L L Iversen's research while affiliated with University of Cambridge and other places
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Publications (297)
Six analogues of substance P were synthesized with the aim of developing a metabolically stable peptide that would retain the biological activity of substance P. A recently isolated and characterized substance-P-degrading enzyme from human brain with a high specificity for substance P described in the preceding paper in this journal was used as a m...
The 'excitotoxic theory' suggests that ischaemia-induced neuronal degeneration is caused, at least in part, by excessive release of glutamate and a subsequent overactivation of post-synaptic receptors. The N-methyl-d-aspartate (NMDA) receptor plays a key role in mediating this toxicity, probably due to its high permeability to calcium, a known medi...
A novel series of 5-amino-1,4-benzodiazepin-2-one derivatives (amidines), which contain a cationic solubilizing group and which are antagonists for the cholecystokinin (CCK)-B receptor, have been identified. Optimization of this series led to the identification of an azabicyclononane amidine, L-740,093 [N-[(3R)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3...
It has been reported that several uncompetitive NMDA receptor ion channel blocking agents (phencyclidine, ketamine, dizocilpine, dextrorphan) cause transient reversible vacuolation in neurons in the posterior cingulate cortex of rats. Similar effects have also been observed with competitive glutamate antagonists such as CPP, CGS 19755 and CGP 37849...
The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagoni...
Antagonist/agonist binding ratios (NMS/Oxo-M ratio) were used as an index of the efficacy of novel compounds acting at muscarinic receptors. These binding ratios have been used with a range of functional pharmacological assays to investigate the effects of varying the efficacy of muscarinic agonists. This strategy has been used as a means of obtain...
Cholecystokinin (CCK) is found in high concentrations in mammalian brain where it appears to act as a neurotransmitter. CCK has been implicated in a number of important physiological processes and disease states, including feeding and feeding disorders, nociception, schizophrenia, movement disorders, anxiety, and panic disorder. The recent increase...
The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist...
1. The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea-pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively)...
The discovery in the 1970’s that choline acetyltransferase (ChAT) is markedly reduced in the brains of patients with Alzheimer’s disease (AD) compared with those of age-matched controls (Bowen et al., 1976) prompted a number of attempts to improve cholinergic transmission in patients with the disease. Initial studies with cholinesterase inhibitors...
Starting with the quinuclidinecarboxylate (I), various oxadiazolylquinuclidines are synthesized.
A series of seventy-three dibenzocycloalkenimines is synthesized as outlined in the reaction scheme.
Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous...
The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+/-)-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagoni...
Ischemia of the brain may occur following a range of pathological conditions. The mechanisms which underlie the central nervous system (CNS) neuropathology arising from the ischemic insult are complex and a number have been considered. Over the past few years evidence has accumulated to suggest a fundamental involvement of excitatory amino acids. G...
Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits N-Me-D-Asp responses by a selective antagonism of glycine at this modulatory site. In rat cortical sli...
1. Radioligand binding assays using [3H]-N-methylscopolamine (NMS) and [3H]-oxotremorine M (Oxo-M) have been devised to predict the efficacy of test compounds at muscarinic receptors in rat cerebral cortex. 2. Muscarinic antagonists, including non-selective and both M1- and M2-selective compounds, displayed similar affinity for both binding assays....
"Psychopharmacology of the Aging Nervous System" was selected as the topic for Volume 20 of the Handbook of PsychopharmacoloffY. Senile dementia is now widely recognized as a medical and social problem likely to reach epidemic proportions by the turn of the century. By that time it is esti mated that almost 20% of the population in most developed...
Behavioural responses to tachykinins were observed following intracisternal administration in mice. The synthetic NK-3 agonists senktide and L-363,851 caused behaviour typically associated with serotonergic stimulation, including head twitches, reciprocal forepaw treading and hindlimb splaying. Neurokinin B produced some features of the serotonin (...
In support of heterogeneity in Alzheimer's disease (AD), the existence of clinical and biologic subtypes has been claimed. We have investigated this claim by a statistical analysis of the relationships between the number of neurons in nucleus locus ceruleus (nLC), cortical levels of neurotransmitters, number of cortical plaques and tangles, and age...
Relationships were examined between neuronal degeneration in the nucleus locus ceruleus (nLC), a parameter of central noradrenergic impairment, and neocortical markers of Alzheimer disease (AD). The loss of nLC neurons was found to correlate significantly with norepinephrine concentration, choline acetyltransferase (ChAT) activity, and numbers of p...
