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Biomedical subjects

F P Bymaster

Publications and source records attributed to F P Bymaster.

At least 91 records · Page 5Linked to original sources
PubMed1986

Elevation of acetylcholine levels in striatum of rat brain by LY163502, trans-(-)-5,5a,6,7,8,9a,10-octahydro-6-propylpyrimido less than 4,5-g greater than quinolin-2-amine dihydrochloride, a potent and stereospecific dopamine (D2) agonist.

LY163502, a partial ergoline and a trans-levorotatory enantiomer, does not stimulate adenylate cyclase in striatal membranes but inhibits 50% binding of 3H-apomorphine, 3H-pergolide and 3H-spiperone at 10, 13 and 151 nM (IC50), respectively. The racemic mixture (LY137157) is less effective, with 3, 2.7 and 1.4 times higher IC50 values, respectively, whereas the dextrorotatory isomer (LY175877) is inactive. LY163502 inhibits binding of 3H-clonidine with an IC50 value of 2600 nM, but not the binding of 3H-WB4101, 3H-dihydroalprenolol, 3H-serotonin, 3H-quinuclidinyl benzilate and 3H-pyramilamine or the uptake of serotonin, norepinephrine or dopamine, suggesting selective affinity toward dopamine receptors in vitro. Both LY163502 and LY137157 elevate striatal acetylcholine (Ach) levels. The elevation of Ach levels by LY163502 is reversed by dopamine antagonists haloperidol, cis-flupenthixol and metoclopramide. Therefore, the levorotatory enantiomer exhibits pharmacology of a D2 type of dopamine agonist.

Acetylcholine↗
PubMed1986

Hemodynamic and electrocardiographic effects of fluoxetine and its major metabolite, norfluoxetine, in anesthetized dogs.

The cardiovascular effects of the selective serotonin uptake inhibitor, fluoxetine, and its N-desmethyl metabolite, norfluoxetine, were studied in anesthetized dogs during constant iv infusion of supratherapeutic doses (0.1 mg/kg/min for 50 min). Fluoxetine and norfluoxetine did not significantly affect mean blood pressure, pulmonary artery wedge pressure, or heart rate compared to a corresponding vehicle group. Cardiac output fell 15 to 20% during fluoxetine infusion due to nonsignificant decreases in both heart rate (10%) and stroke volume (5 to 10%). In contrast, the tricyclic antidepressant agent, amitriptyline, infused at the same dose, decreased both mean pressure and systemic vascular resistance (20%) and increased heart rate (20%). Pulmonary wedge pressure rose by 35%, and stroke volume fell by 20% suggesting impaired ventricular contractility. Both intramyocardial and infranodal conduction was slowed during amitriptyline infusion as indicated by increases in the QRS duration, and the PQ and HV interval. Fluoxetine and norfluoxetine had no influence on cardiac impulse conduction velocity as assessed by either surface or intracardiac conduction indices. Plasma concentrations of fluoxetine, norfluoxetine, and amitriptyline reached during infusion ranged from 1.0 to 2.5 micrograms/ml. Platelet [3H]serotonin uptake was inhibited by 95% during infusion of fluoxetine and about 75% during infusion of norfluoxetine or amitriptyline. These observations indicate that large iv doses of fluoxetine or norfluoxetine lack prominent cardiodepressant effects in dogs, suggesting a greater margin of safety for fluoxetine compared to tricyclic antidepressant drugs.

Amitriptyline↗
PubMed1985

Measurement of acetylcholine and choline in brain by HPLC with electrochemical detection.

A simple and rapid method for measuring acetylcholine and choline using high performance liquid chromatography (HPLC) with electrochemical detection is presented. Acetylcholine and choline were first separated using reverse-phase chromatography; acetylcholine was then hydrolyzed post-column to choline by acetylcholinesterase. Choline was oxidized enzymatically by choline oxidase to betaine and hydrogen peroxide, and the peroxide was detected electrochemically. Changes in methodology from previous procedures include a different mobile phase, controlled heating of chromatography column and post-column reaction coil, and a different extraction method for quaternary amines. The changes resulted in less inhibition of derivatizing enzymes by mobile phase, narrow and consistent elution of peaks, and a rapid and efficient extraction of quaternary amines. Measurement of acetylcholine and choline in brain tissue was found to be replicable, and the levels agreed with literature values.

