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Biomedical subjects

A C Andorn

Publications and source records attributed to A C Andorn.

At least 19 recordsLinked to original sources
PubMed1991

The low affinity component of [3H]clonidine binding is absent in the prefrontal cortex of presumptive suicide victims.

Dysfunction in alpha-adrenergic receptor systems has been implicated to be of etiologic significance in depressive illness. The alpha 2-adrenergic ligand [3H]clonidine labels at least two sets of binding sites in normal human prefrontal cortex. We now report that the lower affinity component of [3H]clonidine binding is apparently absent in the prefrontal cortices of presumptive suicide victims.

Cell Membrane↗
PubMed1991

Binding of [3H]-p-aminoclonidine to alpha 2-adrenoceptor states plus a non-adrenergic site on human platelet plasma membranes.

Characterization of the binding of [3H]p-aminoclonidine ([3H]PAC) to purified plasma membranes from human platelets has revealed multiple binding sites. [3H]PAC identified site-1 in the picomolar affinity range (site-1 KD estimates ranged from 13 to 94 pM). Site-1 displayed a rank order of competition by various compounds for [3H]PAC, indicative of an alpha 2-adrenoceptor, and was sensitive to 0.1 mM GTP. [3H]PAC also identified a second site with nanomolar affinity (site-2 KD estimates ranged from 0.7 to 1.7 nM). In the presence of 0.1 mM GTP, site-2 was not diminished significantly. Also in contrast to site-1, site-2 displayed low affinity for yohimbine (YOH), (-)-epinephrine and (-)-norepinephrine (NE). Therefore, site-2 could not be an active alpha 2-adrenoceptor; instead it had properties similar to a previously reported imidazoline-preferring binding site. A third site (site-3) bound [3H]PAC with a KD for site-3 of 26.6 +/- 10.0 nM (SD). Site-3 had a rank order of competition by various compounds for 5 nM [3H]yohimbine ([3H]YOH) binding which was indicative of an alpha 2-adrenoceptor. (-)-NE competed for 5 nM [3H]YOH binding at two sites: site-1 Ki = 32 pM, site-3 Ki = 239 nM. Treatment with 0.1 mM GTP completely removed site-1 and transferred the competitive binding of (-)-NE to low affinity (Ki = 437 nM). Thus, site-3 appears to be a free alpha 2-adrenoceptor. Bmax estimates for untreated membranes, derived from simultaneous multi-experiment curve-fitting analyses, were site-1 = 36 +/- 29 fmol/mg plasma membrane protein, site-2 = 95 +/- 34 fmol/mg and site-3 = 154 +/- 35 fmol/mg. We are the first to report a site for [3H]PAC binding on platelets (site-2) with properties uncharacteristic of an adrenoceptor. This observation appears to be due to our use of purified plasma membrane and low ionic strength buffer. These studies relate to reports of increased binding of [3H]PAC to platelets from depressed patients.

Adrenergic alpha-Agonists↗
PubMed1989

3H-spiroperidol binding in human temporal cortex (Brodmann areas 41-42) occurs at multiple high affinity states with serotonergic selectivity.

3H-Spiroperidol labels multiple high affinity states with serotonergic selectivity in human prefrontal cortex and with dopaminergic selectivity in human caudate and putamen. The characteristics of the binding of this ligand in human temporal cortex have not been previously described. Brodmann areas 41-42 in the temporal cortex are associated with primary auditory sensation and, in epileptics, with auditory hallucinatory experiences. We found that in this region of the human brain, antipsychotic ligands bind at multiple high affinity states, the majority of which exhibit serotonergic, rather than dopaminergic, selectivity. Dose-response data is best resolved by a three-site fit. Results of the co-analysis of dose-response data with saturation data indicates that two of the 3H-spiroperidol affinity states may represent the high and low affinity states of the serotonin (5HT)2 receptor, while a third affinity state may represent the 5-HT1A receptor.

Adult↗
PubMed1989

Adrenergic receptors in aging and Alzheimer's disease: increased beta 2-receptors in prefrontal cortex and hippocampus.

