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Biomedical subjects

A Frazer

Publications and source records attributed to A Frazer.

At least 73 records · Page 4Linked to original sources
PubMed1988

Application of [125I]iodocyanopindolol to measure 5-hydroxytryptamine1B receptors in the brain of the rat.

In this study, [125I]iodocyanopindolol ([125I]ICYP), in the presence of isoproterenol, was used to label 5-hydroxytryptamine1B (5-HT1B) receptors in homogenates of the cortex, substantia nigra and caudate-putamen of the rat. The determination of the appropriate concentrations of isoproterenol required to block optimally beta adrenoceptors whereas producing minimal occupancy of 5-HT1B receptors was achieved by generating isotherms for isoproterenol at multiple concentrations of [125I]ICYP. When different concentrations of isoproterenol were used with increasing concentrations of [125I]ICYP, a linear Scatchard transformation of the saturation curve was achieved, even with ligand concentrations about 6-fold greater than the KD for [125I]ICYP. Competition for [125I]ICYP (100 pM) labeled binding sites by 15 serotonin agonists or antagonists was adequately described by a single site model, and the affinity of these drugs for the site labeled by [125I]ICYP was similar to that determined previously when using indirect methods to label 5-HT1B receptors. Serotonin itself showed high affinity for this binding site as did two antagonists, metergoline and methiothepin. By contrast, drugs thought to be selective for the 5-HT1A receptor (e.g., 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone and spiperone) showed very weak affinity for the binding site labeled with [125I]ICYP. The effect of nucleotide regulation on [125I]ICYP binding at 5-HT1B receptors also was evaluated. It was determined that GTP had little effect on the binding of [125I]ICYP, reducing total binding by only 15% and shifting the displacement curve of 5-HT by a factor of less than two. The regulation of 5-HT1B receptors, labeled by [125I]ICYP, also was evaluated. Intraventricular injections of 5.7-dihydroxytryptamine increased significantly the number of 5-HT1B receptors in the caudate-putamen; this treatment had no effect on 5-HT1B binding sites either in the cortex or substantia nigra. The regulatable binding site for [125I]ICYP in the caudate-putamen had a pharmacological profile very similar to that of the 5-HT1B binding site in the cortex. [125I]ICYP appears to be a useful ligand to measure 5-HT1B receptors in the brain of the rat. The localized increase in 5-HT1B receptors in the caudate-putamen after destruction of central serotonergic neurons might indicate that the majority of 5-HT1B receptors in this area of brain are not located on serotonergic nerve terminals.

5,7-Dihydroxytryptamine↗
PubMed1987

Transforming growth factor beta inhibits DNA synthesis in hepatocytes isolated from normal and regenerating rat liver.

The inhibitory action of transforming growth factor beta (TGF beta) on DNA synthesis in hepatocytes isolated from the liver of normal rats or from the liver remnant of rats 18 h following partial hepatectomy was compared. Continuous exposure to TGF beta inhibited DNA synthesis of cultured hepatocytes to a similar degree in both groups when labelled with 3H thymidine from 24-48 h or 48-72 h. At 20 pM TGF beta, 3H-thymidine incorporation was reduced by 64-78% in hepatocytes from normal liver and by 60-73% in cells from 18 h regenerating liver. The nuclear labelling index was reduced by 70-80% in all cells. Exposure to TGF beta at concentrations up to 500 pM from 0-24 h had no effect on 3H-thymidine incorporation, but exposure at 20 pM for 24 h periods thereafter was uniformally effective. These results indicate that there is no change in sensitivity of hepatocytes from 18 h regenerating liver to TGF beta, compared with normal cells, and that TGF beta may act at some point in the G1 phase of the cell cycle to inhibit hepatocyte growth.

Animals↗
PubMed1987

Catecholamine metabolism and disposition in healthy and depressed subjects.