Acetylcholine↗
PubMed1985

Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors.

Fluoxetine administration to rats at a dose of 10 mg/kg i.p. daily up to 12 or 24 days failed to change the concentration-dependent binding of [3H]WB4101, [3H]clonidine and [3H]dihydroalprenolol to alpha 1-, alpha 2- and beta-adrenergic receptors, respectively; [3H]quinuclidinyl benzilate to muscarinic receptors; [3H]pyrilamine to histamine H1 receptors and [3H]naloxone to opiate receptors. Persistent and significant decreases in receptor number (Bmax value) without changes in the dissociation constant (KD value) of [3H]5-HT binding in cortical membranes were observed upon chronic treatment with fluoxetine administered either by intraperitoneal injection or incorporation in the diet. A detectable reduction of 5-HT1 receptor number occurred after once-daily injections of fluoxetine at 10 mg/kg i.p. within 49 hours. After pretreatment for 3 days with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, followed by repeated administration of fluoxetine, 5-HT1 receptor numbers were higher than those of normal rats, suggesting a dependence on synaptic concentration of 5-HT for fluoxetine to affect a receptor down-regulation. These studies provide further evidence for the selectivity of fluoxetine as an inhibitor of 5-HT reuptake, resulting in a selective down-regulation of 5-HT1 receptors in the cerebral cortex of rat brain.

Animals↗
PubMed1984

Saturable binding of 35S-t-butylbicyclophosphorothionate to the sites linked to the GABA receptor and the interaction with GABAergic agents.

35S-t-Butylbicyclophosphorothionate (35S-TBPS) binds in a concentration-saturable manner to specific sites on membranes from rat cerebral cortex. Using a filtration assay at 25 degrees C, in 250 mM NaCl, specific binding of 35S-TBPS constitutes about 84 to 94 percent of total binding, depending on radioligand concentrations. 35S-TBPS binding is optimal in the presence of NaCl or NaBr and substantially less in the presence of NaI or NaF. It is sensitive to the treatment with 0.05 percent Triton X-100 but not to repeated freezing and thawing, procedures which increase 3H-GABA binding. Pharmacological studies show that 35S-TBPS binding is strongly inhibited by GABA-A receptor agonists (e.g., GABA and muscimol) and by the noncompetitive antagonist, picrotoxin, but not the competitive antagonist, bicuculline. Compounds which enhance binding of radioactive GABA and benzodiazepines, such as the pyrazolopyridines, cartazolate and tracazolate, and a diaryltriazine, LY81067, are also potent inhibitors of 35S-TBPS binding, with LY81067 being the most effective. The effects of GABA, picrotoxin and LY81067 on the saturable binding of 35S-TBPS in cortical membranes are compared. The present findings are consistent with the interpretation that 35S-TBPS binds at or near the picrotoxin-sensitive anion recognition sites of the GABA/benzodiazepine/picrotoxin receptor complex.

Animals↗
PubMed1983

Enhanced binding of radioligands to receptors of gamma-aminobutyric acid and benzodiazepine by a new anticonvulsive agent, LY81067.

A diaryltriazine, LY81067, effectively protects against pentylenetetrazole- and picrotoxin-induced convulsions in mice, with ED50 values of 5.7 and 5.8 mg/kg i.p., respectively. LY81067 enhances the binding of both 3H-GABA and 3H-flunitrazepam to specific sites in rat brain membranes. The degree of enhancement by LY81067 varies from one brain region to another and is different for the binding of 3H-GABA and 3H-flunitrazepam. In cortical membranes, LY81067 increases the affinity of 3H-GABA for both high and low affinity sites and increases the number of sites. LY81067 increases the affinity of 3H-flunitrazepam for its binding sites without greatly increasing the number of sites. Like the pyrazolopyridines, the enhancement of 3H-flunitrazepam binding by LY81067 is dependent on chloride or related anions and is reversed by picrotoxin, suggesting that LY81067 exerts its anticonvulsant effects by binding to or near picrotoxin binding sites. The differential effects of LY81067 on the enhancements of 3H-GABA and 3H-flunitrazepam binding in several brain regions suggest extensive multiplicity of GABA/benzodiazepine/picrotoxin/anioin receptor complexes.