Loss of pigmented noradrenergic locus ceruleus neurons occurs in Alzheimer's disease (AD) and, to a lesser extent, in aging. We studied beta-adrenergic receptors and their subtypes, beta 1 and beta 2, by the specific binding of 125I-pindolol to particulate membrane preparations from prefrontal cortex, hippocampus, putamen, and cerebellum and to sections from frontal cortex by in vitro autoradiography. In prefrontal cortex from controls, numbers of total beta- and beta 2-adrenoceptors did not significantly correlate with age, but number of beta 1-adrenoceptors showed a weak but significant negative correlation. Binding in tissue particulate preparations to total beta-receptors did not reveal significant differences in samples from prefrontal cortex between AD subjects and age-matched controls. However, beta 1-adrenoceptors were decreased and beta 2-adrenoceptors were increased in number by approximately 30-50% in AD subjects. Thus, the relative ratio of beta 1-/beta 2-receptors was decreased in AD. Binding by in vitro receptor autoradiography performed in a subset of samples of frontal cortex also showed beta 2-adrenoceptors, and less consistently total beta- and beta 1-receptors, to be increased significantly in number in cortical laminae II, III, IV, and V of tissue sections from AD subjects. In these subjects, number of locus ceruleus cells and norepinephrine concentrations in putamen and frontal cortex were markedly reduced compared with values in controls. In the hippocampus, total beta- and both beta 2- and beta 1-adrenoceptors were increased in number in AD. In contrast, in the putamen, where beta 1-receptors predominate, total beta- and beta 1-receptors were significantly decreased in number with no consistent change in content of beta 2-receptors in AD. There were no significant changes in the cerebellum. Specific pindolol binding was not affected by interval between death and sampling of tissue at autopsy. Our results indicate selective changes in number of beta-receptors in AD. These changes in the cortex and hippocampus suggest receptor upregulation in response to noradrenergic deafferentation from the locus ceruleus or may simply reflect glial proliferation in AD.

Aged↗
PubMed1989

Alterations in adrenergic receptors of frontal cortex and cerebral microvessels in Alzheimer's disease and aging.

Biochemical and pathological abnormalities are evident in the noradrenergic innervation of the cerebral cortex in Alzheimer's Disease (AD), and there is also a decline in aging, which may lead to changes in adrenergic receptors. To assess this question, we analyzed adrenergic receptor subtypes by ligand binding methods in prefrontal cortex and brain microvessels from subjects with AD and aging controls. Ligand binding to adrenoceptors and their subtypes did not change with postmortem delay in obtaining tissues. alpha 1-adrenergic receptors of the frontal cortex did not correlate with age but there was a small (approximately 25%), though significant, reduction in AD subjects. In cerebral microvessels, there were no changes in these receptors. alpha 2-receptors of the cortex significantly declined with age in controls and were also significantly reduced by approximately 50% in AD subjects. However, in cerebral microvessels alpha 2-adrenergic receptors were significantly increased by approximately 60% in AD. We suggest that presynaptic alpha 2-adrenoceptors on noradrenergic synapses may be those that are selectively decreased in the prefrontal cortex in AD. Total beta-receptors in cortex did not correlate with age, nor were they altered in AD. However, beta 1-receptors were decreased but beta 2-receptors were significantly increased in AD, indicating a change in the relative ratio of beta 1/beta 2-receptors. Similarly, beta 2-receptors of cerebral microvessels were significantly increased in AD. These changes suggest receptor "up-regulation" in response to noradrenergic denervation in AD and may reflect functional changes at the blood-brain barrier.

Adult↗
PubMed1988

Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims.

Previous studies have provided evidence that corticotropin releasing factor (CRF) is hypersecreted in patients with major depression. This CRF hypersecretion is believed to contribute at least in part to hyperactivity of the hypothalamic-pituitary-adrenal axis in depressed patients. If CRF is chronically hypersecreted in depressed patients, then, due to down-regulation, a reduced number of CRF receptor binding sites should be present in patients with profound depressive disorder. To test this hypothesis, we measured the number and affinity of CRF binding sites in the frontal cortex of 26 suicide victims and 29 controls who died of a variety of causes. There was a marked (23%) reduction in the number of CRF binding sites in the frontal cortex of the suicide victims compared with the controls. These data are consistent with the hypothesis that CRF is hypersecreted in depression.

Adult↗
PubMed1988

Specific [3H]UK 14,304 binding in human cortex occurs at multiple high affinity states with alpha 2-adrenergic selectivity and differing affinities for GTP.