Depressed patients as a group have been found to excrete greater amounts of catecholamines (CAs) and metabolites than healthy control subjects, but these differences were not uniform for all metabolites. Patients may differ from controls in the metabolism and/or disposition of CAs. We analyzed the suggested metabolic-dispositional differences by determining 24-hour urine values for norepinephrine (NE), epinephrine (E), normetanephrine (NM), metanephrine (M), vanillylmandelic acid (VMA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). For each subject, we calculated ratios of CAs or metabolites to an estimate of CA synthesis and determined ratios of CAs and metabolites to each other based on a precursor-product paradigm. The results indicate that as a group, patients have modestly but significantly greater CA synthesis rates than controls; patients excrete disproportionately more NE and E and disproportionately less MHPG relative to estimated CA synthesis, as well as other metabolites, than do controls; in contrast to NE, E, and MHPG, the increased NM, M, and VMA excretion rates by patients are proportional to each other as well as to the increase in CA synthesis; and the differences in NE, E, and metabolite excretion in the patients as a group are due principally to unipolar rather than bipolar depressives. The differences would be expected if patients, relative to controls, released more NE and E into the circulation. These data indicate the need to measure several CAs and metabolites when evaluating differences between groups since the significance of any given metabolite value needs to be examined in the context of total CA and metabolite production and excretion.

Adult↗
PubMed1987

Lithium distribution in mania: plasma and red blood cell lithium, clinical state, and monoamine metabolites during lithium treatment.

We examined red blood cell (RBC) and plasma lithium concentrations and RBC/plasma lithium ratios in 14 manic patients during lithium treatment as part of the National Institute of Mental Health's Collaborative Program on the Psychobiology of Depression, Biological Studies. All of the lithium measures increased during treatment, especially RBC lithium. There were positive correlations between the RBC lithium concentration and the RBC/plasma lithium ratio and their maximal values in a single-dose pharmacokinetic experiment before treatment. After 5 and 16 days of treatment, patients with good subsequent outcome had higher RBC/plasma lithium ratios than did patients with poor outcome. Early in treatment, there was a negative correlation between lithium concentrations and severity of mania. During treatment, there was a negative correlation between RBC lithium and urinary MHPG excretion. There was a positive correlation between RBC or plasma lithium during the first few days of treatment and subsequent reduction in norepinephrine excretion during treatment. At 3 weeks, there were negative correlations between reductions in catecholamine measures and lithium concentrations. These data suggest that there are changes in the sensitivity of behavior and catecholamine function to lithium during treatment. RBC concentrations of lithium appear to be a potentially useful indicator of its behavioral and neurochemical effects.

Adult↗
PubMed1987

The timing, specificity and clinical prediction of tricyclic drug effects in depression.

This research was aimed at studying the rate of action of tricyclic drugs in depressive disorders, specifying the behavioural effects associated with recovery, and predicting clinical response. The research design involved comparison of a recovered group with a group treated for the equivalent four weeks, who showed minimal to no response. The findings indicated significant differences in baseline characteristics between responders and non-responders. Further, the drugs were found to act early in the responders, within the first week of treatment. Specific changes at one week which distinguished responder and non-responder groups occurred in the disturbed affects, and in cognitive functioning. Improvements also occurred in somatic symptoms, but these latter changes were general and not associated with later recovery. At 2 1/2 weeks, all facets of the depressed condition showed positive change in the responders. Implications of the results for assessing rate of tricyclic drug actions, their effects on the interaction of affect and neurochemistry, and the practical application of the results for the clinical situation, are discussed.

Adult↗
PubMed1987

Somatomedin-C in human fetal pancreas. Cellular localization and release during organ culture.

