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PubMed1995

Methylmercury modulates GABAA receptor complex differentially in rat cortical and cerebellar membranes in vitro.

Effects of methylmercury (MetHg) on the specific [3H]flunitrazepam binding were studied in rat cortical and cerebellar P2-fractions in vitro. MetHg did not affect significantly the specific [3H]flunitrazepam binding in unwashed P2-fraction but increased it marginally (by 16%) at 100 microM in washed P2-fraction, in both brain regions. Muscimol (3 microM), a GABAA agonist, stimulated the [3H]flunitrazepam binding by 30% to 50% depending on the brain region. In washed cerebellar membranes the enhancing response of muscimol was 10 to 14% lower after preincubation of the tissue with MetHg but in cerebral cortex MetHg did not modulate the muscimol response at all. The results indicate that Met-Hg may have region specific effects on GABAA receptors in vitro and the effect may depend on the occupational state of the GABA binding domain of the receptor complex.

Animals↗
PubMed1995

Benzodiazepine binding sites in alcoholic cirrhotics: evidence for gender differences.

Synaptic plasma membranes were prepared from superior frontal gyrus and motor cortex obtained at autopsy from 17 chronic alcoholics not differentiated on thiamine status, of whom 8 had pathologically confirmed cirrhosis of the liver, and 10 controls. Three of the cirrhotic alcoholic cases were female, as was one control. Cases were closely matched for age at death and post-mortem delay. The affinity of "central-type" benzodiazepine sites for [3H]diazepam tended to be lower in both brain regions of both groups of alcoholics of cf controls, but the reverse was true for [3H]flunitrazepam, especially in cirrhotic cases. [3H]Diazepam affinity was invariant across all males and the female control, but lower in the female cirrhotic alcoholics. Affinity for [3H]flunitrazepam tended to be the reverse of that for [3H]diazepam. [3H]Diazepam Bmax was markedly lower in female cirrhotic alcoholics, especially in superior frontal gyrus, whereas this region showed a much higher Bmax in the female control case. A small regional difference in [3H]flunitrazepam Bmax was the reverse of that for [3H]diazepam Bmax and was seen in all groups. GABA-mediated neurotransmission may be selectively altered in a pathologically abnormal region of cerebral cortex in cirrhotic alcoholics, and the sexes may show differing susceptibilities to change.

Adult↗
PubMed1994

Heterogeneity and differential expression of the gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor in the avian brain during development.

1. The changes in the GABAA/benzodiazepine receptor in chicken brain during development has been studied by using 3H-flunitrazepam as the probe for the benzodiazepine modulator site and the antibodies recognizing the receptor protein. In the telencephalon and optic tectum, the proteins of 48, 50, and 51 kD were markedly labeled by 3H-flunitrazepam from embryonic day 18 to postnatal days, as revealed by photoaffinity labeling and SDS-PAGE of the brain membranes; the 51-kD protein appeared to be the predominant one in labeling intensity except at embryonic day 18 and postnatal days 14 and 28, whereas the 47- and 50-kD proteins were dominant in the cerebellum. However, the 47- and 48-kD proteins were faintly seen after postnatal day 28 in the three regions examined. 2. Immunoblotting using a monoclonal antibody against the 50- and 51-kD proteins showed that the straining pattern in the developing telecephalon or optic tectum was similar to the 50 kD/51 kD pattern obtained from fluorography. The antibody also stained the 50- and 51-kD proteins in the cerebellum despite the fact that the 51-kD protein was barely seen in the fluorogram. Moreover, the 50-kD protein was recognized by an antiserum raised against a partial sequence of the alpha 1 subunit of the receptor expressed in bacteria. The staining levels for the 50-kd protein by the antiserum on immunoblots of the brain regions were low in embryonic animals but higher during postnatal stages, consistent with that seen in fluorograms. 3. Receptor binding autoradiography using 3H-flunitrazepam exhibited that varying degrees of labeling intensity occurred among various brain areas at different ages. High densities of binding were present in the olfactory bulb, paleostriatum, optic tectum, and midbrain. These results support the diversity of the GABAA/benzodiazepine receptor in the vertebrate CNS.

Animals↗
PubMed1993

Effects of benzodiazepines on mid-latency auditory evoked potentials.

