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PubMed1994

Uptake of choline into syncytial microvillus membrane vesicles of human term placenta.

The uptake of the quaternary ammonium compound choline was studied in syncytial microvillus membrane vesicles of human term placenta. Uptake was stimulated by an inside negative membrane potential and by loading the vesicles with unlabeled choline. Imposition of an inwardly directed Na+ or outwardly directed H+ gradient did not stimulate choline uptake. Several organic cations were able to inhibit choline transport in the following order: hemicholinium-3 > or = choline > or = mepiperphenidol > cimetidine > or = famotidine. The kinetics of uptake involved a saturable process for choline with high affinity (Km = 550 microM). Our results confirm the presence of a carrier mediated transport system in human placental syncytial microvillus membranes. The system appears to be electrogenic, and able to transport choline efficiently from the maternal circulation into the placenta.

Biological Transport↗
PubMed1992

The human brain resonance of choline-containing compounds is similar in patients receiving lithium treatment and controls: an in vivo proton magnetic resonance spectroscopy study.

Lithium specifically and potentially inhibits membrane transport of choline. However, the effect of lithium on human neuronal choline content is unknown. This study was performed to determine if lithium alters the human brain choline concentration in vivo. In vivo proton magnetic resonance spectroscopy was used to compare the relative brain concentration of choline-containing compounds in seven lithium-treated patients and six lithium-free controls. No significant difference was observed in the mean relative choline resonance between the patient and control groups. Lithium treatment did not appear to alter the overall brain content of choline-containing compounds. It remains possible that a component of these compounds, particularly free choline, is elevated during lithium treatment.

Adult↗
PubMed1983

Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer's disease.

Sodium-dependent, hemicholinium-sensitive choline transport was measured in purified synaptosomes prepared from fresh necropsy brain of patients with senile dementia of the Alzheimer type and from control subjects. Choline transport velocity was standardized in terms of the occluded lactate dehydrogenase activity of the various synaptosomal preparations, rather than in terms of the protein content, since this enzyme is more representative of the synaptosome content of the purified homogenates. A regional difference in high-affinity choline transport was observed in purified synaptosomes prepared from brains of mentally normal controls; the velocities of sodium-dependent and hemicholinium-sensitive choline uptake into synaptosomes from hippocampus were about twice as great as that into synaptosomes from frontal cortex, indicating a greater relative density of cholinergic innervation in the hippocampus. Hippocampal and neocortical cholinergic nerve cell endings, prepared as synaptosomes, from brains of patients with Alzheimer's disease, also accumulated choline by a high-affinity mechanism; however, the velocity of uptake into both brain areas was decreased in comparison with controls. Choline transport into synaptosomes from Alzheimer frontal cortex was reduced approximately 50%, while uptake into Alzheimer hippocampal synaptosomes represented only 20% of the control activity. The reduction in synaptosomal high-affinity choline transport in Alzheimer's disease could be indicative of degeneration of cholinergic nerve terminal boutons resulting from cholinergic nerve cell death, or could result from an overall decrease in the number of carrier sites per nerve terminal or in the carrier transport velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1986

Increases in the concentration of brain alpha-bungarotoxin binding sites induced by dietary choline are age-dependent.

We have previously reported that a diet supplemented with choline induces an increase in the concentration of a brain nicotinic-like receptor, as measured by alpha-bungarotoxin (BuTX) binding. Here we report the effects of choline administered in the drinking water on BuTX binding in the cortex, midbrain and brainstem of rats at 3 ages. In comparison with animals fed a choline-free diet, choline supplementation produced increases averaging 50% in 23-day-old rats and increases of approximately 30% in 60-day-old rats. Increases were also found in 6-month-old animals (averaging 16%), but the differences were generally not statistically significant. The mechanism responsible for the increase in the concentration of BuTX binding sites following the administration of dietary choline is not known, but the results are discussed in terms of choline as a precursor for the biosynthesis of acetylcholine and the biosynthesis of phospholipids. These data indicate that the administration of dietary choline is not likely to be effective in reversing cholinergic deficits by increasing the concentration of nicotinic-like receptors in aging rats.

