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D J Jenden

Publications and source records attributed to D J Jenden.

At least 73 records · Page 4Linked to original sources
PubMed1987

A model hypocholinergic syndrome produced by a false choline analog, N-aminodeanol.

N-aminodeanol is an analog of choline that serves as a less effective substrate in all of its known enzymatic and transport mechanisms. It was utilized to test the hypothesis that the selective vulnerability of cholinergic neurones in Alzheimer's disease is due to competition for the available choline between pathways for acetylcholine and phospholipid synthesis. Rats placed on a choline free diet containing an equivalent amount of N-aminodeanol develop a model hypocholinergic state comprising hyperreactivity, hyperalgesia, aggressive behavior and a deficit in learning and memory. These effects are associated with a progressive replacement of free and lipid-bound choline and acetylcholine with N-aminodeanol and its corresponding esters. Choline acetyltransferase is reduced in some brain regions, suggesting a loss of cholinergic neurones. We propose that this represents a potentially useful animal model of Alzheimer's disease which deserves further investigation.

Alzheimer Disease↗
PubMed1987

Regional differences in receptor reserve for analogs of oxotremorine in vivo: implications for development of selective muscarinic agonists.

The muscarinic actions of several analogs of oxotremorine were compared in the mouse. Compounds such as AKS 19 and BM 5 having low intrinsic efficacy (partial agonists) differentiated between centrally mediated muscarinic effects as they, like oxotremorine, were potent in producing analgesia and hypothermia but did not produce tremor. Instead they antagonized oxotremorine-induced tremor. They resembled oxotremorine in their ability to stimulate salivary secretion. Excellent correlations were found between the various muscarinic effects measured in vivo and spasmogenic activity on the guinea pig ileum and between tremorolytic potency and affinity for ileal muscarinic receptors. The results suggest that there are regional differences in the receptor reserve for muscarinic agonists that may affect in vivo responses to partial agonists in a qualitative manner. Responses to more efficacious agonists such as oxotremorine are affected only quantitatively by such differences. Efficacious agonists appeared to have a large receptor reserve with respect to salivation, analgesia and hypothermia, whereas their receptor reserve for the tremor response was lower. The possibility is raised of achieving selective muscarinic actions, even in the absence of distinct subtypes of muscarinic receptors, by exploiting regional differences in receptor density, in the efficiency of receptor-effector coupling and in endogenous levels of acetylcholine.

Analgesia↗
PubMed1987

Muscarinic actions of an N-methyl-N-2-bromoethylamino analog of oxotremorine (BR 401) in the mouse.

The pharmacological effects of N-[4-(2-bromoethylmethylamino)-2-butynyl]-2-pyrrolidone (BR 401) were compared in the mouse with those of N-[4-(2-chloroethylmethylamino)-2-butynl]-2-pyrrolidone (BM 123) and oxotremorine. BR 401 was more toxic than oxotremorine and BM 123 when administered i.v. (LD50, 0.7 mumol kg-1), but less toxic than oxotremorine when given i.p. (LD50, 39 mumol kg-1). Atropine and methylatropine (10 mumol kg-1 i.p.) increased the LD50 value of BR 401, given i.v., 75- to 100-fold. Upon i.v. administration, BR 401 was 2- to 3-fold more potent than oxotremorine and 10 to 20 times more potent than BM 123 in producing central (tremor and analgesia) and peripheral (salivation) muscarinic effects. However, after i.p. administration BR 401 was 3-fold less potent than oxotremorine in eliciting tremor and analgesia. The aziridinium ion (BR 401A), formed by cyclization of BR 401, produced salivation but no tremor. These observations suggest that BR 401 when given i.v. penetrates effectively into the central nervous system where it cyclizes rapidly to the pharmacologically active aziridinium ion. In contrast, after i.p. administration a large proportion of BR 401 will cyclize before it can reach the central nervous system. BM 123, because of its slower cyclization, enters the central nervous system effectively also by the i.p. route. Thus, central potency of 2-haloethylamines such as BR 401 and BM 123 is critically dependent not only on the rate of cyclization, but also on the route of administration. The duration of tremor induced by BR 401 and BM 123 was considerably shorter than that induced by oxotremorine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1986

Effects of chronic dietary administration of the cholinergic false precursor N-amino-N,N-dimethylaminoethanol on behavior and cholinergic parameters in rats.

