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L Wecker

Publications and source records attributed to L Wecker.

At least 19 recordsLinked to original sources
PubMed1992

Basal forebrain cholinergic neurons in aged rat brain are more susceptible to ibotenate-induced degeneration than neurons in young adult brain.

Choline acetyltransferase (ChAT) activity, acetylcholinesterase (AChE) activity, and [3H]nicotine binding site density were measured in neocortex from unoperated (control) and nucleus basalis (NB)-lesioned young (2-3 months old) and aged (23-24 months old) rats. In control animals, neither enzyme activities nor the density of nicotine binding sites were altered as a function of age. However, age-related differences were apparent 2 weeks following unilateral infusions of ibotenic acid into the right NB. NB lesion-induced decreases in enzyme activities were significantly greater in ipsilateral neocortices from aged rats; ChAT and AChE activities in young animals decreased by 59 and 53%, respectively, while both enzyme activities in aged rats decreased by 72%. NB lesions decreased significantly the density of nicotine binding sites in ipsilateral neocortices from both young and aged rats; binding decreased by 23-26% in young rats and by 31-34% in aged animals. Results indicate that the basal forebrain cholinergic system in the aged rat is more susceptible to ibotenate-induced degeneration than neurons in young animals.

Acetylcholinesterase↗
PubMed1992

Dietary choline supplementation increases the density of nicotine binding sites in rat brain.

The objective of these studies was to determine whether the chronic administration of choline, like the chronic administration of nicotine, increased the density of nicotine binding sites in brain. To accomplish this, rats were maintained on a choline-deficient (0% choline chloride), basal choline (0.2% choline chloride) or choline-supplemented (2.0% choline chloride) diet for 30 days or were fed a standard rodent chow and received injections of saline or nicotine (3.6 mumol/kg s.c.) twice daily for 10 days. Membranes from striatum, hippocampus and frontal cortex were isolated, and the binding of L-(-)-[N-methyl-3H]nicotine (0.5-60 nM) was studied. A single binding site for nicotine was evident for all brain regions from all animals studied with a dissociation constant (Kd) of approximately 2 to 5 nM. Chronic supplementation with choline, which increased circulating choline levels by 92%, did not alter binding affinity, but increased significantly the maximal number (Bmax) of nicotine binding sites in cortical and hippocampal membranes by 20 and 73%, respectively, compared to animals fed the basal choline diet; the Bmax in striatal membranes was unaltered. Nicotine binding parameters for membranes from animals maintained on the choline-deficient diet were not different from those maintained on the basal diet. The chronic administration of nicotine did not alter binding affinity, but increased significantly the maximal density of nicotine binding sites in striatal and cortical preparations by 47 and 18%, respectively; the Bmax in hippocampal membranes was unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Effects of streptozotocin-induced diabetes on acetylcholine metabolism in rat brain.

The main objective of this study was to determine whether uncontrolled hyperglycemia, as a consequence of diabetes, altered the metabolism of acetylcholine (ACh) in rat brain. To accomplish this, rats received injections of streptozotocin (STZ, 60 mg/kg, i.v.) or vehicle, and were maintained for up to 7 weeks after the injections. Various indices of ACh metabolism were determined in striatum and hippocampus, two brain regions densely innervated by cholinergic neurons. STZ induced diabetes in 96% of the rats injected, as evidenced by glucose spillage into the urine within 48 hours. Serum glucose levels increased to 326% of control values by 1 week and remained at this level for the duration of the study. The steady-state concentrations of ACh and choline, determined in brain tissue from animals killed by head-focused microwave irradiation, did not differ between the control and STZ-injected groups. However, the synthesis and release of neurotransmitter by striatal slices, measured in vitro, decreased in a time-dependent manner. Although the basal release of ACh was unaltered at 1 week, neurotransmitter release decreased significantly by 21% at 5 weeks and by 26% at 7 weeks. The release of ACh evoked by incubation with 35 mM KCl was inhibited significantly by 20% at all time points studied. ACh synthesis by slices incubated under basal conditions decreased by 13% and 27% at 5- and 7-weeks, respectively, the latter significantly less than controls. Synthesis by striatal slices incubated with 35 mM KCl was inhibited by 17% at 7 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

The synthesis and release of acetylcholine by depolarized hippocampal slices is increased by increased choline available in vitro prior to stimulation.