The presence of somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) was investigated in human fetal pancreatic glands obtained after prostaglandin-induced abortion at 14-17 wk of gestation. Pancreatic explants were cultured in medium containing 11.1 or 22.2 mM glucose and 20% fetal calf serum for 8-10 days. During this period they were exposed, on two separate occasions, to serum-free culture medium for 24 h. SM-C/IGF-I and insulin were measured radioimmunologically in the serum-free media and in acid-ethanol-extracted homogenates of the cultured explants. SM-C/IGF-I was measurable in the conditioned media only after extraction by reverse-phase chromatography to remove somatomedin-binding proteins. On gel filtration at neutral pH of extracted medium samples, the immunoreactive SM-C/IGF-I was recovered in the region of the homogeneous peptide with an apparent molecular weight of 7000-8000. Explants cultured in 22.2 mM glucose contained more SM-C/IGF-I and had a tendency to release more of the peptide into the culture medium than explants cultured in 11.1 mM. There was no difference in insulin content or release between the two groups. By immunocytochemistry, SM-C/IGF-I was localized to the beta-cells of the endocrine pancreas in both freshly fixed tissue and cultured explants. We conclude that the human fetal pancreas contains SM-C/IGF-I and secretes the peptide during tissue culture. The presence of SM-C/IGF-I in the islets of Langerhans may contribute to the growth and development of the insulin-producing beta-cell.

Adult↗
PubMed1987

Selective regulation of beta-2 adrenergic receptors by the chronic administration of the lipophilic beta adrenergic receptor agonist clenbuterol: an autoradiographic study.

Many antidepressant drugs, when administered chronically to rats, have been shown to produce decreases in the density of beta adrenergic receptors in the central nervous system. The centrally active beta adrenergic receptor agonist clenbuterol is currently being evaluated clinically as an antidepressant. The chronic administration of this drug to rats resulted in a large decrease in the density of beta adrenergic receptors in some areas of the rat brain but not in others. Thus, autoradiographic studies revealed that the total density of beta adrenergic receptors in the molecular layer of the cerebellum, but not in layers 1 to 3 or layer 4 of the cerebral cortex, was decreased. To examine whether this regional selectivity occurred because of differences in plasticity of cerebellum and cortex or because cerebellum contains mainly beta-2 adrenergic receptors and cortex contains mainly beta-1 adrenergic receptors, separate analyses of the subtypes of beta adrenergic receptors were performed in each area. These experiments indicated that the decrease in receptor density was entirely specific for beta-2 adrenergic receptors, whereas the density of beta-1 receptors was unchanged. Thus, even in layers 1 to 3 and layer 4 of the cerebral cortex, beta-2 receptor density was decreased, with no change in beta-1 receptor density. Using the autoradiographic assay for ligand binding, it was shown that clenbuterol has equal affinity for beta-1 and beta-2 adrenergic receptors, indicating that the selective effect of this drug was not due to a selective affinity for beta-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1987

Effects of clenbuterol on central beta-1 and beta-2 adrenergic receptors of the rat.

Repeated administration of the centrally acting beta adrenoceptor agonist, clenbuterol, to rats reduced the ability of isoproterenol to increase the concentration of cyclic AMP (cAMP) in slices of cerebellum. This reduced responsiveness to isoproterenol was accompanied by a marked reduction in the density of beta adrenoceptors as measured by the binding of the beta adrenoceptor antagonist [125I]iodopindolol. In addition, the agonist-binding properties of remaining cerebellar beta adrenoceptors were altered after clenbuterol treatment. The clenbuterol-induced reduction in the density of beta adrenoceptors in the cerebellum is in marked contrast to its inability to do this in cerebral cortex. Comparison of the ability of clenbuterol to that of isoproterenol to increase levels of cAMP in slices of cerebral cortex or cerebellum showed that clenbuterol is a weakly potent agonist in both brain regions. The increase in cAMP induced by isoproterenol in the cortex was significantly reduced in the presence of the selective beta-1 adrenoceptor antagonist, ICI 89,406. In contrast, the clenbuterol-induced increase in cortical cAMP was unchanged by ICI 89,406 but was reduced significantly by the beta-2 adrenoceptor antagonist, ICI 118,551. In cerebellum, both isoproterenol- and clenbuterol-stimulated accumulation of cAMP were antagonized much more potently by ICI 118,551 than by ICI 89,406. Furthermore, clenbuterol antagonized the cAMP response induced by isoproterenol in the presence of ICI 118,551 in a concentration-dependent manner. In terms of measurement of cAMP in brain slices, clenbuterol is weakly potent as an agonist at beta-2 adrenoceptors and has antagonist properties at beta-1 adrenoceptors.