The choline analog, N-amino-N,N-dimethylaminoethanol (NADe), was fed ad libitum (chloride salt; 0.5%) to weanling rats in a low choline, low methionine synthetic diet. Control rats were fed choline chloride (0.5%) in place of NADe. Initial observation and behavioral screen tests of grasp strength, startle reflex, righting reflex, analgesia (hot plate test) and body temperature did not reveal any toxic effects caused by NADe, although both experimental and control groups gained weight more slowly than rats fed standard lab chow. After 25 days on the diet, the performance of rats fed NADe in a one-trial passive avoidance test was significantly impaired compared to control rats. There was no difference between experimental and control rats in sensitivity to foot shock or in activity monitored in a closed field. A subjective, 6-component behavioral rating scale indicated rats fed NADe were resistant to handling but not aggressive. These behavioral results were similar in two separate feeding experiments using deuterium-labeled and unlabeled NADe. The twitch response of isolated rat phrenic nerve-diaphragms during stimulation did not show any impairment of neuromuscular function in rats fed NADe. Receptor binding experiments indicated there were no differences between experimental and control rats in tritiated quinuclidinyl benzilate [( 3H]QNB) binding capacity in cortex, heart and ileum. Competitive [3H]QNB binding with carbachol indicated there was no difference in the IC50's measured in cortex homogenates. Acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities in cortex were similar in experimental and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1986

Abnormal erythrocyte choline and influx in Alzheimer's disease.

Choline transport and levels were studied in erythrocytes from patients with Alzheimer's disease and age-matched controls using stable isotopic tracer techniques. The mean erythrocyte choline in the Alzheimer group was 50.1 nmol ml-1 compared to 15.5 nmol ml-1 in the controls. This was significant using a Student's t test at a P of less than 0.0005. Influx of choline into the erythrocyte correlated inversely with erythrocyte choline with high significance. This study suggests that erythrocyte choline is elevated in a subset of patients with Alzheimer's disease and that the low affinity transport system is also abnormal in these patients. This abnormality of choline transport may play a role in the pathogenesis of Alzheimer's disease in some patients.

Aged↗
PubMed1986

Behavioral and physiological effects associated with changes in muscarinic receptors following administration of an irreversible cholinergic agonist (BM 123).

Previous work in our laboratory has shown that the aziridinium ion of BM 123 (N-[4(2-chloroethylmethylamino)-2-butynyl]-2 pyrrolidone) is a potent and selective muscarinic agonist and binds irreversibly to muscarinic receptors (mAChR). The present series of experiments was designed to study the effects of BM 123 on behavioral and physiological variables known to be sensitive to manipulations of the cholinergic neurotransmitter system. BM 123 was injected into the tail vein of Sprague-Dawley rats, reducing mAChR to approximately 10% of normal as judged by [3H](-)QNB binding. Oxotremorine was injected IV for purposes of comparison. Behavioral and physiological variables were measured daily for 26 days. Physiological variables (e.g., tremor, chromodacryorrhea, salivation, and temperature) showed effects in less than 5 min after injection and returned to their pretreatment baselines within minutes. Nociceptive thresholds, dependent on sensory-perceptual processes, showed peak changes of approximately +230% and returned to normal within hours. Motoric responses, i.e., drinking and general activity, recovered in 3-4 days. Learned responses and those requiring temporal discrimination took 8-11 days to recover and were the only responses paralleling the return of the mAChRs to their normal levels. Changes elicited by oxotremorine recovered more rapidly than those elicited by BM 123. The results suggest that the different variables measured are dependent on different densities of functional receptors. Implications for a theoretical model are discussed.

Animals↗
PubMed1986

Behavioral and physiological effects of an aziridinium analog of oxotremorine (BM130).

