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Biomedical subjects

I Creese

Publications and source records attributed to I Creese.

At least 73 records · Page 4Linked to original sources
PubMed1984

Dopamine receptor turnover rates in rat striatum are age-dependent.

The time course of recovery of [3H]spiperone binding in the rat striatum after a single injection of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) shows that a slower rate of regeneration/turnover of D-2 dopamine receptors occurs in mid-life-mature versus young male rats. This slower receptor recovery reflects relatively slower rates of both receptor synthesis and degradation. Studies using cycloheximide indicate that protein synthesis plays a significant role in the reappearance of [3H]spiperone-binding sites. Other experiments indicate that chronic reserpine treatment, which produces dopamine receptor up regulation, also produces accelerated receptor recovery after EEDQ blockade. An age-related decline in dopamine receptor turnover, if present in humans and progressive into senescence, could be responsible for the increased risk of developing Parkinson disease and drug-induced parkinsonian-like extrapyramidal side effects with age. On the other hand, the more rapid receptor turnover rates seen in young rats may be a biochemical feature related to plasticity in the striatum during development.

Aging↗
PubMed1984

Agonist interactions with dopamine receptors: focus on radioligand-binding studies.

Radioligand-binding experiments have demonstrated that both D-1 (adenylate cyclase stimulatory) and D-2 (adenylate cyclase inhibitory) dopamine receptors demonstrate high- and low-affinity agonist-binding states. Under appropriate conditions, both D-1 and D-2 high-affinity binding states can be labeled directly with 3H-labeled agonists. Previous studies that identified a portion of high-affinity 3H-labeled agonist binding as a distinct dopamine receptor subclass (D-3 or autoreceptor) were, in fact, labeling the high-affinity agonist-binding state of postsynaptic D-1 receptors.

Adenylyl Cyclases↗
PubMed1983

Behavioral and radioligand binding evidence for irreversible dopamine receptor blockade by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible alpha adrenergic antagonist, also acts as a potent and longlasting in vivo antagonist of D-2 dopamine receptors. Rats given EEDQ 3-10 mg/kg i.p. exhibit catalepsy and greatly reduced apomorphine-induced stereotypy, behavioral effects associated with D-2 dopamine receptor blockade. These effects are apparent up to 4 days after drug administration, with scores returning to control level by day 7. In vitro receptor binding assays of striatal membrane preparations from these animals using the radioligand 3H-spiroperidol directly demonstrate that EEDQ is a potent D-2 dopamine receptor antagonist, revealing the apparent basis of the behavioral effects of EEDQ. This antagonism proceeds via a reduction in D-2 receptor Bmax, with no change in the observed KD for 3H-spiroperidol, and is resistant to extensive washing of the membrane preparation after in vivo EEDQ exposure. These observations suggest that EEDQ inhibition of D-2 receptors is irreversible. Administration of behaviorally active doses of EEDQ effect a reduction of 50-85% in D-2 receptor number. Recovery of this loss roughly parallels recovery of normal catalepsy and apomorphine stereotypy scores. These doses of EEDQ also reduce binding of 3H-flupentixol to D-1 and 3H-dopamine to D-3 type dopaminergic binding sites, putative dopamine receptors with no known behavioral correlates. Recovery of D-1 and D-3 binding also occurs with a similar timecourse. Because of the apparent covalent nature of its interaction with dopamine receptors and because of its activity after peripheral administration, EEDQ may prove useful in the study of the function and turnover of dopamine receptors.

Adrenergic alpha-Antagonists↗
PubMed1983

Regulation of ligand binding to pituitary D-2 dopaminergic receptors. Effects of divalent cations and functional group modification.

