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Biomedical subjects

M F Davies

Publications and source records attributed to M F Davies.

At least 37 records · Page 2Linked to original sources
PubMed1997

Positive test strategies and confirmatory retrieval processes in the evaluation of personality feedback.

Cognitive-response analysis was carried out to investigate people's acceptance of personality feedback. In 3 studies with 223 male and female college students 18-38 years old, participants generated more confirming than disconfirming evidence for personality feedback. Availability of confirmatory evidence was found to be closely related to the rated accuracy of the feedback. Both rated accuracy and amount of confirmatory evidence were greater for general than specific and for true than false feedback. Analyses of covariance showed that availability of confirmatory evidence accounted for the effects of general versus specific and true versus false feedback on rated accuracy. Findings are discussed in terms of the use of positive test strategies and the influence of confirmatory evidence retrieval on working self-concepts.

Adolescent↗
PubMed1997

Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine.

Rats were made tolerant to the hypnotic effects of the alpha-2 adrenergic agonist dexmedetomidine by a 7- or 14-day continuous systemic administration of the same, and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed. Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of nifedipine during induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels. Induction of tolerance reduced the affinity of [3H]PN200-110 for the L-type calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [3H]PN200-110. An increase in Bmax for [3H]PN200-110 was noted in the dexmedetomidine tolerant state which did not change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor rolipram (275 microg/kg i.p.), mimicked the state of tolerance, as it resulted in a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also reversed the rolipram-induced attenuation of the hypnotic response to dexmedetomidine. These data implicate a role for the L-type calcium channel in the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the involvement of the cAMP pathway.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1996

Evidence for mu1-opioid receptor involvement in fentanyl-mediated respiratory depression.

Several fentanyl analogs (Bagley et al., 1989, J. Med. Chem. 32, 663) were compared to fentanyl and morphine for their effects on respiratory depression as determined by arterial blood gas (pH, pCO2 and pO2) measurements. Fentanyl (0.1 mg/kg), morphine (10 mg/kg), #16 (1-phenethyl-4-[N-(pyridin-2-yl)-N-(methoxymethylcarbonyl)amino] piperidine, 1 mg/kg), #17 (1-phenethyl-4-[N-(pyridin-2-yl) -N-(2-furoyl)amino]piperidine, 0.5 mg/kg) and #29 (1-phenethyl-4-[N- (pyrimidin-2-yl)-N-(methoxy-methylcarbonyl) amino]piperidine, 10 mg/kg) produced significant respiratory depression in rats. Pretreatment with the mu1-opioid receptor selective antagonist, naloxonazine (10 mg/kg), blocked the respiratory effect of fentanyl and its analogs, but not that of morphine. The results suggest that the mu1-opioid receptor plays an important role in the respiratory effects of fentanyl and its analogs. Hence, the mechanism of fentanyl-induced respiratory depression appears to be distinct from that produced by morphine. The most likely explanation for this difference is the possible contribution of muscle rigidity and catalepsy to the observed changes in blood gas parameters caused by the fentanyl analogs, while the respiratory depression of morphine, measured by these same parameters, appears to be independent of its effect on muscle rigidity.

Animals↗
PubMed1996

Putative benzodiazepine partial agonists demonstrate receptor heterogeneity.

This study explored whether the behavioral heterogeneity of benzodiazepine receptor (BDZR) ligands is a consequence of multiple receptor subtypes or partial agonism. Putative partial agonists Ro16-6028, Ro23-1590, Ro23-0364, and abecarnil were compared with U78875, a mixed agonist-antagonist, and CGS8216, an inverse agonist, in five BDZR-mediated functions: hyperphagia, anxiolysis, sedation, hypothermia, and anticonvulsant activity. Only abecarnil was an agonist in all end points. Each of the other drugs exhibited qualitatively different responses at these end points. Specifically, Ro23-0364 produced no effect on body temperature, but was an agonist at other tests. Ro23-1590 had no effect on anxiolysis and hypothermia, but was an agonist at other tests. In contrast to other putative partial agonists, Ro16-6028 was found to be an antagonist in sedation and U78875 was an antagonist in hypothermia, but both were agonists at other end points. These qualitative differences in activity in the five behavioral end points studied cannot be explained by partial agonism at a single receptor and indicate that these ligands differentially activate multiple BDZR subtypes.

Animals↗
PubMed1996

The hyperphagic effect of 3 alpha-hydroxylated pregnane steroids in male rats.