Animals↗
PubMed1987

Neurotransmitters of the cerebellar glomeruli: uptake and release of labeled gamma-aminobutyric acid, glycine, serotonin and choline in a purified glomerulus fraction and in granular layer slices.

We have studied some properties of the uptake and release of labeled gamma-aminobutyric acid (GABA), glycine, serotonin and choline in a purified fraction of glomeruli and in slices of the granular layer of the rat cerebellum. The uptake of both GABA and glycine into the glomerulus particles was dependent on the presence of Na+ in the medium. In contrast, the uptake of both serotonin and choline was Na+-independent. In slices of the granular layer also a slight Na+-dependence was observed for both serotonin and choline uptake; imipramine and hemicholinium partially inhibited the uptake of serotonin and choline, respectively. Choline uptake into the glomerulus particles showed two components, with apparent Km values of 16.8 and 102 microM. GABA release was stimulated by K+-depolarization about 100% (peak stimulation) and this value was reduced to 50% when Ca2+ was omitted. The release of glycine was stimulated more rapidly and notably than GABA (200%) and this stimulation was completely abolished in the absence of Ca2+. Serotonin release from the glomerulus particles was only slightly stimulated by depolarization, but this stimulation was strictly Ca2+-dependent. In slices of the granular layer, this stimulation was considerably larger (about 40%) and it was also almost totally dependent on Ca2+. In contrast, after loading with labeled choline the release of radioactivity from both the glomerulus particles and the cerebellar slices was not stimulated at all by K+-depolarization, either in the presence or in the absence of Ca2+. Most of the radioactivity released spontaneously corresponded to choline, and only a small proportion (8-14%) to acetylcholine. From the results of the release experiments and taking into account the pertinent data from the literature, it is concluded that GABA and glycine are probably the transmitters of different populations of Golgi axon terminals, whereas serotonin might be the transmitter of at least a certain population of the mossy fiber giant terminals, in the rat cerebellar glomeruli. In contrast, acetylcholine does not seem to have any transmitter role in the synaptic structures of the glomeruli.

Animals↗
PubMed1988

Methylpiperidine analog of hemicholinium-3: a selective, high affinity non-competitive inhibitor of sodium dependent choline uptake system.

The potency of hemicholinium-3 (HC-3) and its analogs to inhibit sodium dependent high affinity choline uptake were evaluated in rat striatal synaptosomal preparation. Hemicholinium-3 inhibited sodium dependent high affinity choline uptake (IC50 = 18 nM) while the half molecule of HC-3, HC-15, was inactive. The order of potency for choline uptake inhibition of piperidine substituted HC-3 molecule was as follows: 4-methylpiperidine (A-5 and CA-5) much greater than HC-3 much greater than unsubstituted piperidines (CA-1 and A-1) much greater than 2- or 3-methylpiperidine (A-2 and A-3) and 4-hydroxypiperidine (A-7). The tertiary amine derivative of 4-methylpiperidine substituted HC-3 (A-4) was nearly 10-fold less potent than its corresponding quaternary derivative (A-5). Choline uptake was inhibited competitively by HC-3 and non-competitively by A-5. The inhibition of choline uptake by A-5 was readily reversible by washing. A-5 did not inhibit the uptake of dopamine and gamma-aminobutyric acid. These findings suggest that the N-methyl,4-methylpiperidine analog of HC-3 (A-5) is the most potent of all known inhibitors of sodium dependent high affinity choline uptake and that the inhibition of choline uptake by this compound is mediated through a mechanism distinct from a simple competitive one.

Animals↗
PubMed1995

3,4-Diaminopyridine and choline increase in vivo acetylcholine release in rat striatum.

