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D J Jenden

Publications and source records attributed to D J Jenden.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cysteine string proteins: a potential link between synaptic vesicles and presynaptic Ca2+ channels.

Presynaptic calcium channels are key regulators of neurotransmitter release. Oocyte expression studies suggest that cysteine string proteins are essential subunits or modulators of these channels. Subcellular fractionation revealed that cysteine string proteins copurify with synaptic vesicles. An average vesicle had eight protein monomers with both the amino and carboxyl termini detected on the cytoplasmic face. Thus, docked synaptic vesicles may regulate presynaptic calcium channels and neurotransmitter release.

Animals↗
PubMed1994

Choline pharmacokinetics during intermittent intravenous choline infusion in human subjects.

A study of choline pharmacokinetics was undertaken in four patients receiving long-term total parenteral nutrition. On consecutive days, 7, 14, 28, and 56 mmol choline chloride were intravenously infused over a 12-hour period in each subject. The choline concentration was determined in plasma at baseline, 1/4, 1, 3, 6, and 12 hours, and 3 and 12 hours after the infusion ended, and in daily 24-hour urine collections. Analysis of variance showed the data fit a two-compartment model in which elimination from the central compartment was saturable significantly better than a one-compartment model in all four subjects (p < 10(-8) in all cases), and significantly better than a nonsaturating model in three of the four subjects (p = 1.0 x 10(-9), 7.5 x 10(-6), 9.4 x 10(-11), respectively). The model allowed estimates of the rate constant for choline elimination at ambient levels, first-order rate constants for transfer between central and peripheral compartments, the dissociation constant for the saturable elimination process, the apparent volume of distribution in the central compartment, the steady-state volume of distribution, and the quantities of choline in the central compartment and in the readily exchangeable pool.

Adult↗
PubMed1993

Sleep-wake disturbances in an animal model of chronic cholinergic insufficiency.

Rats reared on a diet in which choline is replaced with N-aminodeanol (NADE), undergo > 50% replacement of brain acetylcholine with acetylated NADE, a false cholinergic transmitter. We examined amounts of sleep and wakefulness in 7 littermate pairs of rats fed either NADE-substituted, or a choline control diet for > 100 days after weaning. During the lights-on portion of the 12/12 h light/dark cycle, NADE rats spent more time awake, and less time in both non-REM and REM sleep compared to littermate controls. Average durations of waking episodes were significantly increased in NADE rats. During the 12 h dark period, there were no between-group differences in sleep-waking amounts. Behavioral hyper-responsiveness which interferes with sleep onset, combined with reduced activity in brainstem cholinergic mechanisms involved in REM sleep generation may underlie daytime sleep-waking disturbances in NADE rats.

Acetylation↗
PubMed1993

Low plasma free choline is prevalent in patients receiving long term parenteral nutrition and is associated with hepatic aminotransferase abnormalities.

Hepatic transaminase abnormalities have been previously reported in patients receiving long term total parenteral nutrition (PN). We sought to determine if such abnormalities are caused by choline deficiency-induced hepatocyte damage. In 41 subjects (19 male, 22 female) aged 45.1 +/- 24.3 years (range 0.1-79 years) who have received PN for 5.5 +/- 4.7 years (range 0.1-14.5 years). We determined plasma free and phospholipid bound choline levels, serum albumin, ALT and AST. We also determined the daily volume of intravenous lipid emulsion received by the patients as well as the concentration of free choline and phospholipid bound choline in the lipid emulsion. Plasma free choline was low in 33 41 subjects (mean 7.15 +/- 2.5 nmol/ml, range 3.3-15.6, normal 11.4 +/- 3.7). Phospholipid bound choline was normal in 34 41 subjects (mean 2157 +/- 620 nmol/ml, range 1026-3887, normal 2364 +/- 774). Elevations in ALT and AST were significantly correlated with plasma free choline (r = -0.34, p = 0.03, r = -0.37, p = 0.02 respectively) but not with phospholipid bound choline. No relationship was found between age, PN duration or daily volume of intravenous lipid and plasma free or phospholipid bound choline. The lipid emulsion contained 24 +/- 6 nmol/ml of free choline and 11 630 +/- 552 nmol/ml of phospholipid bound choline. We conclude that low plasma free choline is prevalent in patients receiving long term PN and this abnormality is associated with elevated serum aminotransferases. Furthermore, intravenous lipid emulsion is an inadequate source of choline for this patient group.

Journal Article↗
PubMed1993

Cholinergic mechanisms in startle and prepulse inhibition: effects of the false cholinergic precursor N-aminodeanol.

