disturbances in the GABA(A)-benzodiazepine (BZ) receptor system in the brain, including downregulation of GABA(A) alpha1 and alpha2 subunits in the amygdala. In contrast, the GABA(A)-BZ receptor system seems to function normally in the 5-HT(1A) R KO in the 129/Sv background suggesting that changes in the GABA(A)-BZ receptor system may not be a prerequisite for anxiety but rather could have a modifying effect on this phenotype. It can be concluded that the constitutive absence of the 5-HT(1A) receptor gene and receptor leads to a more "anxious" mouse, dependent on the stress level but independent from the strain. Depending on the genetic background, this null mutation may be associated with changes in GABA(A)-ergic neurotransmission. It is as yet unclear which mechanisms are involved in this intriguing differentiation.

The influences of extremely low frequency magnetic fields on clonidine-induced sleep in 2-day-old chicks.

1. It has been shown that magnetic fields (MFs) affect a variety of biological effects in animal brains. There have been few experiments on the effects of MFs on sleep. Therefore, we investigated whether extremely low frequency (ELF) MFs affect the sleep induced by clonidine, a central alpha(2)-adrenoceptor agonist. Clonidine produced dose-related increase of the sleeping time and dose-related decrease of the onset time in 2-day-old chicks. 2. Exposure of chicks to MFs (5, 10, 20 G; for 3, 6, 9, 12 h) significantly increased the clonidine-induced sleep time as a direct function of intensity and duration of MF application. Clonidine reduced noradrenaline or tyrosine in the brain, an effect which was not further changed in animals exposed to MF. 3. To determine whether the gamma amino butyric acid A (GABA(A))/benzodiazepine (BZD) receptor system is involved in the decrease in clonidine-induced sleep caused by activation of central alpha(2)-adrenergic systems, we examined exposure of chicks to the effects of the BZD receptor antagonist flumazenil (0.5 mg kg(-1), i.p.) and GABA(A) antagonist bicuculline (0.1 mg kg-1, i.p.) on clonidine-induced sleep. Bicuculline and flumazenil inhibited the increase of clonidine-induced sleep time by MFs. Clonidine or MFs did not change GABA levels in the brain. 4. These results suggest that MFs can increase clonidine-induced sleep via a change of GABA(A) and BZD receptor system irrespective of the concentration of GABA or noradrenaline in the brain of 2-day-old chicks.

Prenatal protein malnutrition results in increased frequency of miniature inhibitory synaptic currents in rat CA1 pyramidal cells.

There is growing evidence for an effect of prenatal protein malnutrition on the GABAergic neurotransmitter system in the rat hippocampus and associated structures. In the present study, we examined the functional electrophysiological consequences of observed alterations in GABA(A) and benzodiazepine receptor systems. Whole-cell patch clamp recordings of spontaneous and of miniature inhibitory postsynaptic currents (mIPSCs) generated by CA1 pyramidal cells were performed in in vitro hippocampal slices prepared from control and prenatally protein malnourished adult male rats. The characteristics of spontaneous synaptic currents were unaltered by the prenatal insult, as were the amplitudes and kinetics of GABA(A) receptor-mediated mIPSCs. The frequency of mIPSCs, however, was significantly increased in CA1 pyramidal cells in slices prepared from prenatally malnourished vs. control rats. The effect of the benzodiazepine receptor agonist chlordiazepoxide on the characteristics of mIPSCs was also examined and found to be the same in cells from both nutritional groups. The increased frequency of mIPSCs together with the lack of a change in amplitude, kinetics, or modulation by benzodiazepines of mIPSCs in response to prenatal protein malnutrition indicate a presynaptic locus of effect of this insult.

Preweaning experience as a modifier of prenatal drug effects in rats and mice--a review.