Like benzodiazepines receptor (BDZR) ligands, 3 alpha-hydroxylated, 5 alpha, or 5 beta pregnane steroids are sedative, anticonvulsant, and anxiolytic. BDZR ligands also modulate the feeding response. Therefore, in this study we have investigated the effects of four 3 alpha-hydroxylated pregnane steroids-Pregnanolone (3 alpha-hydroxy-5 beta-pregnan-20-one), allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one), alphaxalone (3 alpha-hydroxy-5 alpha-pregnan-11,20-dione), and 5 beta-pregnanediol (5 beta-pregnan-3 alpha,20 alpha-diol) on food intake. In non-food deprived male rats, all four steroids increased the consumption of a palatable diet. For pregnanolone (1-10 mg/kg), hyperphagia was found at lower doses than its anxiolytic effect (5-10 mg/kg) as determined using the elevated plus maze test. The presumed steroid antagonists, isopregnanolone (3 beta-hydroxy-5 alpha-pregnan-20-one) (10 mg/kg) and pregnenolone sulfate (2 mg/kg), and the BDZ antagonist, Ro15-1788 (20 mg/kg), did not reverse the hyperphagic effect of pregnanolone. Picrotoxin, a GABAA receptor antagonist, dose dependently and at a subconvulsive dose (1.5 mg/kg), reversed the hyperphagic effect of pregnanolone and alphaxalone, but had no effect on allopregnanolone- and 5 beta-pregnanediol-induced hyperphagia. These results indicate that the hyperphagic effects of pregnanolone and alphaxalone are mediated by the GABAA receptor but not by direct interaction with BDZ receptors. However, allopregnanolone- and 5 beta-pregnanediol-induced hyperphagia may be mediated by other receptor systems. Because some 3 alpha-hydroxylated pregnane steroids are endogenous progesterone metabolites, they may play an important role in appetite control.

Animals↗
PubMed1995

Binding of 1,4-benzodiazepines to a novel [3H]Ro15-4513 binding site in the rat spinal cord.

An alpidem-insensitive benzodiazepine binding site in the rat spinal cord has recently been identified in our laboratory. We report here the binding of 23 1,4-benzodiazepines to this site using [3H]Ro15-4513 (ethyl-8-azido-6-dihydro-5-methyl-4H-imidazo[1,2- a][1,4]benzodiazepine-3-carboxylate) in the presence of 65 microM alpidem (6-chloro-2-(4-chlorophenyl)-N,N- dipropylimidazo[1,2-a]pyridine-3-acetamide). This binding site displays a wide affinity for 1,4-benzodiazepines, most of which show much higher affinity for benzodiazepine receptors in various brain regions and transfected cell systems. The highest affinity ligands are: brotizolam (1-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepine) (4.3 nM), Ro15-4513 (5.0 nM), Ro42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihydro- 5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-6-one) (5.7 nM), Ro16-6028 (t-butyl (s)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H- imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate) (5.9 nM) and triazolam (8-chloro-6-(2-chlorophenyl)-1-methyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine) (7.9 nM). The structural feature common to these compounds is an imidazo- or triazolo-ring on the 1- and 2-position of the benzodiazepine. However, the presence of this feature does not guarantee high affinity binding as Ro15-1788 (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester) (100 nM) and Ro23-0364 (6-[2-chlorophenyl]-4H- imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide) (360 nM) display much lower affinity for this site. Studies are currently underway to investigate the functional significance of this unusual benzodiazepine binding site.

Affinity Labels↗
PubMed1995

Evaluation of preoperative cardiac risk index values in patients undergoing vaginal surgery.

OBJECTIVE: Our purpose was to evaluate the Goldman and the New York Heart Association cardiac risk index values in a female surgical population and to evaluate age, hypertension, ischemic heart disease, glucose intolerance, cardiac arrhythmia, and estrogen replacement therapy as risk factors for perioperative cardiac morbidity in older women undergoing major vaginal surgery. STUDY DESIGN: A retrospective analysis was performed of perioperative cardiac morbidity in consecutive patients undergoing elective vaginal surgery between August 1987 and October 1993. RESULTS: Four hundred six patients were entered in the study. Eight patients had perioperative cardiac morbidity. The Goldman cardiac risk index and the New York Heart Association functional classification of heart disease were not significant indicators of perioperative cardiac morbidity in this group of patients. In the postmenopausal subgroup of 168 patients hypertension (p = 0.033) and ischemic heart disease (p = 0.004) were statistically significant risk factors for perioperative cardiac morbidity. Glucose intolerance, cardiac arrhythmia, and estrogen replacement therapy were not significant predictors. CONCLUSION: The Goldman cardiac risk index and the New York Heart Association functional classification of heart disease are of questionable utility in a female surgical population undergoing elective vaginal surgical procedures. Hypertension and ischemic heart disease are risk factors for perioperative cardiac morbidity in a postmenopausal subgroup of these patients.

Age Factors↗
PubMed1995

A behaviorally selective class of thiophene-containing benzodiazepine receptor ligands.