[3H]UK 14,034 is a full agonist at alpha 2-adrenergic receptors. Although the characteristics of the binding of the partial alpha 2-adrenergic agonists in postmortem human brain were known, the binding of [3H]UK 14,304 had not been studied in this tissue. Multi-site binding of this radiolabel had been reported in other tissues and guanosine triphosphate (GTP) had been shown to reduce [3H]UK 14,304 binding. We now report that [3H]UK 14,304 labels at least 2 specific binding sites in human brain that both have the characteristics of an alpha 2-adrenergic binding site. GTP decreases agonist binding at both of these sites, but with different potencies at each site.

Adrenergic alpha-Agonists↗
PubMed1988

Guanyl nucleotide interactions with dopaminergic binding sites labeled by [3H]spiroperidol in human caudate and putamen: guanyl nucleotides enhance ascorbate-induced lipid peroxidation and cause an apparent loss of high affinity binding sites.

The human caudate and putamen contain two high affinity binding sites for [3H]spiroperidol. Both of these affinity states exhibit dopaminergic selectivity. Ascorbic acid, at 0.1 mM, induces a slow loss of the low affinity component of [3H]spiroperidol binding in these tissues. The addition of guanyl nucleotides to the ascorbate produces a more rapid loss of [3H]spiroperidol binding which includes a loss of the highest affinity state for [3H]spiroperidol. Ascorbate induces lipid peroxidation in human caudate and putamen, an effect that is further enhanced by guanyl and inosine nucleotides. In the absence of ascorbate, guanyl nucleotides have no effect on [3H]spiroperidol binding but do decrease the affinity of dopamine at each affinity state greater than 60-fold. In the absence of ascorbate, guanyl nucleotides apparently decrease agonist affinity at human brain dopamine2-binding sites without causing an interconversion of agonist affinity states.

Ascorbic Acid↗
PubMed1987

Serum protein leakage in aged human brain and inhibition of ligand binding at alpha 2-adrenergic and cholinergic binding sites.

Serum proteins are known to extravasate into the brain parenchyma in senile and presenile dementia (Glenner: Hum. Pathol. 16:433-435, 1986; Wisniewski and Kozlowski: Ann. NY Acad. Sci. 396:119-129, 1982). We have recently demonstrated that human serum Cohn fraction IV (alpha-globulin enriched) inhibits ligand binding at putative dopamine and serotonin2 receptors labeled by [3H]spiroperidol in human brain (Andorn, Pappolla, Fox, Klemens, and Martello: Proc. Natl. Acad. Sci. USA 83:4572-4575, 1986). We now demonstrate that serum proteins can be identified in the neuropil and in neuronal cell bodies in normal aged brain, that alpha-globulin-enriched fractions inhibit ligand binding at alpha 2-adrenergic and muscarinic binding sites in human brain as well, and that serum proteins can be identified within neuronal cytoplasm and axons.

Adult↗
PubMed1986

Cations decrease specific [3H]-spiroperidol binding in human prefrontal cortex.

Ligand binding at many physiologically relevant receptors is regulated by divalent cations. To determine whether [3H]-spiroperidol binding sites in prefrontal cortex might be physiologically relevant receptors, we examined the effect of ions on the binding of this ligand in postmortem human prefrontal cortex. Our results indicate that several cations decreased [3H]-spiroperidol binding in a dose-dependent fashion. Of these, Cd++ and Zn++ were the most able to decrease [3H]-spiroperidol binding with IC50 of 5.5 +/- 2.4 X 10(-6)M and 5.6 +/- 1.1 X 10(-5)M respectively. These findings indicate that [3H]-spiroperidol may bind at physiologically relevant receptors in human prefrontal cortex.

Butyrophenones↗
PubMed1986

[3H]clonidine binds at multiple high affinity states in human prefrontal cortex.

