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PubMed1985

Carrier-mediated choline uptake by Krebs II ascites cells.

Krebs II ascites cells have a low affinity uptake system for choline (Km = 36 microM, Vm = 76 nmol/min per 2 X 10(8). Choline entered the cells and was rapidly phosphorylated (95% of total intracellular soluble label). Trans acceleration of labeled choline from cells preloaded with radiolabeled choline and postincubated in the presence of unlabeled choline indicates that choline transport in Krebs II ascites cell is carrier mediated. Ethanolamine competed for the choline carrier. The uptake was reduced by hemicholinium-3, iodoacetamide and ouabain. The mechanism of choline transport in Krebs II ascites cells is in agreement with a linear transport model.

2,4-Dinitrophenol↗
PubMed1991

Erythrocyte choline concentrations in psychiatric disorders.

Erythrocyte choline has been used as a potential indirect measure of cholinergic function in the central nervous system (CNS). We review the literature and present some new data on erythrocyte choline concentrations in patients with neuropsychiatric disorders. Our data and most of the reviewed studies report modest elevations in mean erythrocyte choline values in patients with affective illnesses, psychoses, dementia, and other neuropsychiatric disorders when compared to controls. Within each disorder, the increased mean erythrocyte choline concentrations are due to subgroups of patients with especially high values. These subgroups of patients with elevated erythrocyte choline levels appear to have clinical characteristics that distinguish them from patients with normal choline values. Finally, the dramatic rise in erythrocyte choline concentration produced by lithium therapy is reviewed, and the implication of this effect, in particular, the possibility that pretreatment or posttreatment erythrocyte choline concentrations may predict response to lithium, is discussed.

Adult↗
PubMed1996

Choline in the treatment of rapid-cycling bipolar disorder: clinical and neurochemical findings in lithium-treated patients.

This study examined choline augmentation of lithium for rapid-cycling bipolar disorder. Choline bitartrate was given openly to 6 consecutive lithium-treated outpatients with rapid-cycling bipolar disorder. Five patients also underwent brain proton magnetic resonance spectroscopy. Five of 6 rapid-cycling patients had a substantial reduction in manic symptoms, and 4 patients had a marked reduction in all mood symptoms during choline therapy. The patients who responded to choline all exhibited a substantial rise in the basal ganglia concentration of choline-containing compounds. Choline was well tolerated in all cases. Choline, in the presence of lithium, was a safe and effective treatment for 4 of 6 rapid-cycling patients in our series. A hypothesis is suggested to explain both lithium refractoriness in patients with bipolar disorder and the action of choline in mania, which involves the interaction between phosphatidylinositol and phosphatidylcholine second-messenger systems.

Adult↗
PubMed1986

Agonist and blocking effects of choline at the neuromuscular junction.

The effects of choline chloride were studied at the voltage-clamped frog neuromuscular junction by measuring miniature endplate currents and equilibrium dose response curves for acetylcholine applied by microionophoresis. Choline reduced the amplitude and shortened the time constant of miniature endplate currents in a dose dependent manner. Dose response curves carried out in the presence of low doses of choline (200 microM) were shifted to the right and the apparent dissociation constant for ACh was increased without affecting the Hill coefficient or the maximum conductance at the endplate. Higher doses of choline shifted the curve even further to the right but reduced the Hill coefficient and maximum conductance. Choline ionophoretic dose response curves were carried out but the conductance response was only about 1% of the response to comparable concentrations of ACh. In the presence of ethanol, which reduces the agonist dissociation constant, choline responses were increased and the dose response curve analysis revealed that the efficacy of choline was about 17% in comparison to ACh. Similar effects were measured at rat endplates. Rat nerve-muscle preparations were used to investigate the effects of choline upon neuromuscular transmission.

Acetylcholine↗
PubMed1985

Diisopropylfluorophosphate inhibits choline efflux from the perfused rat hemidiaphragm.