The objective of these experiments was to determine whether preincubating hippocampal slices with choline provides precursor that can be used during a subsequent incubation to support or enhance the synthesis of acetylcholine (ACh). Slices were preincubated for 60 min with 0, 10, 25, or 50 microM choline, washed, resuspended, and then incubated for 10 min in choline-free buffer containing 4.74 (Krebs-Ringer bicarbonate, KRB) or 25 mM KCl. The tissue contents of ACh and choline were determined prior to and after the preincubation, as well as after the incubation; the amounts of ACh and choline released were measured, and ACh synthesis was calculated. Preincubation in the absence of choline increased the tissue content of ACh to 242% of original levels; preincubation with 10 microM choline did not lead to a further increase, but preincubation with 25 or 50 microM choline increased the ACh content to 272% of original levels, significantly greater than that of slices preincubated with either 0 or 10 microM choline. When tissues were subsequently incubated for 10 min with either KRB or 25 mM KCl, ACh release from slices preincubated with 50 microM choline was greater than from slices preincubated with 0, 10, or 25 microM choline. Incubation of slices with KRB did not alter the tissue content of ACh, but when tissues were incubated with 25 mM KCl, the ACh content of slices preincubated with 0 or 10 microM choline decreased significantly, whereas that of slices preincubated with 25 or 50 microM choline did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

The aging population. A critical issue in medicine for the 21st century.

One critical issue facing medical science concerns the aging population. The number of individuals 65 years and older has increased during the past decade and likely will double by the year 2030, when the elderly will represent nearly 20% of the total population. This dramatic increase has numerous ramifications; health care is of utmost importance. Inherent in meeting the medical needs of these individuals is a fundamental understanding of the effects of aging on the functional integrity of numerous organ systems. In recognition of this problem, the Department of Pharmacology and Therapeutics at the University of South Florida College of Medicine has initiated a major effort focused on age-related research. The objectives are to elucidate fundamental biochemical, physiological, and pharmacological alterations that occur as a consequence of normal aging and to investigate the role of these perturbations on the manifestations of disease. Information gained from such studies will provide a rational approach in developing therapeutic strategies for the treatment of diseases affecting older citizens. This article presents a brief overview of four areas of research currently being pursued. These include aging and brain function, age-related alterations in drug metabolism, aging and smooth muscle function, and the effects of aging on the immune system.

Aging↗
PubMed1991

Modulation of acetylcholine release from rat striatal slices: interaction between 4-aminopyridine and atropine.

The objective of these studies was to determine whether the muscarinic receptor-mediated autoregulation of the basal release of acetylcholine (ACh), like the modulation of evoked release, involves 4-aminopyridine (4-AP)-sensitive potassium channels. To accomplish this, striatal and hippocampal slices were incubated with 4-AP in the absence or presence of atropine, and the release of ACh was measured. 4-AP increased the release of ACh in a concentration-dependent manner; a maximal effect (280% of control release) was achieved in the presence of 100 microM. The maximal release of ACh from hippocampal slices was approximately 150% of control release and was achieved in the presence of a broad range of concentrations (33-333 microM 4-AP). Tetrodotoxin (1 microM) totally abolished the 4-AP-induced release of ACh from hippocampal slices, but only attenuated the 4-AP-induced release from striatal slices, i.e., in the presence of tetrodotoxin, the 4-AP-induced release of ACh from the latter was significantly greater than control release by 54%. Atropine (0.1 microM) increased significantly the basal release of ACh from striatal slices by 61%. When striatal slices were incubated with 4-AP in the presence of this maximally effective concentration of atropine, ACh release was significantly greater than release from slices incubated with either atropine or 4-AP alone, suggesting that atropine and 4-AP increase neurotransmitter release by independent mechanisms. Although oxotremorine did not alter either the 4-AP- or atropine-induced release of ACh, it prevented the potentiated response exhibited by slices incubated with both atropine and 4-AP.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed1990

Muscarinic receptor blockade increases basal acetylcholine release from striatal slices.

