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Biomedical subjects

B Beer

Publications and source records attributed to B Beer.

At least 55 records · Page 3Linked to original sources
PubMed1989

Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control.

Drugs that bound to the peripheral-type or mitochondrial benzodiazepine receptors in rat kidney mitochondria produced several effects on mitochondrial respiration with succinate and malate/pyruvate as substrates. These drugs increased state IV and decreased state III respiration rates, which resulted in a significant decrease in the respiratory control ratio. ADP: O ratios were not affected. The receptor binding affinities of a set of 10 compounds (Ro5-4864, PK11195, diazepam, mesoporphyrin IX, flunitrazepam, deuteroporphyrin IX, dipyridamole, dibutylphthalate, cyclosporin A, and CL259,763) correlated over a concentration range of almost 4 orders of magnitude with their potencies at inhibiting respiratory control (r = 0.95). The anxiolytic benzodiazepine clonazepam had no effect on mitochondrial respiratory control and bound with negligible affinity to the receptor. The magnitude of the effect of Ro5-4865 on respiration increased in parallel with the density of mitochondrial benzodiazepine receptors in mitochondria from liver, kidney, and adrenal. These results suggest that ligand binding to mitochondrial benzodiazepine receptors results in inhibition of mitochondrial respiratory control. This effect may help to explain the pleiotropic effects of receptor ligands on intact cells.

Animals↗
PubMed1988

Absence of mutation in the beta-amyloid cDNAs cloned from the brains of three patients with sporadic Alzheimer's disease.

Using an oligonucleotide probe, we isolated cDNA clones corresponding to the precursor of the beta-amyloid peptide (BAP) from brain libraries of 3 patients with sporadic Alzheimer's disease (AD). DNA sequencing showed that the largest cDNA clone encompasses 83% of the open reading frame proposed by Kang et al. to encode the BAP precursor (APP). cDNA clones from each of the 3 AD brain libraries were identical to the sequence of the APP-cDNAs cloned from normal adult human and fetal brain. An antisense-radiolabeled RNA copy of one of the AD clones detected a pattern of 3 gene transcripts measuring 3.5, 3.2 and 1.6 kilobases (kb) in both normal and AD brain RNAs. These data suggest that there are no mutations in or about the 42 amino acid (aa) sequence of BAP and that the accumulation of amyloid consistently found in AD may result from altered post-translational processing of APP.

Aged↗
PubMed1985

Interaction of amoxapine with muscarinic cholinergic receptors: an in vitro assessment.

Amoxapine, an antidepressant with a rapid onset of therapeutic efficacy and great utility in psychotic depression, has been reported to produce anticholinergic side effects in man similar to those observed with imipramine and amitriptyline. To establish its cholinergic disposition, amoxapine and its metabolites 7-hydroxyamoxapine and 8-hydroxyamoxapine, have been evaluated by determining their effects on quinuclidinyl benzilate (QNB) binding to membrane fractions of rat and human brain, on the carbamoylcholine-stimulated accumulation of inositol phosphates in rat cerebral cortex and on the acetylcholine-induced contraction of the guinea pig ileum. In all three preparations, amoxapine was found to be a considerably weaker antagonist of muscarinic cholinergic receptors than either imipramine (4-27 fold) or amitriptyline (51-300 fold). These results indicate that for amoxapine, no correlation exists between the magnitude of muscarinic receptor inhibition and the extent of 'anticholinergic' side effects found in the clinic. Neither the metabolites of amoxapine nor species differences could account for this discrepancy.

Acetylcholine↗
PubMed1985

Heterogeneity of benzodiazepine binding sites: a review of recent research.

This paper reviews selected aspects of benzodiazepine binding site heterogeneity. These include receptor heterogeneity revealed by biochemical determinations of receptor numbers, autoradiographic localization in histological sections of brain, lesion studies, solubilization of receptors, and photoaffinity labelling. The data summarized support the concept of benzodiazepine receptor multiplicity. In addition, we have reviewed recent work on peripheral-type benzodiazepine binding sites and suggest that further study of these sites may increase our understanding of both the central and peripheral actions of benzodiazepines and other ligands.

Affinity Labels↗
PubMed1985

Heterogeneity of brain benzodiazepine receptors: effects of physiological conditions.

A number of investigators have shown compelling evidence for multiplicity of benzodiazepine (BDZ) receptors. The present study addresses the query of BDZ receptor heterogeneity, in vitro, with respect to temperature. In competition studies involving rat cerebellar tissue, CL 218,872 produced Hill slopes near unity at both 0 degree C and 37 degrees C. In contrast, similar experiments utilizing cortical tissue from rats and mice produced Hill slopes of 0.69 and 0.66 at 0 degree C and 37 degrees C respectively. 3H-Flunitrazepam-photoaffinity labeling of cortical and cerebellar membranes was conducted at 0 degree C and 37 degrees C. SDS-PAGE fluorographic analyses of photolysed 3H-flunitrazepam (3H-Flu) revealed one intensely labeled 51K band in the cerebellum at both temperatures, which was specifically chased by diazepam. Similar experiments conducted in cortical tissue revealed photoaffinity labeling of at least three distinct macromolecules, one intense 51K and two less intense 55K and 59K bands. Labeling of each of these bands was chased specifically by diazepam. These data, taken together, indicate the existence of regional BDZ receptor heterogeneity under physiological conditions.