The effects of divalent cations and protein-modifying reagents on the binding of agonist and antagonist ligands to D-2 dopaminergic receptors were studied. The divalent cations Mg2+, Ca2+, and Mn2+ markedly increase the binding of the agonist [3H]N-n-propylnorapomorphine ([3H]NPA) to the high affinity state of the pituitary D-2 receptor. The increase in [3H]NPA binding is due to both an increase in binding capacity (Bmax) and a decrease in the dissociation constant (KD). Monovalent cations have no effect on agonist binding either in the presence or absence of divalent cations. Neither divalent nor monovalent cations exert any effects on the binding of the antagonist, [3H]spiroperidol to pituitary D-2 receptors. Modification of sulfhydryl groups by N-ethylmaleimide and p-hydroxymercuribenzoate inactivates both [3H]NPA and [3H]spiroperidol binding; however, [3H]NPA binding exhibits a 50-fold greater sensitivity to N-ethylmaleimide. Inactivation of both [3H]NPA and [3]spiroperidol binding by N-ethylmaleimide and p-hydroxymercuribenzoate results in a diminished binding capacity for both radioligands. The inactivation of [3H] spiroperidol-binding by N-ethylmaleimide and p-hydroxymercuribenzoate can be protected against by occupying the receptor site with either antagonists or agonists, however, such treatments do not protect against inactivation of [3H]NPA binding. The effects of selectively decreasing the receptor subunit concentration on the proportions of high and low affinity agonist-binding states was additionally examined. A phenoxybenzamine-induced decrease of up to 63% of the receptor-binding sites has no effect on the proportions of agonist-binding states as detected with agonist/[3H]spiroperidol-competition curves. These results can all be incorporated into a two-step, three-component ternary complex model in which the second binding reaction appears to be under equilibrium restraint.

Animals↗
PubMed1983

Septal deafferentation increases hippocampal adrenergic receptors: correlation with sympathetic axon sprouting.

Denervation of the hippocampal formation in adult rats through lesion of the medial septum and diagonal band or by transection of the fimbria/fornix elicits an increase in the number of putative alpha-adrenergic receptor binding sites labeled by the antagonist ligand [3H]WB4101 [2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane]. This increase in [3H]WB4101 binding is observable at 6 days postlesion, preceding the ingrowth of sympathetic axons into the partially denervated regions of the hippocampus. The receptor up-regulation is specific for lesions of the septal (primarily cholinergic) innervation of the hippocampus. Damage to noradrenergic, dopaminergic, or serotonergic afferents as well as kainate injections in the lateral septum had no effect on [3H]WB4101 binding levels. In vivo muscarinic/cholinergic-receptor blockade does not mimic the effects of the lesion on receptor binding levels or upon axonal sprouting of the sympathetic neurons. Although [3H]WB4101 binding consistently increased after septal deafferentation, there was no clear-cut effect upon the other adrenergic ligands, including [3H]prazosin, [3H]yohimbine, P-[3H]aminoclonidine, or [3H]dihydroalprenolol. These observations can be interpreted as demonstrating a unique and selective adrenergic receptor increase after a nonadrenergic denervation but accompanying the ingrowth of anomalous adrenergic fibers. We suggest several possible relationships between the new binding sites and the ingrowing axons.

Animals↗
PubMed1983

Interactions of ergot alkaloids with anterior pituitary D-2 dopamine receptors.

The interactions of ergot alkaloids with bovine anterior pituitary D-2 dopamine receptors have been investigated with radioligand binding techniques and computer modeling procedures. Ergot alkaloids of the ergoline class are found to interact with the receptor in an agonist-specific fashion, exhibiting heterogeneous competition curves which can be resolved into high- and low-affinity components. In the presence of guanine nucleotides, however, only the low-affinity binding component is observable. In contrast, ergot alkaloids possessing a cyclic peptide side chain (ergopeptines) interact with the receptor in a homogeneous fashion, exhibiting competition curves which are monophasic and unaffected by guanine nucleotides. Ergopeptines thus display the binding characteristics of antagonist ligands even though they possess pharmacologically demonstrated agonist properties. These ergot alkaloid receptor binding characteristics determined from indirect competition experiments are also directly demonstrable using radiolabeled ergoline and ergopeptine ligands. The radiolabeled ergopeptine [3H]dihydroergocryptine ([3H]DHE) is shown to label identical binding sites with the same pharmacological characteristics as the antagonist [3H]spiroperidol. However, the dissociation rate of [3H]DHE from these binding sites is much slower than [3H]spiroperidol and is inconsistent with its equilibrium-determined binding affinity. In addition, saturation experiments with radiolabeled antagonists and agonists and unlabeled ergopeptines indicate that ergopeptines interact with these receptor sites in a competitive fashion. A model is presented which may explain these unique binding properties of ergot alkaloid agonists to the pituitary D-2 dopamine receptor.

Animals↗
PubMed1982

Interactions of novel dopaminergic ligands with D-1 and D-2 dopamine receptors.