Acetylcholine (ACh) synthesis by motor nerve terminals requires an adequate supply of its precursor, choline. The results reported here show that diisopropylfluorophosphate (DFP), an acetylcholinesterase inhibitor commonly used in ACh release studies, reduces the rate of endogenous choline efflux from the perfused rat hemidiaphragm. Perfusion of the isolated hemidiaphragm with 10 microM or 100 microM DFP reduced choline efflux by 39% and 69% respectively. DFP administration to rats (6 mg/kg) also lowered the in vitro release of choline by 33%. The rate of ACh release from hemidiaphragm preparations perfused with DFP was significantly lower than the rate of release from preparations perfused with physostigmine, an acetylcholinesterase inhibitor which had no effect on choline efflux. The addition of choline (10-30 micron) to the perfusion medium restored the rate of ACh release from DFP-treated hemidiaphragms but did not further elevated ACh release from physostigmine-treated preparations. These results demonstrate that DFP inhibits choline efflux from the isolated hemidiaphragm and further suggest that, by limiting the availability of choline for ACh synthesis, DFP reduces the rate of ACh release.

Acetylcholine↗
PubMed1985

Interaction of choline and scopolamine in human memory.

In a previous study (1), 8 gm. of oral choline given in a single dose were found to partially reverse the amnestic and subjective effects of 0.43 mg of scopolamine. The present study determined whether similar effects could be produced by 14 gm of choline given in 4 divided doses over 24 hrs and whether choline's effects in either study were related to plasma choline concentration. Ten normal subjects were given memory tests on three separate days, once after receiving 14 gm choline and 0.35 mg scopolamine (Ch-Sc), once following placebo and scopolamine (Pl-Sc), and once following placebo and placebo (Pl-Pl). Scopolamine markedly impaired memory performance but there was no difference between the Ch-Sc and Pl-Sc conditions. Plasma choline levels were significantly elevated in the Ch-Sc condition of both the single dose and divided dose studies. There was no difference in levels between studies nor were differences in memory performance correlated with elevations in plasma choline. These results indicate that any enhancement of cholinergic activity due to increased dietary choline is transient and of small magnitude.

Acetylcholine↗
PubMed1983

The effects of an in vivo administration of phencyclidine on sodium-dependent high affinity choline uptake in rat hippocampus and striatum in vitro.

The effect of phencyclidine and other drugs on sodium-dependent high-affinity uptake of choline in the rat hippocampus and/or striatum was investigated and related to the behavioral changes induced by these agents. In contrast to atropine (40.0 mg/kg), which increased the uptake of choline in synaptosomes from both the rat hippocampus and striatum, the administration of phencyclidine (54.4 mg/kg), 30 min prior to sacrifice, caused a significant decrease in the uptake of choline in synaptosomes from rat striatum (but not hippocampus). This effect of phencyclidine could be seen up to 1 hr after administration of drug, but by 3.5 hr the uptake of choline was essentially back to normal. The inhibition of striatal uptake of choline occurred at a time when brain levels of phencyclidine and its metabolites were at their highest, and the animals were essentially immobile; it did not appear to correlate with behavioral changes (including stereotypy and catalepsy) seen at later times after this dose of phencyclidine (54.4 mg/kg), or at earlier times after smaller doses. Amphetamine (6.0 mg/kg) also decreased the uptake of choline in the striatum. Haloperidol (2.0 and 3.0 mg/kg) blocked both the phencyclidine and amphetamine-induced inhibition of the uptake of choline but only the behavioral effects of amphetamine. The data suggest that phencyclidine may be exerting an indirect effect on the uptake of choline in the striatum via its interaction with the dopaminergic system. However, this neurochemical effect of phencyclidine could not be related in any simple way to the immobility, stereotypy or catalepsy caused by this drug.

Amphetamine↗
PubMed1985

Chronic dietary choline modulates synaptic plasticity in the cerebellar glomeruli of aging mice.