We investigated the effects of choline, 3,4-diaminopyridine and their combination on acetylcholine release from the corpus striatum of freely moving rats which were treated or not with atropine. Intraperitoneal administration of choline or intrastriatal administration of 3,4-diaminopyridine increased acetylcholine levels in striatal dialysates in a dose-dependent manner. When 3,4-diaminopyridine treatment was combined with choline, the observed effect was considerably greater than the sum of the increases produced by choline or 3,4-diaminopyridine alone. Administration of atropine (1 microM) in the dialysing medium was also found to be effective to stimulate striatal acetylcholine levels. 3,4-Diaminopyridine did not affect acetylcholine levels under these conditions. Whereas the choline-induced increase in acetylcholine release was significantly potentiated by atropine, co-administration of 3,4-diaminopyridine with choline failed to produce a further significant increase in the presence of atropine. These results suggest that a highly effective means for increasing acetylcholine release involves two concurrent treatments that increase neuronal choline levels and inhibition of the negative feedback modulation of acetylcholine release.

4-Aminopyridine↗
PubMedDate not supplied

Recovery of erythrocyte Li+/Na+ countertransport and choline transport from lithium therapy.

Li+/Na+ countertransport, choline transport, and intracellular Li+ and choline were measured in the RBC of a manic-depressive subject as a function of time after termination of Li+ therapy. Countertransport recovered from its inhibition by Li+ in 10 days. This recovery involved a decrease in the Michaelis-Menten parameter Km, without change in Vmax. RBC choline decreased, and choline influx rose, much more slowly back towards pre-Li+ values over the course of two months. Thus, choline transport was still inhibited long after Li+ levels in RBC and plasma had become undetectable. Measurements on age-separated RBC fractions showed that recovery of choline transport was mainly in the young-cell fraction. Hence inhibition of choline transport by Li+ may be irreversible at the level of the individual RBC.

Bipolar Disorder↗
PubMed1986

Effects of choline augmentation on acetylcholine synthesis and release in rat atrial minces.

The uptake and acetylation of [3H]-choline, as well as the calcium-dependent release of a newly synthesized [3H]-ACh, was studied in a new rat atrial mince preparation. The hemicholinium-3-sensitive uptake and acetylation of [3H]-choline increased as [3H]-choline concentrations were elevated to 100 microM in atrial minces. In contrast, hemicholinium-3-sensitive [3H]-choline uptake was saturated with 15 microM [3H]-choline in brain synaptosomes. The increased atrial [3H]-ACh synthesized in the presence of [3H]-choline augmentation was releasable by 50 mM K+-depolarization in a 1 mM cobalt-sensitive manner. These results suggest that atrial parasympathetic activity may be more sensitive to circulating choline concentrations than brain cholinergic neurons are.

Acetylation↗
PubMed1992

Caffeine potentiates the enhancement by choline of striatal acetylcholine release.

We investigated the effect of peripherally administered caffeine (50 mg/kg), choline (30, 60, or 120 mg/kg) or combinations of both drugs on the spontaneous release of acetylcholine (ACh) from the corpus striatum of anesthetized rats using in vivo microdialysis. Caffeine alone or choline in the 30 or 60 mg/kg dose failed to increase ACh in microdialysis samples; the 120 mg/kg choline dose significantly enhanced ACh during the 80 min following drug administration. Coadministration of caffeine with choline significantly increased ACh release after each of the choline doses tested. Peak microdialysate levels with the 120 mg/kg dose were increased 112% when caffeine was additionally administered, as compared with 54% without caffeine. These results indicate that choline administration can enhance spontaneous ACh release from neurons, and that caffeine, a drug known to block adenosine receptors on these neurons, can amplify the choline effect.

Acetylcholine↗
PubMed1996

Elevation of cerebrospinal fluid choline levels by nicotinamide involves the enzymatic formation of N1-methylnicotinamide in brain tissue.