The interactions of three novel dopaminergic ligands, SKF38393, SKF82526 and SKF83742, with D-1 and D-2 dopamine (DA) receptors have been investigated using radioligand binding techniques and computer modeling procedures. Using the bovine anterior pituitary D-2 DA receptor system, SKF38393 and SKF82526 behave as agonists demonstrating biphasic agonist/3H-antagonist competition curves. For both drugs, the high affinity phase comprised 30% of the total displacement curve. Such findings are atypical as previously tested classical dopamine agonists demonstrated high and low affinity displacement phases in equal proportions. Such behavior exhibited by the SKF agonists may be related to their activity as partial agonists. In contrast, SKF83742 behaves as an antagonist exhibiting homogeneous monophasic competition curves. Similar results are obtained in the rat striatal membrane D-2 DA receptor system. Both SKF38393 and SKF82526 also demonstrate shallow biphasic displacement curves on rat striatal D-1 receptors labeled with 3H-flupentixol whereas SKF83742/3H-flupentixol curves are uniphasic. Of all the ligands, only SKF38393 clearly demonstrates higher affinity for 3H-flupentixol labeled D-1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1982

Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor.

The interactions of dopaminergic agonists and antagonists with binding sites in bovine anterior pituitary membranes have been investigated with radioligand-binding techniques and computer-modeling procedures. 3H-labeled agonist binding is stereospecific, reversible, saturable, and of high affinity. The rank order of catecholamines, phenothiazines, and related drugs in competing for 3H-agonist binding is indicative of interactions with a D-2 dopamine receptor. Both agonist/3H-agonist and antagonist/3H-agonist competition curves are monophasic and noncooperative (nH = 1) with computer analysis indicating a single class of binding sites. Specific 3H-agonist binding can be completely inhibited by guanine nucleotides. GppNHp us the most potent nucleotide followed by GTP and GDP which are equipotent. The equilibrium binding capacity for 3H-labeled antagonists is twice that for 3H-agonists. Unlabeled antagonists inhibit 3H-antagonist binding competitively and exhibit antagonist/3H-antagonist competition curves which model best to a state of homogeneous affinity. In contrast, unlabeled agonists inhibit 3H-antagonist binding in a heterogeneous fashion displaying multiphasic (nH less than 1) competition curves which can be resolved into high and low affinity binding sites. In the presence of saturating concentrations of guanine nucleotides, however, the agonist/3H-antagonist curves model best to a single affinity state which is identical with the low affinity state seen in control curves. The binding data can be explained by postulating two states of the D-2 dopamine receptor, inducible by agonists but not antagonists and modulated by guanine nucleotides.

Animals↗
PubMed1982

3H-dopamine binding to rat striatal D-2 and D-3 sites: enhancement by magnesium and inhibition by guanine nucleotides and sodium.

Previous studies have demonstrated high affinity 3H-dopamine binding sites on mammalian striatal membranes. These putative dopamine receptors of unknown physiological significance have been termed D-3 sites. Such studies have failed, however, to demonstrate high affinity 3H-dopamine binding to D-2 sites, which can be labeled by 3H-butyrophenones, and which represent the putative dopamine receptors most strongly implicated in the behavioral correlates of dopaminergic CNS activity. We now know that preincubation of membrane homogenates with Mg++ and inclusion of Mg (1-10mM) or other divalent metal cations during binding allows high affinity D-2 specific 3H-dopamine binding in rat striatal membranes, and that these ions also increase the Bmax of D-3 specific 3H-dopamine binding. GTP, GDP, and GppNHp can completely abolish all D-2 specific 3H-dopamine binding, while only a magnesium-dependent portion of D-3 sites appears to be GTP sensitive. These data are consistent with the hypothesis that the striatal D-2 receptor exists in two agonist affinity states whose interconversion is effected by guanine nucleotides and divalent metal cations. The GTP sensitive/magnesium dependent nature of 3H-dopamine binding to so-called D-3 sites suggests that some such sites may in fact represent a high agonist-affinity state of the D-1 adenylate cyclase stimulating dopamine receptor also found in this tissue.

Animals↗
PubMed1982

Increased brain dopamine and dopamine receptors in schizophrenia.

In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients.

Adolescent↗
PubMed1982

Lack of behavioral evidence for dopamine autoreceptor subsensitivity after acute electroconvulsive shock.

A single electroconvulsive shock (ECS) delivered 7 days previously produced a significant decrease in spontaneous locomotion and rearing in non-habituated rats but did not alter the inhibition of these behaviors produced by low dose apomorphine administration. As such apomorphine effects are thought to be mediated by dopamine (DA) autoreceptors, these data are not consistent with previous reports that the ECS treatment produces a persistent subsensitivity of DA autoreceptors.

Animals↗