A morphometric investigation was carried out on ethanolic phosphotungstic acid (E-PTA) stained synaptic junctions in the cerebellar glomeruli of adult, old, old choline-deficient and old choline-supplemented mice. Numerical (Nv) and surface (Sv) density as well as average length (L) of the synapses were calculated on 100 pictures per group. A significant reduction of Nv and Sv, as well as an increase of L was found during aging. Choline deficient animals did not show any change as compared to old animals of the same age. In choline supplemented mice Nv and Sv were significantly increased and L significantly decreased, respectively, as compared to old control littermates. No difference was found between adult and choline supplemented mice. In the cerebellar glomeruli only a small fraction of fibers are cholinergic, therefore the present findings support the idea that dietary choline can influence systems other than cholinergic. The possible role of choline supplementation in the modulation of synaptic plasticity via the synthesis and/or turnover of neuronal membrane choline phospholipids, is discussed.

Animals↗
PubMed1985

Uptake and incorporation of choline by Schistosoma mansoni adults.

Choline uptake and incorporation into Schistosoma mansoni is used as a model for investigating transport across and formation of a double bilayer surface of a syncytial transporting epithelium. Choline uptake reached a maximal rate during the first 2 min (Vmax = 0.27 mumol mg-1 protein min-1; Km = 36 microM). Choline uptake during a 30 min incubation was similar to that of single bilayer transport systems described in the literature. Choline incorporation into phosphatidylcholine was saturated above 40 microM external choline concentration (Vmax = 3.7 pmol mg-1 protein min-1; Km = 7 microM). The low rate of choline efflux and the half life of the tissue choline pool (T 1/2 = 3 h), suggests that free choline pools available for efflux in S. mansoni are small. This model allows the determination of whether a proposed effector of membrane phosphatidylcholine synthesis and turnover alters surface bilayer formation through changes in transport of the precursor across the apical surface.

Animals↗
PubMed1992

Actions of ginsenoside Rb1 on choline uptake in central cholinergic nerve endings.

The ginsenoside Rb1 has previously been reported to improve memory deficits induced by anticholinergic drug treatment, and to facilitate acetylcholine (Ach) release from rat brain hippocampal slices. The increase in ACh release was not associated with an increase in calcium uptake into nerve terminals, but was associated with an increase in uptake of the precursor choline. In the present studies, analysis of choline uptake kinetics indicated that Rb1 increased the maximum velocity of choline uptake, while the affinity of the choline uptake carrier for choline (Km) was not significantly altered. Acute treatment with Rb1 did not alter the number of [3H]hemicholinium-3 (HC-3) binding sites in any of three cholinergic brain regions examined, suggesting that the increase in the maximum velocity of choline uptake was not associated with an increase in the number of choline carriers. However, chronic (3 day) administration of Rb1 did increase the number of choline uptake sites in the hippocampus, and to a lesser extent in the cortex.

Acetylcholine↗
PubMed1992

Organization of central cholinergic neurons revealed by combined in situ hybridization histochemistry and choline-O-acetyltransferase immunocytochemistry.