Nicotinamide administration can elevate plasma and brain choline levels and produce a marginal increase in striatal acetylcholine levels in the rat. We now report that subcutaneous nicotinamide produces a substantial and long-lasting rise in cisternal cerebrospinal fluid (CSF) levels of choline in free-moving rats, possibly through the enzymatic formation of N1-methylnicotinamide (NMN) in brain. CSF choline levels peaked 2 hours after nicotinamide administration and were accompanied by increases in striatal, cortical, hippocampal and plasma choline levels. The enzymatic formation of [3H]NMN in rat brain was evaluated by incubating aliquots of rat brain cytosol with unlabelled nicotinamide and the methyl donor [3H]S-adenosylmethionine. High performance liquid chromatography and radiochemical detection demonstrated that [3H]NMN was specifically formed by a brain cytosolic enzyme. The production of [3H]NMN was dependent on exogenous nicotinamide and could be prevented by denaturing the cytosol. The metabolism of nicotinamide to NMN in rat brain may explain the rise in CSF choline levels since NMN, a quaternary amine, can inhibit choline transport at the choroid villus and reduce choline clearance.

Acetylcholine↗
PubMed1983

Increased uptake of [3H]choline by rat superior cervical ganglion: an effect of dexamethasone.

The high affinity uptake of [3H]choline by the superior cervical ganglion, isolated from the rat, was found to be increased by dexamethasone. Maximal increase (60-65% above control values) occurred at the steroid concentration of 5 X 10(-5) M. Other glucocorticoids (triamcinolone, corticosterone and hydrocortisone) were without an effect on the [3H]choline uptake. Following administration of dexamethasone (25 mg/kg, i.p.), there was a marked increase in the level of choline in the ganglion. The increase was 3-fold at 1 hr and 10-fold at 6 hr, and by 24 hr the choline levels still remained higher in the steroid-treated animals than in the controls. Levels of acetylcholine in the ganglion were also increased, beginning at 1 hr after the injection of steroid. The increase was 85% by 3 hr and 60% by 6 hr. Triamcinolone, a glucocorticoid that was without an effect on [3H]choline uptake in vitro, was also ineffective in altering the levels of choline and acetylcholine in vivo. It seems probable that the increase of choline uptake in the ganglion induced by dexamethasone may, at least in part, occur in the preganglionic cholinergic terminals, leading to increased synthesis of acetylcholine. Such an effect of dexamethasone provides another case of a selective steroid acting directly on nerve terminals by altering a transport mechanism.

Acetylcholine↗
PubMed1985

A sensitive and specific radioenzymatic assay for the simultaneous determination of choline and phosphatidylcholine.

A radioenzymatic procedure for the simultaneous measurement of picomol quantities of phosphatidylcholine and choline is described. Phospholipase-D from Streptomyces chromofuscus hydrolyzes phosphatidylcholine to choline and phosphatidic acid. Choline kinase in the presence of [32P]ATP phosphorylates the choline to form [32P]phosphorylcholine. The phosphorylcholine, isolated by ion exchange chromatography, is measured by scintillation spectroscopy. Using a chloroform: methanol separation, phosphatidylcholine and choline can be measured from the same sample. Different sources of phospholipase-D were compared for their ability to hydrolyze phosphatidylcholine to choline and phosphatidic acid. Phospholipase-D from Streptomyces chromofuscus was found to result in almost complete hydrolysis. As a measure of specificity, lysophosphatidylcholine and sphingomyelin were assayed using this method and were found to result in, at most, only 2% of the amount of phosphorylcholine produced compared to phosphatidylcholine. This procedure allows for the simultaneous measurement of choline and phosphatidylcholine in brain and serum samples with a very high degree of sensitivity and specificity.

Animals↗
PubMed1986

Developmental changes in choline uptake and acetylcholine metabolism in the larval brain of the tobacco hornworm, Manduca sexta.