[3H]Clonidine binds at particulate membrane fractions of human prefrontal cortex in a process that demonstrates high affinity, saturability, reversibility, alpha 2-adrenergic selectivity and the existence of multiple affinity states. At 37 degrees C maximal specific [3H]clonidine binding was briefly attained at 10 and lasted only until 15 min, while at 21 degrees C maximal binding was maintained from 20 to 90 min. At 21 degrees C, rate dissociation studies and saturation analyses were at least biphasic, and adrenergic competitors decreased [3H]clonidine binding with Hill coefficients less than 0.70. Analysis of these data showed at least two affinity states with apparent KDs of 0.34 and 6.0 nM, and the order in which ligands decreased [3H]clonidine binding was clonidine greater than (-)-epinephrine greater than (-)-norepinephrine greater than yohimbine greater than (+)-norepinephrine greater than (+/-)-isoproterenol greater than prazosin greater than serotonin.

Adult↗
PubMed1986

Do antipsychotic drugs and serotonin down regulate [3H]-spiroperidol binding sites in human cortex?

[3H]-Spiroperidol binds at several specific sites in postmortem human prefrontal cortex at 21 degrees C. The overall selectivity of these sites is serotonergic. At 37 degrees C, there is a marked loss of specific [3H]-spiroperidol binding that occurs between 10 and 60 min. This loss of binding is not apparently due to 3H-ligand degeneration or metabolism, or to non-specific binding site degradation. The loss of binding can also be produced by serotonin (5-HT), haloperidol and chlorpromazine but not by prazosin. The rate of the loss of binding is dependent on 3H-ligand concentration and protein concentration. The loss of binding is correlated with a loss of serotonin selective [3H]-spiroperidol binding sites having a KD of approximately 0.04 nM. Therefore antipsychotic compounds and 5-HT appear to down-regulate a subset of antipsychotic binding sites in human prefrontal cortex.

Adolescent↗
PubMed1986

3H-clonidine and 3H-yohimbine binding to glass fiber filters: implications for studies with platelet membranes.

3H-Clonidine and 3H-yohimbine were observed to bind to glass fiber filters. The binding was displaced by co-filtration with the corresponding non-radioactive ligand. Phentolamine and (--)-norepinephrine were ineffective in displacing either 3H-clonidine or 3H-yohimbine bound to filters. Failure to correct for filter binding resulted in an over-estimation of specific binding to platelet membranes. Certain published methodologies may have consequently misidentified up to 20% of the specific binding to platelets, that was actually due to displaced filter binding. Experimental conditions are described which eliminate filter binding. These results are significant for the interpretation of data from studies of platelet binding in depressed patients.

Binding Sites↗
PubMed1986

Neuronal aging.

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Aging↗
PubMed1986

Human serum Cohn fraction IV (alpha-globulin [correction of globin] enriched) inhibits ligand binding at neurotransmitter receptors in human brain.

Human serum proteins are found in significant density in the neuropil in brains of demented individuals. The functional significance of these abnormally distributed proteins has been unknown. We now report that alpha-globulin-enriched fractions of human serum decrease the specific binding of [3H]spiroperidol at its binding sites in postmortem human frontal cortex and caudate. The substances in this serum fraction apparently exert their effect by a direct action on the binding site. Since [3H]spiroperidol labels serotoninergic and dopaminergic among other neurotransmitter receptors, these results suggest that components of human serum inhibit the binding of ligands at neurotransmitter receptors.

Animals↗
PubMed1984

Guanyl nucleotides decrease antagonist binding at high affinity dopamine receptors.

Guanyl nucleotides induce a loss of high affinity [3H]spiroperidol binding sites in rat striatum that can be demonstrated by rate association, equilibrium dissociation and saturation analyses. [3H]Spiroperidol is an antagonist ligand for rat striatal dopamine receptors. These data therefore demonstrate clear cut effects of guanyl nucleotides on antagonist binding.

Animals↗
PubMed1984

Specific [3H]-spiroperidol binding sites in human prefrontal cortex: potential site multiplicity and overall serotonin-like selectivity.

[3H]-Spiroperidol specifically binds at sites in human prefrontal cortex. The binding of this ligand is apparently anomalous at 37 degrees C, with a substantial loss of specific binding occurring between 5 and 40 min incubation. However, at 21 degrees C, this loss of binding is not observed even at 60 min. At 21 degrees C, [3H]-spiroperidol binding in human prefrontal cortex is apparently occurring at multiple sites or multiple affinity states of single classes of sites, or at a combination of both. The overall selectivity is predominantly serotonergic, rather than dopaminergic.

Adult↗