Digoxigenin-labeled riboprobes and in situ hybridization of choline-O-acetyltransferase mRNA, both alone and in combination with immunohistochemical procedures for the synthetic enzyme of acetylcholine, were used to map the topography of putative cholinergic neurons in the rat central nervous system. Only the anti-sense riboprobe yielded specific labeling, which was absent in brain sections processed with sense riboprobe. Telencephalic neurons demonstrating the mRNA for choline-O-acetyltransferase and choline-O-acetyltransferase-like immunoreactivity were found in the caudate-putamen nucleus, nucleus accumbens, olfactory tubercule, Islands of Calleja complex, medial septal nucleus, vertical and horizontal limbs of the diagonal band, substantia innominata, nucleus basalis, and nucleus of the ansa lenticularis, as well as occasionally in the amygdala. Neurons in the cerebral cortex, hippocampus, and primary olfactory structures did not demonstrate hybridization signal, even though some cells in those areas were observed to exhibit choline-O-acetyltransferase-like immunopositivity. Thalamic cells were devoid of hybrido- and immunoreactivity, with the exception of several neurons located primarily in the ventral two-thirds of the medial habenula. A few cell bodies labeled with riboprobe and co-localizing choline-O-acetyltransferase-like immunopositivity were found in the lateral hypothalamus, caudal extension of the internal capsule, and zona incerta. Neurons in the pedunculopontine and laterodorsal tegmental nuclei evinced moderate hybridization signal, whereas cells of the parabigeminal nucleus were very weakly reactive. In contrast, motor neurons of the cranial nerve nuclei demonstrated high levels of choline-O-acetyltransferase mRNA and choline-O-acetyltransferase-like immunoreactivity. Putative cholinergic somata in the ventral horns and intermediolateral cell columns of the spinal cord and around the central canal were also labeled with riboprobe. It is concluded that hybridocytochemistry with digoxigenin-labeled riboprobes confirms the existence of cholinergic neurons in most of the neural regions believed to contain them on the basis of acetylcholinesterase pharmacohistochemistry and choline-O-acetyltransferase immunocytochemistry, with the prominent exceptions of the cerebral cortex, hippocampus, olfactory bulb, anterior olfactory nucleus, and caudal raphe nuclei, which apparently do not possess neurons expressing detectable levels of the mRNA for the synthetic enzyme of acetylcholine.

Animals↗
PubMedDate not supplied

Inhibition of cytosolic human forebrain choline acetyltransferase activity by phospho-L-serine: a phosphomonoester that accumulates during early stages of Alzheimer's disease.

There is no satisfactory explanation for the cholinergic deficit characteristic of Alzheimer's disease. We have performed a series of experiments which demonstrate that (a) an inhibitor of cytosolic human brain choline acetyltransferase is present in the cytosol of Alzheimer brain tissue, (b) human brain cytosolic choline acetyltransferase activity is inhibited by phospho-L-serine in a competitive manner. Cytosol was prepared from human forebrain or amygdala and the Km for choline and acetyl CoA of the choline acetyltransferase were 750 microM and 12.5 microM, respectively. Phospho-L-serine was found to be a competitive inhibitor of this enzyme with respect to choline but not with respect to acetyl CoA with a Ki of 750 microM for the human forebrain and 3 mM for human amygdala. These concentrations of phospho-L-serine are present in brain tissue at early stages of Alzheimer's disease. Several other phosphomonoesters and phosphodiesters that are increased in Alzheimer's disease were either less inhibitory or without effect. The addition of heat denatured and non-heat denatured cytosol from Alzheimers forebrain inhibited the choline acetyltransferase activity present in control human brain cytosol. The inhibitory activity of the Alzheimers cytosol was retained in TCA deproteinized samples and removed by dialysis or by alkaline phosphatase treatment. Dialysis of the cytosol increased the choline acetyltransferase activity of 5 of 8 Alzheimer's disease samples from 21 to 118% with p values of < 0.025 or < 0.001, respectively. These observations provide evidence that an endogenous non-proteinaceous, dialyzable, phosphomonoester, present in Alzheimers brain inhibits the choline acetyltransferase of both control and Alzheimers brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1987

RBC-choline: a biological marker of the outcome of lithium prophylaxis?

We explored whether the elevation of RBC-choline and choline ratio (RBC-choline/plasma-choline) by lithium is a specific effect of lithium, whether these choline parameters are characteristics of the individual patient, and whether they are related to prophylactic lithium response. In lithium-treated patients RBC-choline and choline ratio were highly elevated compared with untreated controls. In contrast, both values were slightly decreased in patients on antidepressants, and essentially unchanged in patients on neuroleptics. Repeated measurements showed that choline parameters were fairly stable in the individual patient. The interindividual variance was significantly greater than the intraindividual variance. In 58 affective disorder patients with established lithium response, high choline ratios were found to be associated with a poor outcome of stabilizing therapy with lithium. This finding was replicated in a new sample of 15 bipolar patients. If confirmed, it could be an important clue as to the mode of action of lithium.