We examined the effects of cholinergic deficiency on prepulse inhibition (PPI) of the acoustic startle. Rats treated with a choline-free diet that contained the false cholinergic precursor N-aminodeanol showed great deficit in PPI. This deficit does not appear to be secondary to an increase of stereotyped behaviors. Startle threshold was also greatly reduced, as these rats startled to the 70-dB prepulse and the baseline startle amplitude was increased by 60% over the control rats. Arecoline (4 mg/kg) partially reversed the deficit in PPI. This improvement persisted beyond the period of drug treatment. On the other hand, scopolamine (1 mg/kg) reduced PPI in the control rats. These results suggest that cholinergic systems play a major role in both the elicitation and prepulse inhibition of startle.

Acoustic Stimulation↗
PubMed1992

Incomplete reversibility of an experimentally induced hypocholinergic state: biochemical and physiological, but not behavioral, recovery.

In previous reports, we described the experimental development of a hypocholinergic state in rats following the total replacement of dietary choline by an artificial isostere, N-aminodeanol (NADe). NADe shares most of the physicochemical and biochemical characteristics of choline (Ch) but is utilized less efficiently in pathways leading to the formation of both acetylcholine and phospholipids. This experimental model mimics many of the features of human degenrative dementias. We now discuss the behavioral and physiological effects of restoring a normal diet after the hypocholinergic state has become well established. The procedure by which that state was induced has been described in detail in earlier publications. After replacing Ch in the diets of weanling rats for 270 days, NADe replaced 70-85% of the phospholipid-bound Ch in plasma, brain, and peripheral tissue. When dietary NADe was removed and Ch was restored in the diet, NADe disappeared and plasma and erythrocyte (RBC) choline levels returned to normal within 30-60 days. Quinuclidinyl benzilate (QNB) binding showed that muscarinic receptors continued to be depressed in animals remaining on the NADe diet, but returned to control levels in the reversal group. There were no differences in cholinesterase activity among the three treatments. Choline acetyltransferase activity returned to control levels, while continuing to be lower in the NADe animals. Liver lipids were elevated in the latter and not significantly different in the control and reversal groups. Among physiological functions, body weight increased more rapidly in the reversal group than in animals continuing on the NADe diet. Brain weights of the reversal animals were significantly greater than those of animals not reversed, but less than controls. Core body temperatures did not differ from controls at any time during the reversal period. Behaviorally, nociceptive thresholds indicative of sensory-reflexive and sensory-perceptual responses remained significantly below normal, that is, a hyperalgesic state. Reversal animals also remained hyperactive and displayed memory significantly poorer than those on the normal diet, that is, no improvement over animals continuing on NADe. In general, the results suggest that behavioral losses induced by NADe reflect persisting changes in the CNS, despite essentially complete recovery of biochemical parameters. The changes may be morphological or be associated with adaptive changes in other neurochemical events in the CNS.

Animals↗
PubMed1992

Pharmacological stimulation reveals recombinant human nerve growth factor-induced increases of in vivo hippocampal cholinergic function measured in rats with partial fimbrial transections.

The present study determined the effects of chronic recombinant human nerve growth factor administration [1 microgram given intracerebroventricularly q.i.d. (every other day) for three weeks] on in vivo hippocampal cholinergic function in adult rats with unilateral partial fimbrial transections. Partial fimbrial transections did not significantly alter the levels of endogenous acetylcholine or [2H4]acetylcholine in the hippocampus due to functional compensation by surviving cholinergic terminals. In animals chronically treated with nerve growth factor, the levels of endogenous choline, endogenous acetylcholine, [2H4]choline and [2H4]acetylcholine accumulated in the hippocampus on the lesioned side were not significantly different from those on the contralateral unlesioned side or from values measured in animals treated with cytochrome c, a control protein. However, changes in cholinergic parameters induced by the partial lesions or recombinant human nerve growth factor treatment became manifest when animals were challenged using pharmacological agents such as pentylenetetrazole or pilocarpine given after lithium chloride pretreatment. First, in nerve growth factor-treated animals administered the general stimulant pentylenetetrazole (10 mg/kg) 2 min prior to measuring in vivo cholinergic parameters, we observed a significant increase in the hippocampal content of [2H4]choline in both lesioned and unlesioned hippocampi. The magnitude of the increase was significantly higher on the lesioned compared to the unlesioned side. Although chronic recombinant human nerve growth factor treatment induced increases of hippocampal [2H4]choline levels, there were no concomitant increases in the level of [2H4]acetylcholine. Second, in nerve growth factor-treated animals administered lithium chloride (3 mmol/kg) 20 h prior to pilocarpine (30 mg/kg), we observed a significant enhancement of the content of endogenous acetylcholine in the hippocampus of the lesioned side. Partial fimbrial transections also reduced in vitro cholinergic parameters reflecting endogenous acetylcholine levels in hippocampal slices. The content of endogenous acetylcholine in the slices was decreased by approximately 50% and chronic nerve growth factor treatment significantly elevated this value to approximately non-lesioned control values. Similarly, reductions in spontaneous and veratridine-evoked release of endogenous acetylcholine induced by partial fimbrial transections were counteracted by recombinant human nerve growth factor treatment. These findings demonstrate that chronic recombinant human nerve growth factor treatment effectively enhances the in vivo and in vitro synthesis, storage and release of endogenous acetylcholine. The results from the in vivo studies suggest that recombinant human nerve growth factor-induced differences in functional performance of hippocampal neurons may only be manifest during behavioral and/or pharmacological stimulation.