The main objective of these studies was to determine whether the basal release of acetylcholine (ACh) from brain slices was subject to modulation by muscarinic receptor blockade. Incubation of striatal slices with the muscarinic antagonist atropine increased ACh release in a concentration-dependent manner with a maximal effect (1.4-1.8 times control release) achieved with 0.1 to 1.0 microM. In contrast, ACh release from hippocampal slices was unaltered by any concentration of atropine tested, indicating that the basal release of neurotransmitter from striatum, but not hippocampus, was subject to modulation by muscarinic receptor blockade. Incubation of striatal slices with 1 microM tetrodotoxin or removal of Ca++ from the medium decreased the basal release of ACh by 20% and abolished the atropine-induced release of ACh; neurotransmitter release from hippocampal slices was unaltered by tetrodotoxin. Thus, part of the basal release of ACh from striatal slices is a consequence of the intrinsic impulse activity of cholinergic neurons and it is this component of release that is atropine-sensitive. Oxotremorine was unable to antagonize the atropine-induced release of ACh, even with concentrations 100 times that of atropine, whereas pirenzepine increased ACh release and, like that of atropine, the effect of pirenzepine was sensitive to tetrodotoxin and resistant to oxotremorine. These results indicate that a component of basal ACh release from striatal slices is subject to modulation by a receptor that is sensitive to atropine and pirenzepine, but not to oxotremorine, suggesting that this site differs from the nerve terminal muscarinic autoreceptor.

Acetylcholine↗
PubMed1989

Acute choline supplementation in vivo enhances acetylcholine synthesis in vitro when neurotransmitter release is increased by potassium.

The main objective of these studies was to determine whether the acute administration of choline to rats provides supplemental precursor that can be used to support acetylcholine synthesis when the demand for choline is increased by increasing neurotransmitter release. For these experiments, hippocampal and striatal slices were prepared form rats that had received saline or an acute injection of choline. Slices were incubated in a choline-free buffer containing 4.74-35 mM KCl, and acetylcholine synthesis and release and choline production were measured. The initial tissue contents of acetylcholine and choline did not differ between experimental groups for either brain region. When hippocampal slices from the controls were incubated for 10 min with depolarizing concentrations of KCl, acetylcholine release increased and the tissue content decreased in a concentration-dependent fashion; no net synthesis of acetylcholine occurred. In contrast, hippocampal slices from the choline-injected animals maintained their tissue content in the presence of high concentrations of KCl, despite an increase in acetylcholine release that was similar in magnitude to that of the controls; positive net synthesis of acetylcholine resulted. Although the molar concentration of choline achieved in the incubation media at the end of the 10-min period did not differ between groups, the mobilization of free choline from bound stores was significantly greater in hippocampal slices from the choline-injected group than the controls. In addition, the synthesis of acetylcholine by hippocampal slices from the choline-injected group was prevented by the presence of hemicholinium-3 (1 microM) in the media.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Dietary choline intake modulates benzodiazepine receptor binding and gamma-aminobutyric acidA receptor function in mouse brain.

Several lines of evidence suggest that dietary choline intake influences the metabolism of membrane phospholipids with possible effects on GABAergic neurotransmission. Based on these findings, the present experiments determined whether chronic choline supplementation or deficiency alters GABAergic function at the level of the gamma-aminobutyric acid (GABA)/benzodiazepine-chloride channel complex. To accomplish this, mice were fed diets containing 0% (deficient), 0.2% (basal) or 2.0% (supplemented) choline chloride for 28 days, and behavior, ligand binding at several sites in the complex and chloride uptake were determined in various brain regions. For both rotarod ataxia and open-field activity, mice receiving choline supplementation had a decreased response to clonazepam compared to those receiving basal and deficient diets. Choline supplementation significantly increased the in vivo binding of [3H]Ro15-1788 to cortex and cerebellum by 19% and 24%, respectively, and in vitro studies in cortical membranes indicated a significant 36% increase in the maximal number of [3H]flunitrazepam binding sites without a change in affinity, as compared to basal controls. In contrast, [3H]Ro15-1788 binding in vivo in all brain regions from mice fed the deficient diet decreased significantly to 20 to 58% of control values. Dietary choline intake did not alter GABA levels in brain, the binding of [35S]t-butylbicyclophosphorothionate to the chloride channel or the coupling between GABA and either the t-butylbicyclophosphorothionate site or the benzodiazepine site. However, the function of the GABAA receptor, determined by muscimol-stimulated chloride uptake into cortical synaptoneurosomes, was increased significantly in tissue from the supplemented group as compared to both control and deficient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Influence of dietary choline availability and neuronal demand on acetylcholine synthesis by rat brain.