Based on the different rank order of potencies as well as the lack of complete cross-tachyphylaxis observed among different tachykinins and their analogues in several biological assays, we have previously proposed the existence of multiple subtypes of SP receptors in different tissues [1–3]. For the SP-P subtype, both physalaemin (PHY) and SP are a...
Volumes 7 and 8 of the Handbook were published in 1977. In Volume 7 methods for studying unconditioned and conditioned behavior were reviewed. Attention was given to both ethological methods and operant conditioning techniques as applied to some selected aspects of behavior. Genetic, developmental, and environmental factors influencing behavior wer...
The evidence for the existence of multiple classes of receptor for the naturally occurring tachykinins has been reviewed previously [1–4]. Our original proposal for a sub-division of SP-P and SP-E receptors [1] was based on pharmacological data. showing differences in the relative potencies of tachykinins in different peripheral tissue bioassays. T...
Tachykinin binding sites in guinea pig urinary bladder (GPUB), rat salivary gland (RSG), hamster urinary bladder (HUB), rat vas deferens (RVD) and rat cerebral cortex (RCC) were compared using 125I-Bolton Hunter conjugates of substance P (125I-BHSP), eledoisin (125I-BHE) and neurokinin A (125I-BHNKA). In typical SP-P tissues (GPUB, RSG) and in RCC,...
The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereos...
Apart from the damage to ascending cholinergic projections in Alzheimer's disease, biochemical studies on human brain post mortem have revealed a number of other neurochemical abnormalities. These include reductions in 5-hydroxytryptamine (5-HT) and 5-HT receptors, and in noradrenaline. There is also evidence of selective damage to somatostatin-con...
Apart from the damago to ascending cholinergic projections in Alzheimer's disease, biochemical studies on human brain post mortem have revealed a number of other neurochemical abnormalities. These include reductions in 5-hydroxytryptamine (5-HT) and 5-HT receptors, and in noradrenaline. There is also evidence of selective damage to somatostatin-con...
Cerebellar Purkinje neurons accumulated propidium iodide, granular blue, and horseradish peroxidase conjugated to wheat germ
agglutinin but not unconjugated horseradish peroxidase, bisbenzimide, or Evans blue when these compounds were infused into
the lateral cerebral ventricles of awake, unrestrained rats. Accumulation of propidium iodide by Purki...
Pirenzepine, a compound with selective anti-muscarinic activity, was used to distinguish muscarinic acetylcholine receptor subtypes in normal human brain. Hill coefficients and IC50 values derived from the inhibition of specific [3H]l-quinuclidinyl benzilate receptor binding suggest the presence of two muscarinic binding sites, differing both in af...
Specific binding of 3H-substance P was studied in guinea-pig ileum longitudinal smooth muscle membranes. A single population of non-interacting sites with an apparent dissociation constant of 1.8 nM was observed. The relative potencies of some structural analogues of substance P, notably eledoisin and substance P (5-11), in competing for 3H-substan...
The present paper examines the relationship between choline acetyltransferase (ChAT) activity and gamma aminobutyric acid (GABA) concentrations with neuronal counts, senile plaque counts and estimates of neurofibrillary tangles in a series of 25 cases of senile dementia of Alzheimer type (SDAT) with appropriate controls.
ChAT activity was significa...
Brains of 49 patients who had died with Alzheimer's disease and 54 controls were examined. The Alzheimer group exhibited noticeably reduced activity of the cholinergic marker enzyme choline acetyltransferase in the cerebral cortex, but cortical concentrations of noradrenaline, gamma-aminobutyric acid, and somatostatin were also significantly reduce...
The concentrations of arginine vasopressin, oxytocin, and their related neurophysins were compared in many areas of postmortem human brain and spinal cord using specific radioimmunoassays. In the hypothalamus the ratio of vasopressin to oxytocin was approximately 3:1, and in the extrahypothalamic areas of the brain the greatest amount of both pepti...
Using [3H]ketanserin, a specific ligand for the 5-HT2 receptor, the amount of specific binding was measured in preparations of post-mortem frontal cortex from subjects diagnosed as suffering from dementia. A highly significant 42% loss of binding was observed which reflected a decrease in receptor density compared to psychiatrically normal controls...
Neuronal peptides are recent additions to the catalogue of substances which may act as intracellular signals in the nervous system. As a result, little is known of the receptors or biochemical mechanisms mediating their actions. Substance P (SP) was the first peptide for which a neurotransmitter role was proposed, and is currently speculated to be...