In a continued effort to probe the role of the aromatic rings in classical 1,4-benzodiazepine (BDZ) ligand pharmacology, a series of new thiophene-containing benzodiazepine receptor (BDZR) ligands were synthesized. As a first step in determining the binding profile and selectivity to BDZR functional subtypes, the affinities in two central nervous system (CNS) regions, cerebellum, in which a single 'Type I' BDZR could be labeled; and spinal cord, in which we have previously demonstrated some receptor heterogeneity, were determined. These compounds were also assessed for their compliance with a recently developed three dimensional pharmacophore for recognition and activation of the 'Type I' BDZR, using the techniques of computational chemistry. The computations showed all ligands synthesized fulfilled the minimum requirements for recognition, further validating the current pharmacophore. Using the criteria for activation, the new ligands were all predicted to be agonists at the cerebellar 'Type I' BDZR. Since the compounds showed reasonable affinity, the behavioral profile of one of them at five in vivo endpoints was determined. This compound demonstrated more behavioral selectivity than the typical 1,4-BDZ ligand. While they fulfilled the requirements for agonist activity at the 'Type I' BDZR, these ligands showed significantly greater delocalization in the electron density distribution in the lowest unoccupied molecular orbital (LUMO), so that either aromatic ring could serve as an electron accepting site, not just the one comparable to the more classical BDZR agonist, flunitrazepam. It is possible that the ability of the second ring in the tested compound (5a) to also function as an electron acceptor can affect the recognition and activation of other receptor types leading to the more discriminate behavioral profile of this thiophene analog compared to flunitrazepam.

Animals↗
PubMed1995

Resolving receptor heterogeneity using Fourier-derived affinity spectrum analysis and LIGAND: benzodiazepine receptors in the rat spinal cord.

In the present study, we combined a powerful and novel receptor binding data analysis technique. Fourier-derived affinity spectrum analysis (FASA), with the nonlinear regression analysis program LIGAND to resolve benzodiazepine receptor heterogeneity in rat spinal cord. With FASA, we identified three distinct [3H]Ro15-1788 binding populations: two high-affinity sites (0.4 and 5 nM) for the radioligand and a lower-affinity site (150 nM) that is insensitive to the imidazopyridine alpidem. With the affinities for the radioligand determined with FASA, the Ki values of 13 competing ligands were calculated with LIGAND. All of the ligands studied displayed the highest affinity for site 1 (the highest-affinity [3H]Ro15-1788 binding site), with the exception of AHR 11797. Site 2 had high affinity for Ro15-1788, lower affinity for flunitrazepam and beta-CCM and very low, but measurable, affinity for zolpidem. The alpidem-insensitive binding site, studied in isolation by performing competitive binding assays in the presence of 65 microM alpidem, showed relatively low affinity for all of the ligands studied, and its physiological relevance is not yet known.

Animals↗
PubMed1994

Evidence for central benzodiazepine receptor heterogeneity from behavior tests.

To explore behavioral selectivity as a consequence of multiple receptor subtypes, four benzodiazepine receptor ligands, flunitrazepam, CGS 9896, zolpidem, and AHR 11797, were tested at five in vivo endpoints: anticonvulsant action, anxiolysis/anxiogenesis as determined in the plus-maze test, locomotor activity, changes in food consumption, and hypothermia. All compounds produced hypothermia. In the plus-maze test, flunitrazepam, CGS 9896, and a low dose of zolpidem (0.05 mg/kg) increased the time spent in the open arms, although AHR 11797 and higher doses of zolpidem decreased time spent in the open arms. Flunitrazepam and zolpidem greatly reduced, CGS 9896 slightly reduced, and AHR 11797 did not affect locomotor activity. Flunitrazepam and CGS 9896 increased food consumption, but AHR 11797 and zolpidem had no effect. Only flunitrazepam fully protected the animals from pentylenetetrazol-induced seizures. The qualitative differences in the effects of these compounds observed are difficult to explain by activation of a single benzodiazepine receptor subtype. As Ro15-1788 antagonized all the observed effects, these compounds act through multiple central benzodiazepine receptors.

Animals↗
PubMed1994

Cognitive style and the reading process: field-dependence differences on a lexical-decision task.

This study examined cognitive-style differences in reading strategies on a lexical-decision task. Subjects made word/nonword judgments for letter sequences consisting of either real words, English-sounding nonwords, or non-English-sounding nonwords. In line with previous findings, responses were significantly slower to English-sounding nonwords than to non-English-sounding nonwords. This effect was qualified by a significant interaction with field dependence such that field-dependent subjects were significantly slower than field-independent subjects for English-sounding nonwords but not for non-English-sounding nonwords or for real words. These findings complement a 1988 finding by Davies that field-dependent scores prefer a phonological strategy for lexical access and they provide better evidence for the role of such process differences in normal reading.

Adult↗
PubMed1993

Zinc selectively inhibits flux through benzodiazepine-insensitive gamma-aminobutyric acid chloride channels in cortical and cerebellar microsacs.