Acetylcholine↗
PubMed1992

Effects of hypoxia on choline exchange among organs.

Cerebral blood flow (CBF) and the arteriovenous (A-V) difference for choline (Ch) across brain, lung, splanchnic territory, liver, kidney, and lower limb were studied in anesthetized, mechanically ventilated rats subjected to 10-20-min periods of hypoxia induced by lowering the inspired O2 concentration to 13%. A large, time-dependent increase in arterial blood Ch concentration occurred during hypoxia. This phenomenon coincided with a net rate of uptake of Ch by the brain during hypoxia (0.81 +/- 0.24 nmol/min, n = 10; p less than 0.05), which contrasted with a net rate of loss of Ch by this organ during the control period that preceded hypoxia (-0.20 +/- 0.08 nmol/min, n = 10; p less than 0.05). During hypoxia, lungs and splanchnic territory showed negative A-V differences for Ch levels (net Ch loss), whereas brain, liver, kidney, and lower limb showed positive A-V differences for Ch levels (net Ch uptake). Ch output from lungs was already detected at 5 min within the period of hypoxia and reversed rapidly after restoration of normal oxygenation. On the other hand, Ch output from the splanchnic territory became evident only 10 min after commencement of hypoxia and outlasted this experimental condition. It is concluded that extracerebral production of Ch during hypocapnic hypoxia raises the arterial concentration of this molecule and, by reversing the gradient across cerebral capillaries, prevents the cerebral loss of Ch in this condition.

Animals↗
PubMed1992

Characterization of the irreversible inhibition of high-affinity choline transport produced by hemicholinium mustard.

The inhibition of high-affinity choline transport by hemicholinium mustard (HCM), an alkylating analogue of hemicholinium-3, was examined in rat brain synaptosomes and guinea pig myenteric plexus. In synaptosomes, 50% high-affinity choline transport inhibition occurs with an HCM concentration of 104 nM (4-min incubation). A 10-min preincubation with 10 microM HCM results in essentially complete (greater than 95%) inactivation that persists after washing. Low-affinity choline transport in synaptosomes is unaffected by HCM inhibition at all concentrations examined (1-50 microM). Time course experiments indicate that the maximum irreversible inhibition (58%) seen after a 1-min preincubation with 500 nM HCM decreases to 46% inhibition after a 15-min preincubation; however, analysis of variance reveals that this difference is not significant. HCM inhibition of acetylcholine release from myenteric plexus-longitudinal muscle preparations persists for at least 2 h after removal of drug from the incubation bath; this inactivation can be prevented by coincubation with a high choline concentration during treatment with the mustard. In contrast, inhibition produced by the parent compound hemicholinium-3 is largely reversed by washing in both preparations examined. The observed potency and selectivity of HCM suggest its usefulness as a covalent probe for high-affinity choline transport.

Acetylcholine↗
PubMed1992

Subdiaphragmatic vagotomy in rats induces systemic hypertension and sodium retention.

