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Biomedical subjects

I Creese

Publications and source records attributed to I Creese.

At least 91 records · Page 5Linked to original sources
PubMed1982

Phenoxybenzamine treatment differentiates dopaminergic 3H-ligand binding sites in bovine caudate membranes.

Phenoxybenzamine, the classic alpha-adrenergic receptor alkylating agent, also acts as an irreversible antagonist of the binding of [3H]spiroperidol, a D-2-selective dopaminergic ligand, to bovine caudate membranes. Doses completely eliminating the binding of this ligand leave the binding of [3H]dopamine to D-3 sites virtually unaffected. The binding sites for these two ligands thus represent distinct subtypes of dopamine receptors, not interconverting states of a single receptor. This phenoxybenzamine-mediated inhibition proceeds via a dose-dependent (pseudo-IC50 = 1 microM) decrease in Bmax with little or no change in affinity for 3H-ligands at the D-2 site. The effect is site-directed, as the dopaminergic agonists dopamine and apomorphine and the antagonist domperidone are able to protect against phenoxybenzamine-mediated attack in proportion to their affinities for D-2 sites. Epinephrine, norepinephrine, and serotonin are much less effective in protecting these sites. The sensitivity of [3H]apomorphine binding is intermediate to that of [3H]spiroperidol and [3H]dopamine. [3H]Apomorphine binding can be resolved into a phenoxybenzamine-labile population of binding sites which have equal phenoxybenzamine sensitivity, selectivity among protecting agents, and butyrophenone affinity to those of D-2 sites labeled by 3H-butyrophenones, and a separate phenoxybenzamine-stable population of sites which have an affinity for dopamine comparable to that of D-3 sites labeled by [3H]dopamine. [3H]Apomorphine therefore appears to label a portion of D-2 receptor sites in addition to D-3 receptors.

Animals↗
PubMed1982

Heat treatment mimics guanosine-5'-triphosphate effects on dopaminergic 3H-ligand binding to bovine caudate membranes.

Exposure of bovine caudate homogenates to 53 degrees rapidly (less than 4 min) abolishes subsequent specific binding of the agonist ligand [3H]dopamine to D-3 sites but not that of the butyrophenone dopaminergic antagonist [3H]spiroperidol to D-2 sites in bovine caudate membranes. It has been suggested that this represents selective heat inactivation of the binding site for [3H]dopamine. However, the binding of the agonist [3H]apomorphine is decreased with a time course and temperature dependence indistinguishable from that of [3H]dopamine, despite the ability of [3H]apomorphine to label D-2 sites as well as D-3 sites in control membranes. Heat treatment thus appears to mimic the effects on dopaminergic binding of guanine nucleotides, which, rather than causing a reduction in the number of binding sites, radically lowers agonist affinity at both D-2 and D-3 sites while leaving antagonist affinity at these sites unchanged. In addition, heat treatment and maximal guanine nucleotide addition (300 microM GTP) cause identical decreases in the affinities of agonists in the displacement of [3H]spiroperidol, and similar increases in pseudo-Hill coefficient of these displacements. The effects of heat treatment and guanine nucleotides are not additive, suggesting that their effects may involve a common mechanism. Thus, it is strongly suggested that brief exposure to 53 degrees inactivates not the D-3 site itself, but rather a guanine nucleotide binding factor that regulates both D-2 and D-3 agonist affinities and, as in the beta-adrenergic system, is essential for formation of high-affinity agonist/receptor complexes.

Animals↗
PubMed1981

Kainate lesion dissociates striatal dopamine receptor radioligand binding sites.

Kainic acid lesion of rat striata reduces the specific dopamine receptor binding of the butyrophenone antagonist [3H]spiperone and the butyrophenone-like antagonist [3H]domperidone by 56% and 59% respectively. Significantly greater decreases in binding were observed with the agonist [3H]N-propylnorapomorphine (NPA) and the antagonist [3H]flupentixol which showed 79% and 73% losses of high affinity binding respectively. These data indicate that, in part, [3H]spiperone and [3H]domperidone label distinct dopamine receptors with different neuronal localizations from those labeled by [3H]flupentixol and [3H]NPA. Our data is consistent with the hypothesis that [3H]flupentixol and [3H]NPA bind preferentially to adenylate cyclase-linked dopamine (D1) receptors.