The effects of Zn2+ on the activity of gamma-aminobutyric acid (GABA)A receptor-Cl- ionophore complexes found in adult rat cortex and cerebellum were tested by measuring 36Cl- influx into microsacs. In both preparations, the concentration-response curves were biphasic, with 25% of the cerebellar and 20% of the cortical Cl- flux being blocked by less than 10 microM Zn2+ and 45% of the cerebellar and 50% of the cortical flux being blocked by concentrations of Zn2+ exceeding 10 microM. Zn2+ (100 microM) did not affect basal Cl- flux but inhibited that stimulated by 100 microM GABA in a noncompetitive manner. The ability of 1 microM flunitrazepam to enhance Cl- flux was unaffected by 100 microM Zn2+. These results demonstrate that, in adult rat cerebellum and cortex, there are three populations of GABAA receptors, two that are sensitive to Zn2+ and insensitive to benzodiazepines (BDZ) and the remainder that are the reverse, i.e., insensitive to Zn2+ but fully sensitive to BDZ enhancement. This result is consistent with the idea that Zn2+ blocks only those GABAA receptor-Cl- ionophore complexes that lack a gamma subunit, which is required for modulation by BDZ. The results obtained in this study also show that the proportion of Zn(2+)-sensitive GABA receptors is substantial, suggesting that they play an important role in the functioning of the adult central nervous system.

Animals↗
PubMed1992

Thermodynamic analysis of binding to the cerebellar type I benzodiazepine receptor.

The temperature dependence of binding to the type I benzodiazepine receptor in rat cerebellum was determined using [3H]Ro15-1788 and regression analysis techniques. The ligands chosen were from diverse chemical families and display different pharmacological properties. Included were the agonists flunitrazepam, CL 218,872, zolpidem and alpidem; the antagonists Ro15-1788 and propyl-beta-carboline-3-carboxylate (beta-CCP); the inverse agonists ethyl-beta-carboline-3-carboxylate (beta-CCE) and methyl-6,7-dimethoxy-beta-carboline-3-carboxylate (DMCM); and the selective muscle relaxant AHR-11797. Assays were performed at 0 degrees C, 20 degrees C and 37 degrees C and the K(i) at each temperature was used to construct a van't Hoff plot for each compound. The binding of all ligands, with the exception of DMCM, was enthalpy-driven. However, enthalpy alone does not determine the rank order of affinity. There was no relationship between the thermodynamic behavior of binding and the observation of agonism, antagonism or inverse agonism, indicating that activation and recognition are distinct steps in this receptor system.

Animals↗
PubMed1992

Evidence for more than two central benzodiazepine receptors in rat spinal cord.

Competitive binding assays were performed in rat spinal cord membranes at 0 degrees C against [3H]Ro15-1788. The displacement curves of Ro15-1788 and alpidem produced pseudo-Hill slopes of 1.0 and 0.5, respectively. In addition, 5-10% of the specifically bound [3H]Ro15-1788 could not be displaced by greater than 100 microM of alpidem. These two pieces of evidence strongly suggest the presence of at least three central benzodiazepine binding sites in the spinal cord.

Animals↗
PubMed1992

Comparison of behavioral and central BDZ binding profile in three rat lines.

The performance of three widely used rat lines (Sprague-Dawley, Wistar, and Long Evans hooded) were evaluated in behavioral test systems that are sensitive to benzodiazepines. The in vivo effects of flunitrazepam and the brain [3H]Ro 15-1788 binding were determined and compared in these rat lines. The behavioral end points evaluated in this study were anxiolysis, measured using the automated elevated plus-maze; sedation by modification of locomotor activity; hyperphagia following food deprivation; protection for pentylenetetrazol-induced convulsions; and hypothermia. There were comparable results in the hypnotic, hypothermic, anticonvulsant, and feeding tests in these lines following flunitrazepam administration. However, the behavior of the Long Evans hooded rat was most amenable to the detection of drug-induced changes in the anxiety test. There was no difference in the maximum number of binding sites (Bmax) or the affinity (Ki) of the Ro 15-1788 or flunitrazepam binding in either the cerebellum or whole brain (minus cerebellum) in the three rat lines as determined by the competitive binding against [3H]Ro 15-1788. Thus, while these rat lines exhibited similar behavioral profiles in most tests the modest differences in the baseline responses and the ability to detect anxiolysis at lower doses of flunitrazepam observed with Long Evans hooded rats makes them particularly suited for these types of studies.

Animals↗
PubMed1991

Molecular models for recognition and activation at the benzodiazepine receptor: a review.

In this minireview an overview description of the different pharmacophores that have been proposed for the benzodiazepine receptor is presented. The methodology as well as the experimental information used in the development of each model will be described. Finally, the new experimental discoveries that are likely to affect the models presented are briefly indicated.

Animals↗