Midlatency auditory evoked potentials (MLAEP) reflect primary cortical processing of auditory stimuli. The effects of benzodiazepines on MLAEP have not yet been studied. We examined the effects of intravenous induction of general anaesthesia using the benzodiazepines midazolam, diazepam and flunitrazepam on MLAEP in 30 patients scheduled for minor gynaecological procedures. Anaesthesia was induced with midazolam (0.2-0.3 mg.kg-1, Group I, n = 10), diazepam (0.3-0.4 mg.kg-1, Group II, n = 10) or flunitrazepam (0.03-0.04 mg.kg-1, Group III, n = 10). Auditory-evoked potentials were recorded before and five to ten minutes after induction of general anaesthesia. Latencies of the peak V, Na, Pa, Nb and Pl (ms) and amplitudes Na/Pa, Pa/Nb and Nb/P1 (microV) were measured. In the awake state, MLAEP had high peak to peak amplitudes and a periodic waveform. After induction of anaesthesia there was no or only a small increase in latencies of the peaks Na, Pa, Nb and P1, which was significant only for P1 in the midazolam group. Amplitudes Na/Pa, Pa/Nb and Nb/P1 decreased only slightly and which reached statistical significance only for Na/Pa in the flunitrazepam group. The MLAEPs do not change markedly in amplitude or latency during induction of general anaesthesia with benzodiazepines. Primary cortical processing of auditory stimuli seems to be preserved under benzodiazepines. This may be seen in connection with cases of intraoperative awareness and especially the perception of auditory stimuli during anaesthetic regimens where benzodiazepines are used to suppress consciousness.

Acoustic Stimulation↗
PubMed1993

The influence of intravenous anaesthetics on polymorphonuclear leukocyte function.

Polymorphonuclear leukocytes (PMNL) play a vital role in the defence against invading bacteria. It is known that some anaesthetics inhibit PMNL function and, thus, possibly enhance perioperative infection. We investigated the effect of methohexitone, flunitrazepam, and droperidol on three bactericidal PMNL functions, i.e., superoxide anion production, hydrogen peroxide generation, and activity of released myeloperoxidase, in vitro. Approved photometrical assays were used. Superoxide anion was measured by the reduction of cytochrome C, hydrogen peroxide by the horse radish peroxidase catalysed oxidation of phenol red, and myeloperoxidase by the turnover of 2,2'-azino-di(3-ethylbenzthiazoline) sulfonic acid. Methohexitone (P < or = 0.001) and flunitrazepam (P < or = 0.01) inhibited superoxide anion production, and methohexitone (P < or = 0.01) reduced hydrogen peroxide generation but only at concentrations beyond clinical relevance. Droperidol did not cause any alteration of the PMNL functions tested. Consequently, it seems unlikely that the usual doses of methohexitone, flunitrazepam, or droperidol promote bacterial infections in vivo by impairing the activity of myeloperoxidase or by inhibiting the generation of superoxide anion or hydrogen peroxide.

Adult↗
PubMed2003

Alcohol withdrawal severity is decreased by symptom-orientated adjusted bolus therapy in the ICU.

OBJECTIVE: To examine the effect of bolus vs. continuous infusion adjustment on severity and duration of alcohol withdrawal syndrome (AWS), the medication requirements for AWS treatment, and the effect on ICU stay in surgical intensive care unit (ICU) patients. DESIGN AND SETTING: Prospective randomized, double-blind controlled trial in a surgical ICU. PATIENTS: 44 patients who developed AWS after admission to the ICU. INTERVENTIONS: Patients were randomized to either (a). a continuous infusion course of intravenous flunitrazepam (agitation), intravenous clonidine (sympathetic hyperactivity), and intravenous haloperidol (productive psychotic symptoms) if needed (infusion-titrated group), or (b). the same medication (flunitrazepam, clonidine, or haloperidol) bolus adjusted in response to the development of the signs and symptoms of AWS (bolus-titrated group). MEASUREMENTS AND RESULTS: The administration of "as-needed" medication was determined using a validated measure of the severity of AWS (Clinical Institute of Withdrawal Assessment). Although the severity of AWS did not differ between groups initially, it significantly worsened over time in the infusion-titrated group. This required a higher amount of flunitrazepam, clonidine, and haloperidol. ICU treatment was significantly shorter in the bolus-titrated group (median difference 6 days) due to a lower incidence of pneumonia (26% vs. 43%). CONCLUSIONS: We conclude that symptom-orientated bolus-titrated therapy decreases the severity and duration of AWS and of medication requirements, with clinically relevant benefits such as fewer days of ventilation, lower incidence of pneumonia, and shorter ICU stay.