When injected IV BM130, a mustard analog of oxotremorine, acts initially as a cholinergic agonist and thereafter produces a sustained resistance to muscarinic agonists. Control subjects were injected with saline or with BM130A, the active aziridinium intermediate of BM130. Acute injections of BM130 were followed initially by effects that were characteristically cholinomimetic in nature: e.g., tremor, chromodacryorrhea, salivation, hypothermia. The effects were dose-dependent and of limited duration. They were not seen in behavioral variables measured 30 min after drug treatment. Injection of BM130A produced peripheral, but not central effects; saline had no effects. The prediction that initial cholinomimetic effects should be followed by sustained resistance to cholinergic agonists was tested by subjecting animals to oxotremorine challenges at weekly intervals following single injections of BM130. In none of the measures taken did animals injected with BM130A or saline show resistance to the muscarinic challenges. Those administered BM130 showed resistance, which in some variables was sustained for 3-4 weeks. The resistance was statistically significant at high BM130 doses and appeared to be dose dependent over the range studied.

Animals↗
PubMed1985

Cortical acetylcholine efflux with hypercapnia and nociceptive stimulation.

In rabbits anesthetized with 70% N2O-30% O2, the rate of efflux of acetylcholine (ACh) from the cerebral cortex doubled during hypercapnia (increase of end-tidal CO2 from 4 to 8%), and during mild nociceptive stimulation of the tail. Under 0.7% halothane anesthesia, the control rate of ACh efflux was lower than that under N2O; the rate rose 2-fold during hypercapnia and 4-fold during tail stimulation. In the absence of systemic atropinization, increase in ACh efflux was correlated with a shift in EEG from high- to low-voltage ('activated'); after systemic atropinization EEG remained in the high-voltage state, but the changes in ACh efflux with hypercapnia and stimulation were not affected. Following transection of the midbrain, ACh efflux was markedly depressed and did not change during hypercapnia. Taken in context with the previously known facts that the cerebral hyperemia of hypercapnia is potentiated by cholinesterase inhibition and attenuated by atropine or decerebration, the present results support the concept of a cholinergic regulation of the cerebral vasculature.

Acetylcholine↗
PubMed1985

Further characterizations of the nature of the behavioral and neurochemical effects of lesions to the nucleus basalis of Meynert in the rat.

Converging lines of evidence indicate an important role for the basal forebrain cholinergic system in memory processes. The principal origin of the cholinergic projection to the neocortex appears to be the magnocellular neurons in the region of the nucleus basalis of Meynert (NbM). We examined the effects of bilateral lesions of the NbM on retention of shock avoidance training by stereotaxically injecting rats with 0.5 microliter of ibotenic acid (14 micrograms/microliter) into the NbM. Two weeks later rats were given passive avoidance training and tested for retention of the original avoidance habit 5 min, 30 min, or 24 hr later. Rats with lesions of the NbM showed significantly impaired shock avoidance performance compared to non-operated controls at both 30 min and 24 hr, but not at 5 min after training. Lesioned animals also showed a significant decrease in cortical choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities. No differences in muscarinic receptor binding or plasma cholinesterase activity was observed. The results demonstrate the usefulness of NbM lesions as a model for studying the role of the basal forebrain cholinergic system in memory processes.

Acetylcholinesterase↗
PubMed1985

Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones.

The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine (1) were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities, it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.

Abdominal Muscles↗
PubMed1985

Choline acetyltransferase and acetylcholine in Xenopus oocytes injected with mRNA from the electric lobe of Torpedo.

Xenopus oocytes were injected with poly(A)+ mRNA obtained from the electric lobes of Torpedo marmorata and Torpedo ocellata, which contain the cell bodies of the neurons that innervate the electric organs. The electric lobe mRNA preparation induces the oocytes to synthesize a catalytically active form of the enzyme choline acetyltransferase (EC 2.3.1.6). Enzymatic activity is found almost exclusively in the cytoplasmic fraction of injected, but not control, oocytes. Evidence is presented that distinguishes between the induced choline acetyltransferase activity and an intrinsic carnitine acetyltransferase activity present in the oocytes. This latter enzyme is associated principally with particulate fractions of the oocyte. The level of acetylcholine, which accumulates in mRNA-injected oocytes, is relatively insensitive to pharmacological manipulations that alter the acetylcholine content of other cells. These results show that Xenopus oocytes may be used advantageously to study functional properties of polypeptides associated with presynaptic elements in the nervous system.

Acetylcholine↗
PubMed1985

Therapeutic monitoring of chlorpromazine I: Pitfalls in plasma analysis.