Animals↗
PubMed1983

Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors.

Fluoxetine and nine other antidepressant drugs which interact with brain receptors for neurotransmitters were studied in vitro using radioligand-binding techniques and transmitter-coupled adenylate cyclase assays. Tricyclic antidepressant drugs (desipramine, imipramine, clomipramine, amitriptyline and doxepin) had marked affinity for alpha-adrenergic, muscarinic cholinergic and histaminergic H1 receptors, and lesser affinity for serotonin and dopamine receptors. Mianserin was relatively similar to some of the tricyclic compounds, whereas trazodone had less affinity for most receptors except serotonin and alpha-adrenergic receptors. Fluoxetine had little affinity for any of these receptors, and the same was true for zimelidine and fluvoxamine, two other selective inhibitors of serotonin uptake. None of the compounds showed much affinity for beta-adrenergic receptors, opiate receptors, gamma-aminobutyric acid receptors, or benzodiazepine receptors. The present findings with fluoxetine are consistent with the virtual absence of anticholinergic or other side effects often observed with tricyclic antidepressant drugs in animal models or during the treatment of depressed patients.

Animals↗
PubMed1983

Effect of a stereospecific D2-dopamine agonist on acetylcholine concentration in corpus striatum of rat brain.

The enantiomers of LY141865, trans(+/-)-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo[3,4-g]qu inoline, were compared as dopamine D2 agonists by determining their abilities to elevate acetylcholine concentrations in rat corpus striatum. The levorotatory isomer, LY156258, increased striatal acetylcholine concentration at doses of 0.1-1 mg/kg i.p., whereas the dextrorotatory isomer had no effect even at doses as high as 30 mg/kg. The levorotatory isomer also decreased striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, but did not significantly alter dopamine or 5-hydroxyindoleacetic acid concentration. The dextrorotatory isomer had no effect on any of these substances alone and did not alter the effects of the levorotatory isomer. The elevation of striatal acetylcholine levels by LY156258 was mimicked by pergolide, a dopamine agonist, and was totally prevented by pretreatment with haloperidol, a dopamine antagonist. The elevation of striatal acetylcholine concentration by LY157258 was maximal at 0.5 hour and declined thereafter, following a time course similar to that of pergolide. Neither LY141865 nor LY156258 shared with peroglide and dopamine the ability to activate striatal adenylate cyclase in vitro, an effect mediated by D1 receptors. LY141865 and LY156258 (but not the dextrorotatory isomer) inhibited the binding of tritiated apomorphine and spiperone to striatal membrane receptors, but were not as potent as pergolide, they also had less effect, or no effect, on the binding of other tritiated ligands (dopamine, WB4101, clonidine, dihydroalprenolol, pyrilamine or quinuclidinyl benzilate) to their membrane receptors. These results indicate that LY156258 stereospecifically activates dopamine D2 receptors and the studies are the first evidence of sterospecificity of dopamine receptors mediating an increase in striatal acetylcholine concentration.

Acetylcholine↗
PubMed1982

A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain.

