Investigating benzodiazepine receptor function in vivo using an intravenous infusion of DMCM

1984 ◽  
Vol 103 (3-4) ◽  
pp. 359-362 ◽  
Author(s):  
David J. Nutt ◽  
Hilary J. Little ◽  
Stuart C. Taylor ◽  
Michael C.W. Minchin
Keyword(s):  
Intravenous Infusion ◽  
Benzodiazepine Receptor ◽  
Receptor Function

In vivo modulation of benzodiazepine receptor function after inhibition of endogenous γ-aminobutyric acid synthesis

1997 ◽  
Vol 321 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Michel Bottlaender ◽  
Lorenz Schmid ◽  
Chantal Fuseau ◽  
Denis Fournier ◽  
Emmanuel Brouillet ◽  
...  
Keyword(s):  
Benzodiazepine Receptor ◽  
Acid Synthesis ◽  
Aminobutyric Acid ◽  
Receptor Function

Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity

2007 ◽  
Vol 26 (4) ◽  
pp. 333-338 ◽  
Author(s):  
Anna Forsby ◽  
Bas Blaauboer
Keyword(s):  
Exposure Period ◽  
Cellular Protein ◽  
In Vitro Toxicity ◽  
Target Tissue ◽  
Receptor Function ◽  
Human Neuroblastoma ◽  
Protein Levels ◽  
Effective Doses

Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+concentration were studied as physiological endpoints. Voltage operated Ca2 +channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC 20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10 000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that some knowledge about toxic mechanisms is known. Human & Experimental Toxicology (2007) 26, 333—338

In vivo characterization of the putative 5-HT1A receptor antagonist SDZ 216,525 using two models of somatodendritic 5-HT1A receptor function

1994 ◽  
Vol 33 (3-4) ◽  
pp. 359-366 ◽  
Author(s):  
C. Routledge ◽  
J. Hartley ◽  
J. Gurling ◽  
M. Ashworth-Preece ◽  
G. Brown ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Function ◽  
In Vivo Characterization

Naloxone antagonizes GABA A /benzodiazepine receptor function in rat corticohippocampal synaptoneurosomes

2000 ◽  
Vol 107 (3) ◽  
pp. 261-270 ◽  
Author(s):  
A. I. Svensson ◽  
A. Berntsson ◽  
M. Eirefelt ◽  
B. Söderpalm
Keyword(s):  
Benzodiazepine Receptor ◽  
Receptor Function ◽  
Gaba A

SPECT Quantification of [123I]Iomazenil Binding to Benzodiazepine Receptors in Nonhuman Primates: II. Equilibrium Analysis of Constant Infusion Experiments and Correlation with in vitro Parameters

1994 ◽  
Vol 14 (3) ◽  
pp. 453-465 ◽  
Author(s):  
Marc Laruelle ◽  
Anissa Abi-Dargham ◽  
Mohammed S. AI-Tikriti ◽  
Ronald M. Baldwin ◽  
Yolanda Zea-Ponce ◽  
...  
Keyword(s):  
Specific Activity ◽  
Single Photon ◽  
Benzodiazepine Receptors ◽  
Photon Emission ◽  
Benzodiazepine Receptor ◽  
Equilibrium Analysis ◽  
Constant Infusion ◽  
Scatchard Analysis

In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]iomazenil. Plasma steady-state concentration and receptor–ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4–9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 ± 0.09 n M) and Bmax (from 126 n M in the occipital region to 68 n M in the striatum). Two animals were killed and [125I]iomazenil Bmax and KD were measured at 22 and 37°C on occipital homogenate membranes. In vitro values of Bmax (114 ± 33 n M) and 37°C KD (0.66 ± 0.16 n M) were in good agreement with in vivo values measured by SPECT. This study demonstrates that SPECT can be used to quantify central neuroreceptors density and affinity.

Focus on GABAA receptor function

2014 ◽  
Vol 53 (06) ◽  
pp. 227-337 ◽  
Author(s):  
H. Hautzel ◽  
H.-W. Müller ◽  
S. Nikolaus
Keyword(s):  
Gabaa Receptor ◽  
Receptor Binding ◽  
Temporal Cortex ◽  
Primary Diagnosis ◽  
Receptor Function ◽  
Healthy Individuals ◽  
Major Depressive ◽  
Neuropsychiatric Diseases ◽  
Pubmed Search

SummaryImpairment of GABAA receptor function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD) and schizophrenia (SZ). Patients, method: We conducted a PUBMED search, which provided a total of 23 in vivo investigations with PET and SPECT, in which GABAA receptor binding in patients with the primary diagnosis of AD (n = 14, 160 patients, 172 controls), MDD (n = 2, 24 patients, 28 controls) or SZ (n = 6, 77 patients, 90 controls) was compared to healthy individuals. Results: A retrospective analysis revealed that AD, MDD and SZ differed as to both site(s) and extent(s) of GABAergic impairment. Additionally, it may be stated that, while the decline of GABAA receptor binding AD involved the whole mesolimbocortical system, in SZ it was confined to the frontal and temporal cortex. Conclusion: As GABA is known to inhibit dopamine and serotonin, GABAergic dysfunction may be associated with the disturbances of dopaminergic and serotonergic neurotransmission in neuropsychiatric disorders.

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