The main objective of this study was to test the hypothesis that the chronic administration of choline supplements a bound pool of choline from which free choline can be mobilized and used to support acetylcholine synthesis when the demand for precursor is increased. For these experiments, brain slices from rats fed diets containing different amounts of choline were incubated in a choline-free buffer and acetylcholine synthesis was measured under resting conditions and in the presence of K+-induced increases in acetylcholine synthesis and release. Rats fed the choline-supplemented diet had circulating choline levels that were 52% greater than the controls, and striatal and cerebral cortical slices from this group produced significantly more free choline during the incubation than slices from the controls. However, the synthesis and release of acetylcholine by these tissues did not differ from those by controls, during either resting or K+-evoked conditions. In contrast, acetylcholine synthesis and release by striatal and hippocampal slices from choline-deficient rats, animals that had circulating choline levels that were 80% of control values, decreased significantly; the production of free choline by these tissues was also depressed. Results indicate that, despite an increased production of free choline by brain slices from choline-supplemented rats, the synthesis of acetylcholine was unaltered, even in the presence of an increased neuronal demand. In contrast, the choline-deficient diet led to a decreased release of free choline from bound stores and an impaired ability of brain to synthesize acetylcholine.

Acetylcholine↗
PubMed1988

Adenosine inhibits choline kinase activity and decreases the phosphorylation of choline in striatal synaptosomes.

The main objective of these studies was to determine whether adenosine inhibits choline kinase in rat striata, leading to a decreased incorporation of choline into phosphorylcholine, a mechanism that may mediate seizure-induced increases in the levels of free choline in brain. Incubation of particulate and soluble fractions of striatal synaptosomes with adenosine or its metabolically stable analogues significantly inhibited enzyme activity. The inhibition was noncompetitive versus choline and competitive versus MgATP. Inhibitor constants for adenosine, 2-chloroadenosine, and 2',5'-dideoxyadenosine at the MgATP site were 94, 49, and 207 microM, respectively; these values were less than the Michaelis constant for MgATP (340 microM). To determine whether adenosine altered the phosphorylation of choline in an intact preparation, synaptosomes were incubated with [3H]choline in the presence or absence of adenosine or its analogues and the amount of [3H]-phosphorylcholine formed from the [3H]choline taken up was measured. All compounds tested significantly reduced the synthesis of [3H]phosphorylcholine. Results suggest that following seizures or hypoxia, when levels of adenosine increase and the concentration of ATP decreases, inhibition of choline phosphorylation may be manifest, resulting in increased levels of free choline in brain.

2-Chloroadenosine↗
PubMed1987

Chronic choline supplementation attenuates the behavioral effects of pentobarbital.

The behavioral and neurochemical effects of pentobarbital were investigated in rats maintained for 28-35 days on a standard choline-containing diet or on a diet containing 10 times the concentration of choline present in standard rodent chow. The supplemented dietary regimen increased the concentration of free choline in serum by 52%, but did not alter the steady-state concentrations of either choline or acetylcholine in brain. Choline supplementation attenuated both the sedative/hypnotic and hypothermic effects of pentobarbital through an action that could not be attributed to either an enhanced peripheral metabolism of pentobarbital or to an attenuation of the cholinergic effects of pentobarbital. Rather, results indicate that chronic supplementation with choline increases cerebral glucose metabolism and causes a behavioral hyperactivity, effects that may mediate the attenuation of the behavioral response of pentobarbital.

Acetylcholine↗
PubMed1978

Neuromuscular dysfunction induced by acetylcholinesterase inhibition.

The organophosphate cholinesterase inhibitor paraoxon produces a dose-dependent necrosis in rat skeletal muscle fibers after a single administration. The pathology, which is initiated at the motor end-plate region, is evident as early as 30 minutes after paraoxon administration and is characterized by dilated mitochondria, expanded sarcoplasmic reticulum, fused and widened subsynaptic folds, and coated cleft vesicles. By 24 hours, a generalized breakdown of muscle fiber architecture is evident with an accompanying infiltration of phagocytes. Electrophysiological studies have shown that paraoxon increases neurotransmitter release and causes spontaneous and impulse-related antidromic nerve activity, both of which can be reduced significantly by reactivation of inhibited acetylcholinesterase (AChE) with pyridine-2-aldoxime methiodide. The severity of the myopathy has been found to be positively correlated to the degree and duration of AChE inhibition. It appears that 2 hours of inhibition, with a critical loss in activity, viz., 85%, is necessary to initiate severe muscle fiber necrosis. Prior nerve transection prevents myopathic development and current data support the hypothesis that the induction of skeletal muscle fiber necrosis is triggered by inhibition of a neurally regulated fraction of AChE.

Acetylcholine↗