Adult↗
PubMed2002

Effect of zaleplon on learning and memory in rats.

Although structurally not a benzodiazepine, 3'-(3-cyanopyrazolo [1,5-a] pyrimidin-7-yl)- N-ethylacetamide (zaleplon) it acts via the benzodiazepine site of the GABA(A) receptor. In the present study, we investigated the effects of zaleplon on learning and memory in rats in comparison with triazolam and nitrazepam. Oral administration of zaleplon and the reference drugs dose-dependently lessened the step-through latency in the test session of a passive avoidance task and increased the latency for reaching the hidden platform in the Morris water maze task, indicating the amnesic effect of the test drugs. The amnesic liability ratio for zaleplon in the passive avoidance task to sleep inducing activity was 19.6, for triazolam and nitrazepam 4.2 and 5.9, respectively. The liability ratios derived from the Morris water maze task for zaleplon, triazolam and nitrazepam were 10.2, 0.9 and 0.6, respectively. The results may indicate that zaleplon has a preferential sedative effect and that the sedative dose does not interfere with learning and memory. In a binding study, zaleplon displaced bound [(3)H]flunitrazepam from membrane preparations from the rat hippocampus with an IC(50) of 4,454.5 nM. In contrast, triazolam and nitrazepam displaced the binding of [(3)H]flunitrazepam to the membrane with IC(50) values of 15.5 nM and 83.6 nM, respectively. The efficacy of zaleplon for the competitive inhibition of [(3)H]flunitrazepam binding to the membrane preparation from hippocampus was thus less than that of triazolam and nitrazepam. These results suggest that zaleplon is characterized by a reduced amnesic liability, which may be due to its low affinity for the benzodiazepine site of the GABA(A) receptor in the hippocampus.

Acetamides↗
PubMed1998

Rebound insomnia after hypnotic withdrawal in insomniac outpatients.

The effect of abrupt medication withdrawal (no-pill discontinuation) was investigated in 1507 insomniacs using the patients' self-ratings on visual analogue scales. Drug discontinuation followed a 28-day treatment period with either 7.5 mg zopiclone, 0.25 mg triazolam, 1.0 mg flunitrazepam, or placebo in a randomized, double-blind, parallel group, multicenter study in private practice. Deterioration below individual pretreatment values (no-pill baseline) in at least one of three subjective parameters of sleep quality (sleep latency, total sleep time, nocturnal awakenings) and three parameters of daytime well-being (morning freshness, daytime tiredness, anxiety) were defined as rebound. The number of patients with rebound (rebound rate) was analyzed for every day of a 2-week posttreatment period. The overall rebound rate was higher in the placebo group (p < or = 0.001) than in each group treated with active drugs. Rebound rates affecting sleep quality were higher for placebo than for zopiclone (p < or = 0.001) and for flunitrazepam (p < or = 0.05). Rebound rates were smaller for zopiclone (p < or = 0.001) and flunitrazepam (p < or = 0.01) than for triazolam. Rebound in at least one item per day appeared in 21.5% (sleep quality) and 25.5% (daytime well-being) of the patients. Rebound decreased with increasing numbers of items of sleep quality or daytime well-being. Patients who did not respond to treatment showed higher rebound rates than those who were treatment responders (p < or = 0.001). Concerning treatment nonresponders, highest rebound was seen in the placebo group, whereas rebound was lowest in placebo responders. These results show that pill discontinuation itself may worsen sleep and daytime well-being in the sense of a rebound phenomenon. Furthermore, the number of patients with rebound remained at a high and varying level during the whole posttreatment period. This result indicates that a deterioration of sleep after drug withdrawal is not apparent during a few days but may last for longer periods in some patients and is modified by marked night-to-night variations.

Adolescent↗
PubMed2005

Quantification of benzodiazepines in whole blood and serum.