Alcoholism↗
PubMed1986

Enhancement of choline uptake by glycine in hamster heart.

Choline uptake by the isolated hamster heart has been shown to be inhibited by exogenous ethanolamine. In this study, the effect of glycine on choline uptake was investigated. At 0.01-1.0 mM glycine in the perfusate, an enhancement of choline uptake (30%) by the isolated heart was observed. Despite the higher choline uptake, the presence of glycine did not affect the rate of phosphatidylcholine biosynthesis. At higher glycine concentration (50 mM), the enhancement of choline uptake was abolished. Exogenous choline had no effect on the uptake of glycine. We postulate that choline and glycine are transported by separate mechanisms, and that glycine may play a regulatory role in the control of choline uptake by the hamster heart.

Animals↗
PubMed1982

Regional decreases of cortical choline acetyltransferase after lesions of the septal area and in the area of nucleus basalis magnocellularis.

Choline acetyltransferase and [3H]choline uptake have been measured in neocortical regions and hippocampus one week after lesions which destroyed the septum bilaterally, and after unilateral lesions in the area of nucleus basalis magnocellularis. Lesions of the septal area, which severely decreased choline acetyltransferase in hippocampus, only moderately decreased choline acetyltransferase in a posterior cortical region and had no effect in frontal and parietal regions. In contrast, lesions which included nucleus basalis magnocellularis decreased choline acetyltransferase markedly in frontal and parietal regions and had less of an effect in the posterior cortical regions. Lesion-induced decreases of [3H]choline uptake paralleled those of choline acetyltransferase. Lesion which included nucleus basalis magnocellularis had no effect on choline acetyltransferase in hippocampus, nucleus accumbens, olfactory tubercle, midbrain or pons-medulla. These results suggest that existence of topographically distinct cholinergic inputs to neocortex. In agreement with previous studies, cholinergic projections from the peripallidal region of nucleus basalis magnocellularis are predominantly to frontal and parietal neocortex. In contrast to previous suggestions, cholinergic projections to neocortex from the septal area are limited to the posterior regions of neocortex.

Animals↗
PubMed1983

Immunohistochemical localization of choline acetyltransferase using a monoclonal antibody: a radioautographic method.

Monoclonal antibodies to rat striatal choline acetyltransferase were produced by fusion of sensitized mouse lymphocytes with murine plasmacytoma (NS1) cells. Two stable anti-choline acetyltransferase lines were established by limiting dilution cloning. Specificity of antibody was established by the following criteria: (1) on an enzyme linked immunosorbant assay, antibodies reacted against choline acetyltransferase which was highly purified; (2) by immunoprecipitation, monoclonal antibody bound to its antigen and precipitated choline acetyltransferase activity from solution, when used in conjunction with rabbit antimouse IgG; and (3) monoclonal antibody was shown to specifically localize cholinergic neurons. The monoclonal antibody to choline acetyltransferase was radiolabeled in culture by incubating hybridomas in medium containing 3H-labeled amino acids. This 3H-labeled antibody was used for radioautography on cryostat sections of rat peripheral and central nervous systems. In a sampling of areas, highly specific labeling of cholinergic structures was afforded at both light and electron microscopic levels. Double labeling of tyrosine hydroxylase, a catecholaminergic marker, and choline acetyltransferase was carried out by reacting sections first with the 3H-labeled antibody to choline acetyltransferase and then with rabbit antibody to tyrosine hydroxylase. The choline acetyltransferase label was radioautographically processed and tyrosine hydroxylase was visualized by the peroxidase-antiperoxidase method. The combined techniques of peroxidase and radioautographic histochemistry provide permanent electron dense labels which can be examined simultaneously within a single histologic section.