The larval brain of the tobacco hornworm, Manduca sexta, was maintained in vitro and the uptake of labelled and unlabelled choline as well as their subsequent metabolism were measured by high-voltage paper electrophoresis. Significant levels of choline lipid metabolites, phosphorylcholine and acetylcholine (ACh) were noted. Unbound choline reached equilibrium after 6-8 h of incubation, while ACh accumulation continued to increase after 24 h indicating that the rate of synthesis exceeded the rate of breakdown. An apparent Km could not be determined for these whole-organ studies; however, the Vmax for ACh accumulation for days 5 (70 pmol/brain/h) and 6 (105 pmol/brain/h) of the last larval instar did vary significantly while the level of unbound choline in the brain did not change. The level of choline uptake was dependent upon the presence of Na+ and Ca2+, while the amount of ACh accumulated was affected specifically by the presence of Mg2+, the latter ion activating acetylcholinesterase. The determination of levels of unbound choline and ACh accumulation in the developing brain during the last two larval instars demonstrated increases in acetylcholine accumulation at previously reported times of the release of the hormone that initiates the molting process, prothoracicotropic hormone. These changes in the patterns of ACh accumulation occur during 4-8 h time intervals; this is the first report of such short-range changes in neurotransmitter metabolism in whole brains. The intensity of the ACh accumulation shift is equivalent to the intensity of the hormone burst. Other fluctuations in the levels of ACh accumulation and free choline correlate with the development of the brain.

Acetylcholine↗
PubMed1987

High-affinity uptake of choline, a marker for cholinergic nerve terminals, is not specific in developing rat brain.

Developmental changes in the synthesis of acetylcholine (ACh) were investigated in rat hippocampus and frontal cortex. Particular reference was made to the conversion, into ACh, of the choline accumulated by high-affinity uptake as defined using 1 microM hemicholinium-3 (HC-3). Using solutions containing 11.1 mM glucose, conversions were respectively 31 and 55%, in fine slices from 4-8-day-olds. Free choline accounted very largely for the remainder of the choline accumulated. In samples from adults, ACh accounted for 80% of the uptake. The inefficient conversions (into ACh) in immature brain were not the result of a requirement for ketone bodies as the source of acetyl-coenzyme A (acetyl-CoA). Greater rates of release of newly synthesised ACh, than in mature samples, were not responsible, neither were greater cholinesterase activities. The stimulation of high-affinity choline uptake, caused by prior depolarisation of the tissues using K+, also increased during development from 78 to 238% with hippocampus and from 49 to 170% with frontal cortex. Furthermore, prior depolarisation increased the efficiency with which choline, accumulated by high-affinity uptake, was converted into ACh. At all stages of development 80% of the additional choline accumulated, after depolarisation, was converted into ACh. It is concluded that the specificity of HC-3-sensitive uptake is incomplete in immature brain, i.e. high-affinity choline uptake is not exclusively into cholinergic neurones. The cholinergic neuronal compartment becomes more prominent during development so that the specificity is complete in mature brain.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1995

Regulation of hemicholinium-3 sensitive choline uptake in Xenopus laevis oocytes by the second C2 domain of synaptotagmin.

A size-fractionated torpedo electric lobe cDNA library was screened for the neuronal choline transporter by functional expression in oocytes. A clone, TLC2B, was isolated that induced a component of choline uptake that was hemicholinium-3 sensitive and inhibited by the substitution of lithium for sodium at low choline concentrations. However, [3H]choline uptake by both injected and non-injected oocytes were characterized by high affinity constants, suggesting that TLC2B could be affecting a native choline transporter. Indeed, hemicholinium-3 sensitive choline uptake could also be induced by preincubation of non-injected oocytes with a protein kinase C inhibitor, H-7. By sequence analysis and immuno-precipitation, the peptide produced by injection of TLC2B cRNA was identified as a soluble 24 kDa C-terminal fragment of the neuronal protein, synaptotagmin. Full length synaptotagmin was, however, ineffective in the functional test. The peptide encoded by TLC2B corresponds to the second protein kinase C-homologous domain of torpedo synaptotagmin, and like other soluble C2 domain peptides, was capable of calcium-dependent translocation to membranes. Its action on choline uptake in oocytes was, however, abolished by the addition of calcium in the presence of a calcium ionophore. These results suggest that the interaction of certain C2 domains, such as the C-terminal domain of synaptotagmin, with more specific targets may be anulled in the presence of calcium due to its absorption to membrane phospholipids.