A high-performance liquid chromatography method for the determination of benzodiazepines and their metabolites in whole blood and serum using mass spectrometry (MS) and photodiode array (PDA) detection is presented. The combination of both detection types can complement each other and provides extensive case relevant data. The limits of quantification (LOQ) with the MS detection lie between 2 and 3 microg/l for the following benzodiazepines or metabolites: 7-amino-flunitrazepam, alprazolam, desalkyl-flurazepam, desmethyl-flunitrazepam, diazepam, flunitrazepam, flurazepam, alpha-hydroxy-midazolam, lorazepam, midazolam, nitrazepam, nordazepam and oxazepam, respectively 5 microg/l for lormetazepam and 6 microg/l for bromazepam. The LOQ of clobazam determined with the PDA detector is 10 microg/l. A convenient approach for determining the measurement uncertainty of the presented method--applicable also for other methods in an accreditation process--is presented. At low concentrations (<10 microg/l), measurement uncertainty was estimated to be about 50%, and at concentrations >180 microg/l, it was estimated to be about 15%. One hundred and twenty-eight case data acquired over 1 year are summarised.

Anti-Anxiety Agents↗
PubMed1981

Stimulation of benzodiazepine binding to rat brain membranes and solubilized receptor complex by avermectin B1a and gamma-aminobutyric acid.

The binding of [3H]flunitrazepam to benzodiazepine receptors in synaptic membranes and a digitonin-solubilized receptor fraction of rat brain is increased by avermectin B1a and gamma-aminobutyric acid (GABA). The effects of avermectin B1a and GABA are both sensitive to inhibition by (+)-bicuculline. Avermectin B1a and GABA both decrease the Kd and increase the Bmax of [3H]flunitrazepam binding to membranes. Kinetic analysis of the binding of [3H]flunitrazepam to rat brain membranes indicates that avermectin B1a and GABA reduce the rate constants of both association and dissociation between the ligand and the receptor. These results suggest a similar mechanism of modulation of benzodiazepine binding by avermectin B1a and GABA. This modulation may involve in interaction among the receptors for benzodiazepine, GABA and avermectin B1a.

Animals↗
PubMed1992

Effect of free fatty acids on GABAA receptor ligand binding.

Phospholipase A2 (PLA2) treatment of synaptosomal membranes, which causes the release of fatty acids, particularly unsaturated fatty acids, inhibits the flux of chloride ions through the gamma-aminobutyric acid (GABA) benzodiazepine receptor ion channel in response to activation by agonists. PLA2 treatment has also been shown to affect ligand binding to the receptor. In the present study, we have investigated the effect of unsaturated free fatty acids, arachidonic acid and oleic acid and saturated free fatty acids, arachidic acid and stearic acid on various characteristics of GABAA receptor ligand binding. Only the unsaturated fatty acids showed any effect: arachidonic acid and oleic acid enhanced flunitrazepam binding and muscimol binding but inhibited tert-butylbicyclophosphorothionate (TBPS) binding in a dose-dependent manner. The effects on muscimol and TBPS binding were shown to be due to changes in receptor density by saturation analysis. Oleic acid and arachidonic acid also decreased the enhancement of flunitrazepam and muscimol binding by cartazolate and pentobarbital but did not affect GABA enhancement of flunitrazepam binding. These data indicate that unsaturated free fatty acids can mimic the effects of PLA2 treatment and underline the importance of the lipid microenvironment on ligand binding to the GABAA receptor.

Animals↗
PubMed1985

Aging: effect on the interaction of ethanol and pentobarbital with the benzodiazepine-GABA receptor-ionophore complex.

Benzodiazepine receptor binding and modulation by pentobarbital and ethanol was studied using the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate to solubilize the gamma-aminobutyric acid (GABA)-benzodiazepine receptor-ionophore complex from the brains of Fischer 344 rats of 3-4, 12-15 and more than 28 months of age. The affinity of the benzodiazepine binding site was significantly lower in the young rats compared to either the mature or senescent animals. However, no age-related changes in the maximum number of benzodiazepine binding sites or GABA concentrations occurred in the detergent extract. Pentobarbital produced practically identical dose-dependent enhancement of [3H]flunitrazepam specific binding in all 3 age groups. In contrast, ethanol between 0.1 and 200 microM failed to produce a dose-dependent effect on [3H]flunitrazepam specific binding in any age group. The effect of pentobarbital and ethanol on [35S]t-butyl-bicyclophosphorothionate [( 35S]TBPS) specific binding to the picrotoxinin binding site was examined in the above solubilized receptor/ionophore complex under the same binding conditions. Both sedative-hypnotics produced a dose-dependent decrease in [35S]TBPS specific binding. However, pentobarbital was over 10,000 times more potent. It appears that ethanol may not enhance [3H]flunitrazepam specific binding in this solubilized preparation because of its weak action at the picrotoxinin binding site.