Animals↗
PubMed1981

Neuroleptic serum levels measured by radioreceptor assay and clinical response in schizophrenic patients.

Serum neuroleptic levels and clinical response have been compared serially in 10 schizophrenic patients treated with a variety of neuroleptics using a novel radioreceptor assay for neuroleptics. In this assay the drug in serum completes with [3H]spiroperidol for binding to dopamine receptors on membranes of the caudate nucleus. Serum neuroleptic levels, expressed in terms of dopamine receptor occupancy, were similar for most neuroleptics at therapeutic doses. Thioridazine levels were substantially higher than those of other neuroleptics.

Adult↗
PubMed1981

Dopamine receptors: subtypes, localization and regulation.

Receptor binding studies with a variety of dopaminergic ligands have confirmed behavioral and biochemical findings that the central nervous system and peripheral nervous system contain several dopamine receptor subtypes. These subtypes can be discriminated on the basis of their agonist-antagonist pharmacological specificities, linkage to adenylate cyclase, cellular location, regulation by guanine neucleotides and ions, and involvement in several human diseases. Although questions remain unanswered, progress is rapidly being made in equating the subgroupings arrived at by these different experimental approaches. Dopamine receptors are regulated by a number of factors. Acutely, guanine nucleotides and some ions regulate agonist but not antagonist binding and are essential for receptor coupling with adenylate cyclase. Chronically, changes in the level of dopaminergic stimulation modulate the number of at least some receptor subtypes, resulting in "up or down regulation." An increase in receptor number appears central to the pathology of Parkinson's disease, tardive dyskinesia, and perhaps schizophrenia. Animal models indicate that it may be possible to exploit inherent capabilities for receptor modulation in clinical therapy. The therapeutic precedents set by the indentification of distinct subtypes of adrenoreceptors. histamine, and cholinergic receptors portends and exciting future for dopamine receptor research.

Adenylyl Cyclases↗
PubMed1980

Low neuroleptic serum levels in patients receiving fluphenazine decanoate.

The authors monitored serum levels of fluphenazine in nine patients following injections of fluphenazine decanoate ranging from 10 to 75 mg. Levels were detected by a radioreceptor assay based on the ability of the drug to complete with 3H-spiroperidol for binding to dopamine receptors in rat caudate membranes. Serum levels of fluphenazine were quite stable over a 2- to 3-week period following single intramuscular injections of the decanoate and correlated with injected dose. Following decanoate treatment serum levels of fluphenazine are substantially lower than levels observed for most other neuroleptics administered orally. This raises questions as to how fluphenazine decanoate can exert therapeutic actions.

Administration, Oral↗
PubMed1980

Clinical state and serum neuroleptic levels measured by radioreceptor assay in schizophrenia.

The authors measured serum neuroleptic levels by radioreceptor assay in 30 schizophrenic patients receiving haloperidol, fluphenazine, chlorpromazine, molindone, thiothixene, or trifluoperazine. Neuroleptic levels were significantly correlated with clinical state, monitored by an abbreviated version of the Present State Examination (the mini-PSE). Poor therapeutic responses were associated with serum levels under 50 ng/ml chlorpromazine equivalents. There was no correlation between neuroleptic dosage and mini-PSE score or between neuroleptic dose and serum neuroleptic levels.

Adolescent↗
PubMed1980

Dopamine receptor binding in bovine intermediate lobe pituitary membranes.

[3H]Spiroperidol ([3H]SPIRO) and [3H]N-n-propylnorapomorphine ([3H]NPA), a dopamine antagonist and agonist, respectively, were found to bind stereospecifically to bovine intermediate lobe pituitary membranes. The specific binding was saturable ([3H]SPIRO maximum number of binding sites, 11.2 pmol/g tissue; [3H]NPA maximum number of binding sites, 5.0 pmol/g tissue) and of high affinity affinity ([3H]SPIRO dissociation constant, 0.17 nM; [3H]NPA dissociation constant, 0.35 nM). The rank order of catecholamines, phenothiazines, and related drugs in competing for [3H]SPIRO and [3H]NPA binding is consistent with interactions at a dopamine receptor. Guanine nucleotides were found to selectively decrease agonist but not antagonist affinities for these binding sites. With the addition of 0.1 mM GTP, the ability of agonists to displace [3H]SPIRO binding is decreased 5- to 7-fold, while the dissociation constant for [3H]NPA is increased to 0.8 nM.

Animals↗