Amino Acid Sequence↗
PubMed1983

Co-localization of acetylcholinesterase and choline acetyltransferase in the rat cerebrum.

Acetylcholinesterase-histochemistry has been widely used for localizing cholinergic neurons despite specificity problems. The distribution of cells stained with this method has never been directly compared on a histochemical level with the specific cholinergic marker, choline acetyltransferase. We recently reported the immunohistochemical localization of choline acetyltransferase using monoclonal antibodies [Levey A. I., Armstrong D., Atweh S. F., Terry R. D. & Wainer B. H. (1983) J. Neurosci 3, 1-9]. Here we report the development of a combined histochemical and immunohistochemical method for the co-localization of the 2 cholinergic markers, and their comparison in the rat cerebrum. Although the precise relationship between the markers was complex, the important results were: (1) all neurons which contained choline acetyltransferase also contained some acetylcholinesterase; (2) many acetylcholinesterase-containing neurons did not contain any demonstrable choline acetyltransferase; (3) all neurons which stained intensely for acetylcholinesterase in the neostriatum and basal forebrain also contained choline acetyltransferase; and (4) many choline acetyltransferase-containing neurons did not stain intensely for acetylcholinesterase. The results corroborate the assumption that choline acetyltransferase is a more specific marker for cholinergic neurons than acetylcholinesterase. Intense staining for acetylcholinesterase can be reliably used in some regions of the cerebrum for identifying cholinergic neurons, however, it should be recognized that this criterion s not essential for all cholinergic neurons.

Acetylcholinesterase↗
PubMed1991

Choline acetyltransferase immunoreactivity in the cat cerebellum.

Choline acetyltransferase immunoreactivity was demonstrated in particular projection systems in cat cerebellum by combining immunohistochemistry, retrograde tracing and lesioning paradigms. The monoclonal antibody used in this study recognized a 68,000 mol. wt protein on immunoblots of cat cerebellum and striatum. Choline acetyltransferase immunoreactivity was localized to some neurons and varicose fibers in the cerebellar nuclei, and also to some mossy fibers and endings (rosettes), fiber plexuses around Purkinje cells, granule cells and parallel fibers in the cerebellar cortex. In addition, the presence of choline acetyltransferase-immunoreactive large cells, presumptive Golgi cells, in the granular layer was confirmed. In each cerebellar nucleus, choline acetyltransferase-immunoreactive neurons contained either large, medium-sized or small cell bodies and were distributed evenly in the entire nuclear domain. Large and medium-sized ones were frequently encountered. Choline acetyltransferase-immunoreactive mossy fibers and rosettes were most abundant in the vermal lobules I-III, VIII, IX and the simple lobule, moderately accumulated in the vermal lobules IV-VII, X, crus I and crus II, and less abundant in the paramedian lobule, paraflocculus and flocculus. Some granule cells with prominent dendritic claws and bifurcating parallel axons were immunolabeled in the entire vermis with infrequent occurrence in the remaining cortices. Following unilateral lesioning of the cerebellar nuclei with electrocoagulation or kainate injections, a reduction in number of choline acetyltransferase-immunoreactive fibers occurred ipsilaterally in the cerebellar cortex and contralaterally in the red nucleus, ventrolateral thalamic nucleus and ventroanterior thalamic nucleus. In addition, perikarya of some cerebellothalamic neurons were shown to contain choline acetyltransferase immunoreactivity. The results indicate that some nucleocortical, cerebellorubral and cerebellothalamic projections are cholinergic and that a subpopulation of cholinergic granule cell-parallel fibers exists.

Animals↗