Pooled plasma from healthy volunteers was spiked with pure, synthetic chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), or chlorpromazine N-oxide (CPZNO), and then made alkaline with either sodium hydroxide or sodium carbonate. The samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvent. It was found that CPZNO was reduced to CPZ in plasma made alkaline with sodium hydroxide, but not in protein-free buffer solution at high pH nor in plasma made alkaline with sodium carbonate. The reaction appears to take place through reducing equivalents generated by the action of sodium hydroxide on plasma proteins. Thus, apparent concentrations of CPZ in plasma from patients were elevated by as much as 343% when sodium hydroxide was used compared with concentrations in aliquots of the same plasma samples alkalinized with sodium carbonate. The amount of CPZ produced from CPZNO depends on the type of extraction procedure employed as well as on the quantity of sodium hydroxide added to the plasma. By contrast, no interconversion between CPZ and CPZSO or CPZNO and CPZSO was observed in plasma alkalinized and extracted under any of the conditions tested.

Chlorpromazine↗
PubMed1985

Changes in presynaptic release of acetylcholine during development of tolerance to the anticholinesterase, DFP.

The rat myenteric plexus was used as a peripheral model for studying muscarinic modulation of acetylcholine (ACh) release from presynaptic muscarinic neurons during development of tolerance to the anticholinesterase agent, diisopropylfluorophosphate (DFP). DFP in arachis oil was administered subcutaneously to intact animals according to both acute and chronic regimens, with arachis oil injections serving as controls. Post-mortem analyses showed that the mean AChE activity level in whole brain was reduced under all DFP conditions to 18.0 +/- 1.4% when compared with the control level. After 10 days of DFP treatment, the AChE level was 22.3 +/- 2.1% of control in the myenteric plexus. There were no significant differences among the treatment groups in resting ACh release. Release evoked by electrical stimulation (difference between stimulated and resting release) in the absence of atropine, i.e., "basal rate," for strips taken at various times after a single injection of DFP did not differ from that for strips from animals receiving arachis oil only. However, basal release for strips from chronically treated subjects was significantly greater than that of controls (p less than 10(-3), although not different from each other. Analysis of variance (ANOVA) for repeated measures showed that there existed a highly significant atropine dependency in strips from all treatments when they were stimulated in concentrations of atropine from 10(-9) to 10(-5) M (p less than 10(-10). Further analyses established that the increases in rates of evoked ACh release as concentrations of atropine increased were similar for strips from chronically treated DFP and arachis oil animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1985

Acetyl-N-aminodeanol: a cholinergic false transmitter in rat phrenic nerve-diaphragm and guinea-pig myenteric plexus preparations.

The metabolism of the choline analog N-amino-N,N-dimethylaminoethanol (N-aminodeanol) by isolated rat diaphragm and guinea-pig myenteric plexus preparations and the pharmacological properties of the acetate ester were studied. Deuterium-labeled N-aminodeanol was transported and acetylated by rat diaphragm and guinea-pig myenteric plexus preparations. Diaphragms stimulated indirectly in the presence of [2H4]N-aminodeanol (2 X 10(-5) M) released [2H4]acetyl-N-aminodeanol at 38% the rate at which [2H4]acetylcholine was released from controls incubated with [2H4]choline (2 X 10(-5) M). In the guinea-pig myenteric plexus, [2H4]acetyl-N-aminodeanol was synthesized and released at a rate up to 70% that measured for [2H4] acetylcholine. N-methylatropine (10(-7) M) enhanced the stimulated release of [2H4]acetyl-N-aminodeanol and [2H4] acetylcholine (in separate controls) by the same amount (2,3-fold). After incubation in the presence of [2H4]N-aminodeanol, [2H4]acetyl-N-aminodeanol replaced (mole for mole) 17 and 50% of the endogenous acetylcholine tissue content in diaphragm and myenteric plexus, respectively. As the tissue [2H0]acetylcholine was replaced, its release was reduced to 38 and 22% of control in diaphragm and myenteric plexus, respectively. Combined transmitter release (true + false) was reduced to 56 to 79% of release from controls. Endogenous choline efflux apparently limited the replacement of true with false transmitter in these preparations. Acetyl-N-aminodeanol had 4 and 17% the potency of acetylcholine on the guinea-pig ileum and frog rectus abdominis preparations, respectively. These findings indicate that [2H4]N-aminodeanol forms a false transmitter in rat diaphragm and guinea-pig myenteric plexus and may potentially interfere with cholinergic function. Effective replacement of endogenous acetylcholine in vivo would also require replacement of endogenous sources of choline for transmitter synthesis.