Animals↗
PubMed1996

Changes in choline acetyltransferase activity and distribution following incomplete cervical spinal cord injury in the rat.

Incomplete cervical spinal cord injuries were produced in rats by placing 10 g or 20 g weight on exposed dura at the C6 level for 5 min (Mild or Moderate injury). These two degrees of the injury resulted in initial motor functional deficits, followed by recoveries. In this study, changes in choline acetyltransferase activity and distribution following the incomplete cervical cord injuries were investigated using radioenzyme assay, and fluorescence microphotometry. We demonstrated that mild injury led to a transient decrease of choline acetyltransferase activity in the compressed spinal cord segment, but showed almost no histologic change at two days after injury. Although a low level of choline acetyltransferase immunofluorescence was found in the ventrolateral anterior horn at two days after injury, it recovered completely by one week after injury. These findings suggest that there was a strong correlation between the transient motor functional deficit and the decrease in choline acetyltransferase activity following mild injury. Moderate injury resulted in persistent low level of choline acetyltransferase activity in the compressed spinal cord segment accompanied by a striking loss of gray matter. On the other hand, at seven, 14 and 28 days after injury, over-expression of choline acetyltransferase activity was found in the neighboring spinal cord segments located both rostral and caudal to the injury, which showed no histologic change. In addition, excessively high levels of choline acetyltransferase immunofluorescence were found in the ventrolateral anterior horn of these segments. A strong correlation was found between the motor functional recovery and the late, excessive high levels of choline acetyltransferase activity in the neighboring regions. These results suggest that cholinergic neurons, especially spinal motor neurons may play an important role in the motor functional recovery following incomplete cervical spinal cord injury.

Animals↗
PubMed2004

[11C]Choline as a PET biomarker for assessment of prostate cancer tumor models.

[(11)C]Choline has been evaluated as a positron emission tomography (PET) biomarker for assessment of established human prostate cancer tumor models. [(11)C]Choline was prepared by the reaction of [(11)C]methyl triflate with 2-dimethylaminoethanol (DMAE) and isolated and purified by solid-phase extraction (SPE) method in 60-85% yield based on [(11)C]CO(2), 15-20 min overall synthesis time from end of bombardment (EOB), 95-99% radiochemical purity and specific activity >0.8 Ci/micromol at end of synthesis (EOS). The biodistribution of [(11)C]choline was determined at 30 min post iv injection in prostate cancer tumor models C4-2, PC-3, CWR22rv, and LNCaP tumor-bearing athymic mice. The results showed the accumulation of [(11)C]choline in these tumors was 1.0% dose/g in C4-2 mouse, 0.4% dose/g in PC-3 mice, 3.2% dose/g in CWR22rv mice, and 1.4% dose/g in LNCaP mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 2.3 (T/M, C4-2), 1.4 (T/M, PC-3), 2.5 (T/M, CWR22rv), 1.2 (T/M, LNCaP) and 2.6 (T/B, C4-2), 2.6 (T/B, PC-3), 7.8 (T/B, CWR22rv), 3.2 (T/B, LNCaP), respectively. The micro-PET imaging of [(11)C]choline in prostate cancer tumor models was acquired from a C4-2, PC-3, CWR22rv, or LNCaP implanted mouse at 30 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, IndyPET-II scanner, developed in our laboratory, which showed the accumulation of [(11)C]choline in C4-2, PC-3, CWR22rv, or LNCaP tumor implanted in a nude athymic mouse. The initial dynamic micro-PET imaging data indicated the average T/M ratios were approximately 3.0 (C4-2), 2.1 (PC-3), 3.5 (CWR22rv), and 3.3 (LNCaP), respectively, which showed the tumor accumulation of [(11)C]choline in all four tumor models is high. These results suggest that there are significant differences in [(11)C]choline accumulation between these different tumor types, and these differences might offer some useful measure of tumor biological process.

Animals↗