Animals↗
PubMed1983

Chronic administration of cholinergic agents: effects on behavior and calmodulin.

Rats were implanted subcutaneously with Alza pumps and 0.9% saline, physostigmine, or scopolamine were continuously infused for 15 days. Twenty-four hours after removal of the pumps all animals were trained on a single trail passive avoidance task. Twenty-four hours after training they were tested for retention. Following behavioral testing, animals were sacrificed, brain regions dissected, frozen and stored (-20 degrees C) for calmodulin determinations. Animals which had previously received chronic infusions of scopolamine performed significantly better than controls, while those which previously received chronic infusions of physostigmine performed significantly worse during the retention test. No significant differences in calmodulin levels (soluble or particulate) were detected across brain regions or drug groups. These results indicate that continuous chronic infusion of drugs which can facilitate or inhibit CNS cholinergic activity can induce performance changes on a learning task opposite to those resulting following the acute administration of these same drugs.

Animals↗
PubMed1983

The separation of 3H-benzodiazepine binding sites in brain and of benzodiazepine pharmacological properties.

In addition to anxiolytic and anticonvulsant properties, benzodiazepines (BDZ) produce sedation, ataxia, and muscular relaxation. In general, it was difficult to separate these properties within this chemical class during the search for clinically useful anxiolytics; and when BDZ's were used to characterize 3H-BDZ binding sites they indicated only a single homogenous class of receptors. A new chemical series was discovered, triazolopyridazines (TPZ, prototype CL 218,872), which showed anticonflict activity in rats and monkeys without sedation or ataxia and inhibited 3H-BDZ binding in brain membranes with kinetic characteristics suggesting the presence of multiple BDZ receptors. High affinity and low affinity sites for the TPZ were demonstrated, the former designated at Type 1 and the latter as Type 2. Anatomical and in vivo studies have supported different distributions of each receptor in brain. Lately, the physical separation of discrete proteins which bind 3H-BDZ has been reported. The multiple receptors and the variety of endogenous substances which have been proposed as modulators and ligands of the receptors might explain variability as well as selectivity in pharmacological properties in these drugs.

Animals↗
PubMed1983

Psychomotor performance in the senescent rodent: reduction of deficits via striatal dopamine receptor up-regulation.

In order to determine the relationship between striatal dopamine (DA) receptor density and psychomotor performance in senescent animals, two experiments were carried out. In the first, the age-related motor deficits were characterized using a battery of four psychomotor tests (rod walking, wire hanging, inclined screen, plank walking). These tests were administered to three groups of male Fischer rats (mature, 6-8 months; middle aged, 12-18 months; and senescent, 25 months) and performance measured. Age-related differences were observed on all the tasks, with the oldest animals showing the poorest performance. These animals were then used in a second experiment in which one-half of the group of animals from each age was administered 1.86 mg/kg/day of haloperidol for 14 days (via surgically implanted Alza Minipumps. Control groups of animals from each age were given pumps which contained only the vehicle (HCl diluted with distilled water, pH = 2.9). Following the 14 day drug administration, the pumps were surgically removed and 3 days later all the groups were retested on the psychomotor tests. Stereotypy (to 0.5 mg/kg of apomorphine, sniffing, licking, grooming and cage crossings) was also re-examined. Results show that haloperidol-treated animals from all three age groups display greater response times (i.e., better performance) than vehicle-treated animals on the battery of four motor tests and, the haloperidol-treated old animals exhibit more sniffing and grooming than the vehicle-treated old animals. Parallel increases in [3H]spiperone binding seen in all haloperidol-treated groups suggest a relationship between increases in the density of striatal DA receptors and improvement in motor performance.

Aging↗
PubMed1983

The effect of rapid eye movement sleep deprivation on cortical beta-adrenergic receptors.

The relationship between rapid eye movement sleep deprivation (REMD) and rat beta-adrenergic receptors was evaluated. REMD was achieved using the platform method and verified by EEG and EMG recordings. Although the amount of REM sleep was diminished 90%, there was no alteration in either the number of binding sites or their affinity for [3H]-dihydroalprenolol. Periods of stress as well as recovery periods after REMD were also without effect on the cortical beta-adrenergic receptors. Thus no support is garnered for the interaction of REMD and the cortical beta-adrenergic receptor binding parameters, although REMD is sometimes used as a mode of therapy for depression and other antidepressives do in fact affect the beta-adrenergic system. The mechanism of REMD as a potential antidepressive therapy is yet to be elucidated.

Animals↗
PubMed1982

The cholinergic hypothesis of geriatric memory dysfunction.

Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

Acetylcholine↗
PubMed1982

Human brain receptor alterations in suicide victims.