LY135252, (+/-)-N-methyl-gamma-(2-methylphenoxy) phenylpropylamine hydrochloride, is a competitive inhibitor of norepinephrine uptake in synaptosomes of rat hypothalamus. The resolved optical (-)-isomer, LY139603, is 2 and 9 times more effective than the racemate and the (+)-isomer, LY139602, with inhibitor constants (Ki) of 1.9, 3.4 and 16.8 nM, respectively. All three compounds are relatively weak in the inhibition of dopamine and serotonin uptake, with Ki values at least two orders of magnitude greater. The racemate and the two optical isomers in vivo are potent inhibitors of norepinephrine uptake with relative effectiveness being parallel with their K1 values. The most potent and long-acting compound was the (-)-isomer, LY139603, which inhibited norepinephrine uptake ex vivo with an ED50 value of 2.2 mg/kg i.p, and a half-life of 6.4 hr. In comparison with the tricyclic antidepressants desipramine and imipramine, LY139603 is a relatively weak ligand for alpha-1, alpha-2, and beta adrenergic receptors, acetylcholine-muscarinic receptors, histaminergic H1 receptors and the receptors of gamma-aminobutyric acid and benzodiazepines. Thus, LY139603 is a remarkably specific inhibitor of norepinephrine uptake. Its potential as an antidepressant is discussed.

Animals↗
PubMed1981

Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine.

Binding of [3H]-serotonin ([3H]5-hydroxytryptamine, [3H]5HT) to high and low affinity sites in brain membranes from frontal cortex was compared in rats fed control chow or fluoxetine (0.01%) containing chow. A reduction in the number of high affinity binding sites and in the affinity of the low affinity binding sites was observed after 2, 4 or 6 weeks. Reduction in the number of [3H]5HT binding sites was also observed in cerebral cortex of rats given fluoxetine by daily intraperitoneal injection for 4 or 6 weeks. Thus, long-term treatment with a selective inhibitor of serotonin uptake, fluoxetine, caused subsensitivity of 5HT receptors in frontal cortex and cerebral cortex of rat brain.

Animals↗
PubMed1980

Binding of [3H]pergolide mesylate to dopamine receptors of mammalian brains.

The ergoline dopamine agonist, [3H]pergolide, binds with pharmacological specificity to particulate fractions of rat and calf brains. Dopamine agonists (apomorphine, 5,6-dihydroxy-2-dimethylaminotetralin, 6.7-dihydroxy-2-methylaminotetralin, lergotrileand bromocriptine) and dopamine antagonists (haloperidol and (+)butaclamol but not its pharmacologically inactive isomer, (-)butaclamol) were potent inhibitors, while monoamines (dopamine, norepinephrine, epinephrine and serotonin) were weaker inhibitors of [3H]pergolide binding. Olfactory tubercle was the only brain region other than striatum which exhibited significant [3H]pergolide binding displaceable by 1 microM (+)butaclamol. Saturable of calf and rat striatum with dissociation constants, kd values, of 1.2 to 3.1 nM. The number of binding sites was enriched in crude synaptosomal fractions. The relationship of [3H]pergolide binding to the binding of other dopaminergic ligands is discussed.

Animals↗
PubMed1979

Dopaminergic effects of non-hydroxylated rigid analogs of apomorphine.

A series of rigid analogs of apomorphine lacking aromatic hydroxyl substitutents were evaluated for dopaminergic properties. Three compounds, N-methyl-N-propyl-2-aminotetralin (Me-Pr-2-AT), N-N-dipropyl-2-aminotetralin (Di-pr-2-AT) and N,N-dipropyl-2-aminoindane (Di-Pr-2-AI) induced emesis in dogs, contralateral circling in unilaterally lesioned rats, and inhibited prolactin secretion. The induced circling responses, however, were attenuated by prior treatment with alpha-methyl-p-tyrosine methyl ester (AMPTME) and the compounds were weak inhibitors of 3-H-dopamine binding in calf caudate homogenates. The possibility that these agents may be metabolically activated in vivo is discussed.

Animals↗
PubMed1978

Pharmacologic effects in man of a specific serotonin-reuptake inhibitor.

Fluoxetine (Li-ly 110140) caused a 63 percent inhibition of [3H]serotonin uptake into platelets obtained from normal volunteers to whom the drug was administered daily for 7 days. This dose had no effect on the usual pressor response produced by injections of norepinephrine or tyramine.

Behavior↗