We examined the acute effects of bilateral subdiaphragmatic vagotomy (BSV) on blood pressure and renal function in female Sprague-Dawley rats. Mean arterial pressure was greater (p < 0.0001) in rats with BSV than in sham-operated rats (SOR). Rats with BSV had a significantly lower effective renal plasma flow (p < 0.01), total sodium excretion (p < 0.005), fractional sodium excretion (p < 0.01), urine flow (p < 0.01), and fractional excretion of water (p < 0.02) than SOR. The glomerular filtration rate was not significantly different between the 2 groups of rats. Plasma potassium was greater in rats with BSV than in SOR (p < 0.02). Pretreatment with an inhibitor of the angiotensin-converting enzyme prevented the above changes in rats with BSV. Changes in renal function and mean arterial pressure could not be attributed to antidiuretic hormone since plasma levels of antidiuretic hormone were lower in rats with BSV than in SOR (p < 0.002). In addition, the activity of the sympathetic system was decreased in rats with BSV, as suggested by the lower plasma levels of epinephrine (p < 0.003) and norepinephrine (p < 0.02) and the significantly lower renal tissue concentrations of norepinephrine (p < 0.03). No significant changes in renal tissue concentrations of acetylcholine or choline, its precursor, were observed in BSV rats when compared to SOR, suggesting a lack of renal parasympathetic innervation. Plasma renin activity was lower in rats with BSV (p < 0.02) than in SOR, but this effect was blunted in rats given an angiotensin-converting enzyme inhibitor prior to BSV.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1991

Difficulties in using animal data to predict pharmacological response in man.

Variation among species in their response to xenobiotic agents depends upon two sets of factors: pharmacokinetic and pharmacodynamic. Pharmacokinetic factors, of which the rate of metabolic transformation is the most important, determine the concentration of the agent in plasma and tissues as a function of time after it is administered, while pharmacodynamic factors define the tissue response to a given concentration. Both are subject to considerable uncertainty when dealing with a new compound, so that it is not in general possible to predict reliably the response of human subjects to a new compound solely from studies on experimental animals. This uncertainty can be reduced substantially by understanding its mechanisms of action. Greater accuracy in predicting the metabolism of foreign compounds in man is also likely to be achieved by studies of the species variation of cytochrome P450s, and by the use of human hepatocytes and other cell lines to study xenobiotic metabolism.

Animals↗
PubMed1991

Time-dependent changes in cerebral choline and acetylcholine induced by transient global ischemia in rats.

We occluded the carotid and vertebral arteries of 12 rats for 15 minutes to measure the brain concentrations of choline and acetylcholine and cerebral blood flow at the end of the ischemic period or 15, 30, or 150 minutes after circulation was reestablished. The animals were sacrificed with microwave radiation focused to the head immediately after a brief infusion of [14C]iodoantipyrine with rapid sampling of arterial blood. Brain tissue samples were extracted with ether to separate the tracer, which was subsequently measured by liquid scintillation counting and used to calculate local cerebral blood flow. The aqueous phase was then processed for the measurement of choline and acetylcholine concentrations by gas chromatography/mass spectrometry. The results showed a large increase in tissue choline content and a decrease in tissue acetylcholine content during ischemia. During recirculation, choline levels progressively declined, reaching levels lower than those in four control rats after 150 minutes of recirculation for most brain regions. A reciprocal relation between the brain choline concentration and local cerebral blood flow was found. Acetylcholine levels showed an initial rebound to greater than control during recirculation, with subsequent normalization. Brain acetylcholine concentration was positively correlated with brain choline concentration, provided that cerebral blood flow was greater than 0.3 ml x g-1 x min-1. Because tissue free choline was depleted in most brain regions 150 minutes after transient ischemia, we speculate that prolonged ischemia may produce a greater depletion of tissue free choline with a resulting decline in tissue acetylcholine. This could play an important role in the cognitive deficit associated with vascular dementia.

Acetylcholine↗
PubMed1991

Compensatory elevation of acetylcholine synthesis in vivo by cholinergic neurons surviving partial lesions of the septohippocampal pathway.

The present study characterized the effects of partial destruction of the cholinergic septohippocampal pathway on transmitter functions of surviving cholinergic neurons in the hippocampus. Partial and full fimbrial transections were performed, and 3 weeks after lesioning, cholinergic functions were assessed in vivo and in vitro. Hippocampal ChAT activity and the capacity of hippocampal slices to synthesize [3H]ACh in vitro decreased by 35% and 45%, respectively, following partial fimbrial lesions and by 68% and 85%, respectively, following full fimbrial lesions. [3H]ACh release from hippocampal slices in vitro was decreased by 57% and 87%, respectively, following partial and full fimbrial lesions. Partial lesions decreased high-affinity choline uptake into hippocampal synaptosomes by 52%. In contrast to the significant reductions in cholinergic parameters measured in vitro after partial fimbrial lesions, such partial lesions did not significantly alter in vivo measures of hippocampal cholinergic function. Levels of endogenous ACh and choline measured in the hippocampus following partial lesions were similar to that of control values. Also, the hippocampal content of newly synthesized [2H4]ACh and the [2H4]ACh synthesis rate were not significantly different from control values. However, following full fimbrial lesions, in vivo measures of hippocampal cholinergic function were decreased to a degree similar to that observed in vitro. Hippocampal levels of endogenous ACh and [2H4]ACh and the synthesis rate for [2H4]ACh were decreased by 73%, 72%, and 83%, respectively. These results suggest that, following partial destruction of afferent cholinergic fibers that innervate the hippocampal formation, residual cholinergic neurons are able to upregulate their capacity to synthesize and store ACh in vivo, thus compensating for lesion-induced losses of cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Effects of combined serotonin depletion and lesions of the nucleus basalis magnocellularis on acquisition of a complex spatial discrimination task in the rat.