Acetylcholine↗
PubMed1985

The binding of a 2-chloroethylamine derivative of oxotremorine (BM 123) to muscarinic receptors in the rat cerebral cortex.

The interaction of a mustard analogue of oxotremorine, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), with muscarinic receptors in the rat cerebral cortex was investigated using 3H-ligand-binding methods. When cortical homogenates were preincubated with BM 123 (1.0 mM), washed extensively, and then assayed for the binding of the specific muscarinic antagonist, [3H](-)-N-methylscopolamine, a decrease in binding capacity was noted without an accompanying change in affinity. The rate at which BM 123 alkylated muscarinic receptors was sensitive to temperature, with little or no receptor alkylation occurring at 0 degree. Thus, it was possible to estimate the affinity of BM 123 and its transformation products for muscarinic receptors by measuring their ability to competitively inhibit 3H-ligand binding to cortical homogenates at 0 degree. When measured by competitive inhibition of [3H]oxotremorine-M and [3H](-)-N-methylscopolamine binding, the concentrations of the aziridinium ion of BM 123 required to displace 50% of specific 3H-ligand binding were 3.5 nM and 4.5 microM, respectively. In contrast, the parent 2-chloroethylamine and its alcoholic hydrolysis product were much less active. The kinetics of the alkylation of muscarinic receptors by BM 123 were consistent with a model in which the aziridinium ion rapidly forms reversible complexes with superhigh high and low affinity sites which slowly convert to covalent complexes. The rate of alkylation of the superhigh affinity site was slowest whereas the converse was true for the low affinity site. It was possible to alkylate the high and low affinity sites selectively with BM 123 by taking advantage of kinetic differences in the rates of alkylation of these two sites. Atropine, oxotremorine, and oxotremorine-M antagonized the rate of alkylation of muscarinic receptors in a manner that was consistent with competitive inhibition.

Alkylation↗
PubMed1985

Metabolism and subcellular distribution of N-amino-N,N-dimethylaminoethanol (N-aminodeanol) in rat striatal synaptosomes.

The metabolism and subcellular distribution of a novel choline analog, N-amino-N,N-dimethylaminoethanol (N-aminodeanol) in rat striatal synaptosomes was studied using combined gas chromatography mass spectrometry for simultaneous estimation of N-aminodeanol, choline, tracer choline and their acetate esters. The enzymes choline acetyltransferase, acetylcholinesterase and choline kinase were assayed in kinetic studies using N-aminodeanol or acetyl-N-aminodeanol as substrates. The results demonstrate that [2H4]N-aminodeanol is transported and acetylated in synaptosomes at rates approximately 30% of those measured for [2H4]choline. Of the [2H4]N-aminodeanol that was transported by the high affinity choline uptake system, the proportion acetylated was similar to that measured for [2H4]choline. [2H4]Acetyl-N-aminodeanol replaced endogenous acetylcholine stores and was released. The combined release of endogenous and false transmitters from synaptosomes in the presence of [2H4]N-aminodeanol was reduced compared to controls in the presence of [2H4]choline, although combined tissue stores did not change significantly. After coincubation with [2H4]N-aminodeanol and [2H4]choline, the molar ratios of true and false transmitter in the tissue appeared to reflect the kinetic parameters for high affinity transport of the precursors. Subcellular fractionation experiments indicated that [2H4]acetyl-N-aminodeanol was incorporated into vesicles more slowly than [2H4]acetylcholine. These results indicate that the reduced rate of turnover in the presence of false precursor is not due to its rate of acetylation or to the rate of release of previously formed false transmitter, but rather to the slower membrane transport of N-aminodeanol by the high affinity uptake system. The replacement of endogenous acetylcholine in synaptosomes by acetyl-N-aminodeanol, which has 4% the potency of acetylcholine at muscarinic receptors, suggests that N-aminodeanol may be useful in studying the in vivo effects of a false cholinergic transmitter.

Acetylation↗