The effects of preweaning experience in rats and mice on neuroendocrine and behavioral end points and their implications for prenatal drug effects are reviewed. The hypothalamo-pituitary-adrenal axis and the dopaminergic system were shown to be affected. Behavior related to hippocampal, adrenocortical functions and to the benzodiazepine receptor system was also modified. Other paradigms (nociception, conditioned taste aversion) exhibited susceptibility to such preweaning manipulations also. The effects of these early experiences seem to be mediated through complex factors including neuroendocrine responses of the pup to hypothermia and a permanent alteration of mother-infant interactions, with subsequent effects on neuroendocrine functions that are important for postnatal brain organization. Studies of interactions between prenatal drug effects and preweaning manipulations have been performed only with ethanol. When extending this work to other compounds, the systems and functions described above may provide some guidance in looking for possible interactions. In most cases the preweaning manipulations alleviated the effects of prenatal ethanol exposure. These findings may have important implications regarding the controversy about environmental influences affecting the outcome of exposure to neurobehavioral teratogens.

Increased expression of peripheral benzodiazepine receptors and diazepam binding inhibitor in human tumors sited in the liver

The peripheral benzodiazepine receptor system triggers intracellular metabolic events and has been associated with cell proliferation. Its endogenous ligand, the diazepam binding inhibitor, contributes to steroidogenesis by promoting cholesterol delivery to the inner mitochondrial membrane. The present study was undertaken to verify whether this system is altered in tumors sited in the liver. Peripheral benzodiazepine receptors and diazepam binding inhibitor were studied using immunocytochemistry and in situ hybridization in 9 human tumors sited in the liver, in liver hyperplasia, cirrhotic nodular regeneration, intestinal adenocarcinoma and in surrounding non-tumoral tissue. Immunocytochemical staining and in situ hybridization demonstrated that peripheral benzodiazepine receptors and diazepam binding inhibitor were more prominently expressed in neoplastic cells than in non-tumoral tissue. They were present in the same cells, suggesting that diazepam binding inhibitor may act in an intracrine manner in these cells. Higher peripheral benzodiazepine receptors and diazepam binding inhibitor expression in tumor cells suggest an implication of this system in the metabolism of neoplastic cells. Furthermore the evaluation of peripheral benzodiazepine receptor and diazepam binding inhibitor expression might be useful in evaluating malignancy and in diagnostic approaches of tumors in liver tissue.

Up-regulation of peripheral benzodiazepine receptor system in hepatocellular carcinoma

Increased number of peripheral benzodiazepine receptors (PBRs) have been found in some tumors outside the liver. The present study was to verify whether the PBR system is altered in hepatocellular carcinoma (HCC). The levels of endogenous benzodiazepine-like compounds (BZDs). measured by radioreceptor binding technique after HPLC purification and the endogenous ligand for PBRs. termed diazepam binding inhibitor (DBI). measured by radioimmunoassay utilizing a specific antibody for human DBI, were studied in the blood of 15 normal subjects, 12 liver cirrhosis and 10 patients with HCC. The levels of BZDs in serum were increased hundred fold in liver cirrhosis patients and slightly elevated in HCC patients. DBI was found to be increased in HCC patients. The binding recognition sites for PBRs (B max) were increased 4 to 7 fold in HCC tissue in comparison with that found in non-tumoral liver tissue (NTLT). On the contrary the concentrations of DBI were found to be significantly decreased in HCC tissue in comparison with the respective NTLT. These results seem to suggest an implication of PBRs and of their putative endogenous ligands in the metabolism of these neoplastic cells and possibly in their proliferation. The up-regulation of PBRs found in HCC tissue seems to indicate an increased functional activity of these receptors and opens up the possibility of new pharmacological and diagnostic approaches while the changes in the circulating endogenous ligands for the above receptors might be envisaged as early markers of tumorigenesis in liver cirrhosis.

A possible mechanism of resistance to death during cell proliferation in hepatocellular carcinoma: The mitochondrial benzodiazepine receptor system

A possible mechanism of resistance to death during cell proliferation in hepatocellular carcinoma: The mitochondrial benzodiazepine receptor system