Animals↗
PubMed1986

Effect of repeated administration of clenbuterol on the regulation of beta-adrenoceptors in the central nervous system of the rat.

The effect of the centrally acting beta-adrenoceptor agonist clenbuterol on beta-adrenergic responsiveness, beta-receptor density and N-protein coupling was studied in the rat cerebral cortex (which contains primarily beta 1-receptors) and cerebellum (containing mostly beta 2-receptors). The objective was to determine whether clenbuterol's effect on these variables was similar to that produced by standard antidepressants. When given to rats repeatedly, clenbuterol caused a decrease in beta-adrenergic responsiveness in slices from either the cerebral cortex or the cerebellum. The decreased beta-responsiveness in the cerebellum was associated with a decrease both in the density of beta-receptors and in receptor/N-protein coupling. In the cortex, only reduced receptor/N-protein coupling was observed by in vitro ligand-binding methods. However, when quantitative autoradiography was employed, clenbuterol treatment was found to reduce the binding of [125I]iodopindolol to beta 2-receptors throughout the brain, whereas binding to beta 1-receptors was not reduced. The down-regulation of beta 2-receptors by clenbuterol is due to its acting centrally as a beta 2-agonist. Although clenbuterol has about an equal affinity for beta 1-receptors and beta 2-receptors, no evidence was found for agonist activity of this drug at beta 1-receptors in the cerebral cortex. The strategies described here should be helpful in investigating important properties of centrally acting beta-agonists that might have potential as antidepressants.

Animals↗
PubMed1986

Patterns of melatonin rhythms in depression.

The nocturnal rise of melatonin in serum of humans is the result of endogenously released norepinephrine (NE) acting upon beta-adrenergic receptors of the pineal gland. As there is much interest in the possibility of there being changes in the function of beta-receptors in depressed patients, the nocturnal rise of melatonin was measured in depressives and healthy control subjects. In one study, multiple serum samples were taken between 4.30 p.m. to 7.30 a.m. in seven male depressed patients with melancholia and five healthy male control subjects. The melancholic patients had a significantly reduced nocturnal elevation of melatonin. In a separate study, serum samples were taken at 8 a.m. and 11 p.m. in melancholic depressives, non-melancholic depressives and healthy control subjects. The melancholic patients had a significantly lower concentration of melatonin at 11 p.m., but not at 9 a.m., than that measured in either the control subjects or the non-melancholic depressed patients. These results are similar to those found recently by several other groups of investigators. Further research is indicated to elucidate mechanism(s) responsible for this phenomenon.

Adult↗
PubMed1985

Development of selective tolerance to the serotonin behavioral syndrome and suppression of locomotor activity after repeated administration of either 5-MeODMT or mCPP.

Repeated administration to rats of the 5-HT1A-selective agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) produced tolerance to the ability of a test dose of 5-MeODMT to produce the serotonin behavioral syndrome, but not to the ability of a test dose of the 5-HT1B-selective agonist m-chlorophenylpiperazine (mCPP) to decrease locomotor activity. Conversely, repeated administration of mCPP produced tolerance to the ability of a test dose of mCPP to decrease locomotor activity, but not to the ability of a test dose of 5-MeODMT to elicit the serotonin behavioral syndrome. The lack of cross-tolerance between these two selective agonists is consistent with the idea that the serotonin behavioral syndrome and suppression of locomotor activity are mediated by different subtypes of the 5-HT1 receptor.

Animals↗
PubMed1985

Performance and extinction of lever press behavior following chronic administration of desipramine to rats.