The purpose of the present experiment was to determine the effects of lesions of cholinergic neurons originating from the nucleus basalis magnocellularis (NBM), alone or in combination with central serotonin depletion, on learning and memory in rats trained in the Stone 14-unit T-maze--a complex, positively-reinforced spatial discrimination task. Lesion of cholinergic neurons within the NBM was accomplished by bilateral infusion of ibotenic acid. Serotonin depletion was accomplished by the systemic administration of p-chloroamphetamine (PCA). The results show that PCA-induced serotonin depletion enhanced learning. This effect was completely prevented by NBM lesions, despite the fact that NBM lesions alone did not affect the performance of rats in this task. The results of this study support the view that the cholinergic and serotonergic systems may functionally interact in learning and memory processes. The significance of this interaction in the etiology and treatment of dementia should be further investigated.

Analysis of Variance↗
PubMed1990

Changes in red blood cell choline and choline-bound lipids with oral lithium.

The influence of oral lithium on the concentration of red blood cell choline (Ch), lecithin, glycerophosphorylcholine (GPCh) and phosphorylcholine (PCh) was studied. The concentration of RBC Ch was significantly elevated and the concentration of lecithin, GPCh and PCh significantly depressed in 16 patients on oral lithium compared to 9 age-matched controls. We conclude that lithium markedly depletes the red blood cell of choline containing compounds including lecithin. These changes may be responsible for both the therapeutic efficacy and the toxicity of lithium.

Administration, Oral↗
PubMed1990

Global in vivo replacement of choline by N-aminodeanol. Testing a hypothesis about progressive degenerative dementia: I. Dynamics of choline replacement.

Severe disruption of certain cholinergic pathways is a characteristic feature of Alzheimer's disease. Attempts to establish animal models by interfering with cholinergic function have not been very successful. We now present data which show a substantial and progressive replacement of free and phospholipid-bound choline by the novel choline isostere N-amino-N,N-dimethylaminoethanol during its dietary administration in place of choline. Free choline in blood fell to approximately 20% of controls after 10 to 30 days on diet. Phospholipid-bound choline in plasma was reduced to less than 15%, and in erythrocytes to about 22%. After 120 days of diet free and bound choline were reduced in most tissues to approximately 30% of controls. Only liver retained more than 80% of free choline. Acetylcholine was decreased to 33 to 50% of control. Total true and false transmitter in experimental animals was in all tissues less that acetylcholine in controls, suggesting that muscarinic transmission would be impaired. Moderate reduction of choline acetyltransferase activity was seen in striatum and myenteric plexus, and of QNB-binding in hippocampus, striatum and myenteric plexus.

Acetylation↗
PubMed1990

Global in vivo replacement of choline by N-aminodeanol. Testing a hypothesis about progressive degenerative dementia: II. Physiological and behavioral effects.

We have examined the progressive effects of replacement of dietary choline with NADe for a period of 120 days on a broad spectrum of behavioral and physiological functions known to involve the cholinergic system. The magnitudes of these effects tended to increase with time on the NADe diet, but those related to learning and memory were largely confined to the 60-120-day period. Neurochemical effects were concomitant with the replacement of Ch by NADe, being consistent with a hypocholinergic state as found in such progressive degenerative dementias as Alzheimer's disease. As cholinergic functioning was progressively impaired, basic physiological ("vegetative") processes appeared not to be affected. Apparently the rate at which the hypofunctional state developed was sufficiently slow for adjustments to occur, allowing the animal to adapt at a survival level to neurochemical changes. More complex behavioral functions were affected progressively, cognitive processes (e.g., learning and memory) being most sensitive and showing the least adaptability. We propose that the syndrome generated by NADe replacement of Ch represents an experimental model of progressive degenerative dementia.

Alzheimer Disease↗