Aging↗
PubMed1988

Developmental aspects of benzodiazepine receptors and GABA-gated chloride channels in primary cultures of spinal cord neurons.

The developmental aspects of gamma-aminobutyric acid (GABA)-benzodiazepine receptor ionophore complex in mouse cultured spinal cord neurons was investigated in vitro. We examined benzodiazepine binding, GABA enhancement of benzodiazepine binding and GABA activation of chloride channels to intact cultured neurons during the development (days 1-14). Specific benzodiazepine binding increased with time from day 3 (Bmax = 546 fmol/mg protein) to day 14 (Bmax = 1746 fmol/mg protein). There was no significant difference in the affinity (Kd) of [3H]flunitrazepam for its receptor sites from day 3 to 14. Specific binding of [3H]flunitrazepam to the intact cells was also increased in the presence of GABA during all stages of development. The EC50 value of the GABA concentration (14-16 microM) required to enhance [3H]flunitrazepam binding did not change from day 3 to 14. GABA receptor-activated chloride channels, studied by 36Cl-influx was also observed at all ages in culture, and indicated an early development (as early as day 3) of these GABA-gated channels. These studies indicate that GABA-benzodiazepine-ionophore complex develop early in cultured spinal cord neurons, and these neurons provide an ideal system to study GABAergic events.

Animals↗
PubMed1989

Chronic exposure of developing cortical neurons to GABA down-regulates GABA/benzodiazepine receptors and GABA-gated chloride currents.

Cultures of cerebral neurons were prepared from chick embryos, 8.5 days in ovo, and maintained in vitro. Following chronic exposure of these cells to GABA, the levels of [3H]flunitrazepam binding in situ and electrophysiological responsiveness to gamma-aminobutyric acid (GABA) was examined. Treatment with 100 microM GABA for 7 days reduced [3H]flunitrazepam binding in situ by 70 +/- 8% compared to untreated controls. The binding of [3H]N-methylscopolamine was unaffected by this treatment. The reduction in [3H]flunitrazepam binding was prevented by concomitant exposure of developing neurons to the GABA antagonist R 5135, suggesting that GABAA receptor occupancy is required. The loss of bezodiazepine receptors was dependent on the GABA concentration in the culture medium and a half-saturation (IC50) value of 11.2 +/- 3.7 microM was estimated. Whole-cell patch-clamp recordings were obtained to assess the functional properties of the labile receptor pool observed in the binding studies. Neurons cultured with 100 microM GABA for 7 days showed a 60-70% reduction in the peak current amplitudes observed in response to application of 10-100 microM GABA. However, the rate of rapid desensitization, quantified by measuring changes in input conductance, was unchanged by chronic GABA exposure, yielding decay time constants of 27.1 +/- 2.1 and 34.7 +/- 4.7 s for control and treated cells, respectively. The results are consistent with a GABA modulation of the GABAA/benzodiazepine receptor complex by means of down-regulation.

Animals↗
PubMed1991

Peptide heterogeneity of GABAA/benzodiazepine receptors in bovine cerebral cortex and cerebellum.