A comparison was made of human postmortem muscarinic-cholinergic, beta-adrenergic and serotonergic (presynaptic) recognition sites in cortical tissues derived from suicide and homicide (control) victims. An elevation of 47% and 35% in the suicide group compared to controls was observed in receptor ligand binding for 3H-quinuclidinyl benzilate (QNB, muscarinic antagonist) and 3H-imipramine (IMI, a presynaptic serotonin marker), respectively. In contrast, no appreciable differences in 3H-dihydroalprenolol (DHA, beta-adrenergic antagonist) binding were observed between the two groups. Additionally, tissues from both groups of subjects were analyzed for tricyclic antidepressive agent (TAD) content. High performance liquid chromatographic (HPLC) tissue analysis revealed no detectable levels of tricyclic agents with an assay sensitivity of 50 picograms/mg tissue. The results presented herein demonstrate neurotransmitter-receptor alterations in suicide subjects compared to homicide (control) victims. The attendant roles of serotonergic and muscarinic-cholinergic processes in the psychobiology of suicide and depression are addressed.

Antidepressive Agents, Tricyclic↗
PubMed1982

Neuropeptide effects on memory in aged monkeys.

The effects of several neuropeptides were evaluated using a non-human primate model of age-related memory impairments. Several doses of ACTH4-10, lysine vasopressin, arginine vasopressin, oxytocin and somatostatin were each tested in several aged monkeys. Because data from a large number of non-drug control sessions was collected before, during and after this study, it was possible to define the normal range of control performance for each monkey and statistically determine whether a change in performance under any single dose of drug reflected a significant change from the particular monkey's normal baseline performance. Although none of the neuropeptides produced consistent group effects, evaluations of individual subjects against their own baseline performance revealed reliable changes at certain doses. Arginine vasopressin appeared to produce the best overall effects with three of the five monkeys exhibiting reliable changes in performance from baseline. These same three monkeys also responded positively to the lysine form. Oxytocin impaired memory in three of the six aged monkeys tested over a wide range of doses. Three of six aged monkeys performed better under ACTH4-10 compared to baseline; however, in two of these cases only a single dose was effective. The performance of only one subject was improved under somatostatin, and this was at a single dose only. The data reported here provide evidence for neuropeptides producing behavioral improvement in non-human primates using an appetitive task, eliminating a popular criticism that the data in this literature has depended too heavily on the testing of rodents in shock-motivated tasks. Additionally, the improvements observed in this study involve a behavior that it naturally impaired by age and one which has many operational similarities and some empirical relevance to measures of recent memory in humans. However, these positive findings must be tempered by the lack of robust effects and high individual variation observed.

Adrenocorticotropic Hormone↗
PubMed1982

A computer-based analysis of injuries sustained by victims of a major air disaster.

A computer-based analysis of the injury patterns sustained by victims in the DC-10 aircraft that crashed into Mt. Erebus, Antarctica, On November 28, 1979, is presented. The distribution of these injury patterns supports the hypothesis that at impact the plane was in a nose-high attitude with respect to the slope and the impact point was the underside of the rear section of the fuselage.

Accidents, Aviation↗
PubMed1981

Lateral olfactory tract lesions reveal neuronal localization of benzodiazepine recognition sites.

The effects of neuronal degeneration on benzodiazepine binding parameters were assessed following bilateral electrolytic lesions of rat brain lateral olfactory tracts. [3H]Flunitrazepam binding was measured in olfactory bulb homogenates 1, 7 and 14 days post-lesion. Specific [3H]flunitrazepam binding was significantly decreased two weeks after lesions. Diminution in binding was associated with a decreased population of sites (Bmax) rather than affinity alterations (KD). The time course for the loss of receptors is compatible with retrograde degeneration and suggests that specific benzodiazepine binding sites are in part located on mitral cell-bodies.

Animals↗
PubMed1981

The effects of acute administration of diazepam on the binding of [3H]-diazepam and [3H]-gaba to rat cortical membranes.

Specific [3H]-diazepam binding and [3H]-GABA binding were measured in cortical membranes of untreated rats and rats which had been administered unlabeled diazepam (5.0 mg/kg, IP) thirty minutes prior to sacrifice. Washed and unwashed membranes from control animals showed identical levels of [3H]-diazepam binding. Unwashed membranes of diazepam-treated animals showed consistently and significantly lower binding of [3H]-diazepam than membranes derived from control animals and treated similarly. [3H]-GABA was almost non-existent in unwashed membranes of either group of animals. The binding capability of membranes of treated animals for [3H]-diazepam returned to control levels upon washing with buffer prior to the binding assay. The specific binding of [3H]-GABA in membranes derived from either group of animals also improved after the buffer washes. However, no difference could be detected in [3H]-GABA binding between control and diazepam-treated animals. The failure of diazepam to modulate [3H]-GABA binding in unwashed membranes and the participation of an endogenous inhibitory material repressing [3H]-GABA binding are discussed.

Animals↗