The effect of repeated administration of desipramine (DMI) on the acquisition, performance, and extinction of a lever press response for food reward was studied. Chronic administration of DMI caused a reduction in pressing under a CRF schedule both in naive and well-trained rats. Responding during extinction sessions did not differ between saline-treated rats and rats given DMI chronically. In addition, chronic administration of DMI reduced the body weight and food intake of rats on either a free-feeding or a restricted-feeding schedule. Consequently, lever pressing was also studied in a group of rats whose body weight was regulated to match the body weight of rats were administered DMI chronically. In comparison to this control group, rats administered DMI chronically responded significantly less during both reinforcement and extinction sessions. These results fail to replicate earlier reports that chronic DMI administration produces increased resistance to extinction. The results also show that assessment of food-motivated performance in rats treated chronically with DMI is difficult because of long-term changes in body weight and food intake.

Animals↗
PubMed1985

Cerebrospinal fluid levels of amitriptyline, nortriptyline, imipramine and desmethylimipramine. Relationship to plasma levels and treatment outcome.

Fifty-five (55) depressed patients were treated with amitriptyline (AMI) or imipramine (IMI). Concentrations of AMI, IMI, and their metabolites, nortriptyline (NT) and desmethylimipramine (DMI), were measured in cerebrospinal fluid (CSF) and plasma at steady state by gas chromatography mass spectrometry (GC/MS). Highly significant correlations between CSF and plasma levels of AMI, NT, IMI, and DMI were found (r greater than 0.75; P less than 0.0001 in all cases). There were no significant sex, diagnostic subgroup, or geographic difference in any of the drug parameters measured. An evaluation of the relationship between CSF levels of drug variables and clinical response showed essentially no significant correlations between these various parameters. The results obtained do not support the concept of a 'therapeutic window' for levels of plasma NT in AMI-treated patients. Furthermore, the highly significant correlations between CSF and plasma compartments in terms of drug and metabolite levels would argue against the need to measure CSF levels of these parameters in clinical practice. Plasma level measurements should be equally informative, and simpler to obtain.

Amitriptyline↗
PubMed1985

Differences in nocturnal melatonin secretion between melancholic depressed patients and control subjects.

The authors took multiple serum samples for measurement of melatonin between 4:30 p.m. and 7:30 a.m. in seven male depressed patients with melancholia and five healthy male control subjects and found that melancholic patients had a significantly lower rise of melatonin. They also compared a second, separate group of 14 women and five men suffering from melancholic depression with seven healthy male control subjects and nine depressed women without melancholia. The melancholic patients had a significantly lower concentration of serum melatonin at 11:00 p.m. than either the control subjects or the nonmelancholic depressed patients. These findings support the possibility that the functioning of the pineal gland is altered in these patients.

Adult↗
PubMed1985

Effects of clenbuterol and antidepressant drugs on beta adrenergic receptor/N-protein coupling in the cerebral cortex of the rat.

Repeated administration of the centrally acting beta adrenergic agonist clenbuterol to rats reduced the ability of isoproterenol to increase levels of cyclic AMP in slices of cerebral cortex. This lessened response to isoproterenol was not due to a reduction in beta receptor density but appeared to be due to diminished receptor/N-protein coupling. This was determined by measuring the ability of isoproterenol to inhibit the binding of the beta adrenergic antagonist [125I]iodopindolol to membranes prepared from cerebral cortex. Using membranes prepared from vehicle-treated rats, isoproterenol, in the absence of GTP, inhibited the binding of [125I]iodopindolol with an IC50 value of 85 nM and a Hill coefficient of 0.65. GTP (250 microM) increased the IC50 value to 290 nM and the Hill coefficient to 0.98. After repeated administration of 10mg/kg of clenbuterol to rats for 8 days, isoproterenol inhibited the binding of [125I]iodopindolol with an IC50 value of 125 nM and a Hill coefficient of 0.90; GTP increased the IC50 value to 170 nM and the Hill coefficient to 0.98. It was inferred from the results of modeling of the isoproterenol competition curves that the repeated administration of clenbuterol reduced or eliminated the high-affinity component of isoproterenol binding. These effects of clenbuterol were found to depend on dose and duration of treatment and were reversible. Repeated administration of the antidepressant drugs desipramine, imipramine, phenelzine, zimelidine and mianserin twice daily for 21 days, by contrast, did not affect receptor/N-protein coupling.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