The GABAA/benzodiazepine receptor complex has been purified from both bovine cerebral cortex and cerebellum by immunoaffinity chromatography on immobilized monoclonal antibody 62-3G1. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified receptor from either cerebral cortex or cerebellum revealed 3 main bands corresponding to 51,000, 55,000 and 57,000 Mr silver-stained peptides. In addition, a minor band corresponding to a 53,000 Mr peptide was also found. The differences between the two receptor preparations were: (1) that the main silver-stained 55,000 Mr subunit was present in a relative smaller quantity in cerebellum than in cerebral cortex, and (2) when the membrane-bound receptor was photoaffinity-labeled with [3H]flunitrazepam and subsequently immunoaffinity-purified, two photolabeled peptide bands of 51,000 and 57,000 Mr were found in cerebral cortex while only the 51,000 Mr photolabeled peptide was detected in cerebellum following one-dimension sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Peptide maps of the 57,000 Mr [3H]flunitrazepam photoaffinity-labeled peptide indicated that it was composed of two closely migrating photolabeled peptides of 55,000 Mr and 57,000 Mr. Peptide mapping and deglycosylation experiments using the [3H]flunitrazepam photolabeled receptor suggested that the photolabeled peptides commonly present in cerebellum and cerebral cortex are qualitatively similar if not identical. The results suggest that there are subunits of some type(s) of GABAA R/BZDR complex(es) which are more abundant in cerebral cortex than in cerebellum. Photoaffinity labeling with [3H]muscimol showed similar photolabeled peptides in both cerebral cortex and cerebellum: two main peptides of 54,000 and 57,000 Mr were photolabeled with [3H]muscimol to a similar extent in both receptor preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Steroid modulation of GABAA receptors in an amphibian brain.

Steroids can modulate gamma-aminobutyric acid (GABAA) receptor function in rat brains, but the physiological relevance of this mechanism is still unclear. To determine whether this phenomenon is widespread among vertebrates, we investigated steroid modulation of GABAA receptors in amphibian brain tissue. Equilibrium binding parameters for t-butylbicyclophosphorothionate ([35S]TBPS) and [3H]flunitrazepam were similar in Taricha granulosa and mammalian brains, as was the allosteric regulation of [35S]TBPS and [3H]flunitrazepam binding by GABA. The rank order and absolute potencies of steroids to inhibit [35S]TBPS binding and enhance [3H]flunitrazepam binding were also similar in Taricha and rat brains. As in mammalian studies, physiological concentrations of corticosterone had no effect on ligand binding or GABA-stimulated Cl- uptake. In autoradiographic studies, 3 alpha-hydroxy-5 alpha-pregnan-20-one inhibited [35S]TBPS binding sites in all brain regions examined, whereas corticosterone had no effect on [35S]TBPS binding. These studies suggest that the steroid recognition sites on GABAA receptors have been highly conserved through vertebrate evolution and thus portend physiologically important functions. However, the pharmacological profiles for the GABAA receptor and the high-affinity corticosteroid receptor are apparently different, suggesting there are multiple types of steroid recognition sites on neuronal membranes.

Animals↗
PubMed1982

Effects of agents which enhance GABA-mediated neurotransmission on licking conflict in rats and exploration in mice.

On the holeboard, exploration (dipping) and locomotion of mice were enhanced by non-sedative doses of anxiolytics; clobazam, diazepam, nitrazepam and flunitrazepam. After chronic dosing the sedative effects of flunitrazepam showed tolerance and the increases in exploration remained while locomotion was less increased. Sodium valproate and to a lesser extent GAG also increased both exploration and locomotion at non-sedative doses. Muscimol, AOAA and urethane increased locomotion at threshold sedative doses with little or no increase in exploration. Baclofen only decreased behaviour. In a drinking test benzodiazepines evoked large increases in punished drinking. After chronic dosing of flunitrazepam there was a greater increase. Sodium valproate evoked a response of similar magnitude to the benzodiazepines whilst GAG evoked a smaller increase. Muscimol did not increase punished drinking. It is suggested that anxiolytic drug actions result from a more selective enhancement of brain GABA transmission.

Animals↗
PubMed1984

Interaction of benzodiazepines with mouse macrophages.

Mouse peritoneal inflammatory macrophages have a saturable binding site for [3H]flunitrazepam with a KD of 43 +/- 7 nM and Bmax of 391 +/- 58 fmol per 10(6) cells, which corresponds to 250 000 sites per cell. The IC50 values for PK 11195, Ro 5-4864, diazepam, flunitrazepam, clonazepam, ethyl-beta carboline 3-carboxylate and Ro 15-1788 were 5.6, 6.5, 21, 40, 3 000, 12 000 and 80 000 nM respectively; gamma-aminobutyric acid did not displace [3H]flunitrazepam. These results indicate that the benzodiazepine binding site on the macrophage is of the peripheral type. In vivo experiments show that, at 1 mg/kg, peripheral and mixed type molecules stimulate the humoral response to sheep red blood cells while central type benzodiazepines are inactive. The hypothesis that this effect is mediated through the binding on the macrophage may be considered.

Animals↗