Volume 18 of the Handbook of Psychopharmacology represents the first of a series of volumes intended to bring earlier sections of the work up to date. Volumes 7, 8, and 9, published in 1977 and 1978, dealt with principles of behavior, drugs and neurotransmitters, and neuroanatomy. In subsequent volumes dedicated to these issues, a mixture of topics...
The breakdown of phosphatidylinositol lipids in cell membranes may have a key role in controlling the rise in cytosolic Ca2+ which occurs on stimulation of a variety of cell-surface receptors. Pre-iously this phenomenon has been studied by monitoring the rate of incorporation or loss of radioactivity from isotopically labelled membrane phospholipid...
The dopamine (DA) innervation to the forebrain arises from subpopulations of midbrain DA neurones broadly classified as nigrostriatal, mesolimbic and mesocortical. Significant differences in the autoregulatory mechanisms and neuronal inputs of these DA pathways may account for their differences in physiological and pharmacological responsiveness. F...
A hypothalamo-neurohypophyseal enkephalinergic pathway has been described and the pars nervosa of the rat pituitary contains enkephalin-like material which may coexist in vasopressin and oxytocin terminals. At the level of the pars nervosa itself, stereospecific opiate receptors with properties very similar to those of brain receptors have been des...
Serial sections of human brainstem were used to determine the total number of pigmented cells in locus coeruleus and, by immunohistochemical staining using an antiserum directed against human dopamine-beta-hydroxylase (DBH), the number of DBH-positive cells. In 12 brains from elderly control and dementia subjects there wer not significant differenc...
The numbers of myelinated and unmyelinated fibers were counted in dorsal roots of adult rats treated neonatally with capsaicin in doses ranging from 5 to 100 mg/kg. Substance P and somatostatin levels in the spinal cord, dorsal roots, and sensory ganglia also were determined in control and treated animals. Capsaicin administration lead to the loss...
It is well established that neuroleptic drugs are antagonists of brain dopamine receptors. The role of the reported increase in dopamine receptors (measured as 3H-spiperone binding sites) in post-mortem brain tissue from patients with schizophrenia in the aetiology of the disease is, however, unclear. We have found this increase only in chronically...
Previous studies from this laboratory suggested that two subtypes of substance P receptor may exist, based on the observations that substance P and related peptides did not exhibit complete cross-desensitisation on guinea-pig ileum, and that two distinct rank orders of potency of tachykinins were observed in various test systems. The present study...
It is now eight years since the first Handbook volumes on Basic Neuro pharmacology were published, and there have been many important advances. As in many other areas in science, progress in this field has depended to a considerable extent on the availability of new experimental methods, and Volume 15 reviews some major recent developments, includ...
It is now eight years since the first Handbook volumes on Basic Neuro pharmacology were published, and there have been many important advances. As in many other areas in science, progress in this field has depended to a considerable extent on the availability of new experimental methods, and Volume 15 reviews some major recent developments, includ...
Vasopressin immunoreactivity was measured post-mortem in the locus coeruleus and substantia nigra of 16 cases of Parkinson's disease and multisystem atrophy, 10 cases of Huntington's chorea and 28 normal controls. Amounts of vasopressin did not differ significantly (P greater than 0.05) between the 3 groups. Immunohistochemistry demonstrated vasopr...
Receptors for the biologically-active peptide, substance P, have been studied in the nervous system and in peripheral tissues using radio-ligand binding, stimulation of phospholipid turnover, and pharmacological bioassays. The binding of 3H-substance P to rat brain membranes indicates the presence of a single saturable population of sites. They are...
Substance P has been prepared 3H labeled at Phe8 by catalytic deiodination of a protected precursor. Synthesis of the precursor was by solid-phase methodology on polydimethylacrylamide resin and by condensation in solution of fragments covering sequences 1-4, 5-7, and 8-11. Free peptide made by each route analyzed satisfactorily and had the same ch...
In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes...
Choline acetyltransferase (ChAT) activity and gamma-aminobutyric acid (GABA) concentration were measured in 19 cerebral cortical areas and 22 subcortical areas of brains from 26 control and 25 histologically proven cases of Alzheimer's disease. Reduced ChAt activity was observed in all the cortical areas examined in the Alzheimer cases dying before...
Neurotensin (NT) is an endogenous neuropeptide that is active in many preclinical screening tests for neuroleptic drugs. Using a radioimmunoassay, we have studied the regional distribution of NT in postmortem human brain and in cerebrospinal fluid. Highest levels were present in the hypothalamus, substantia nigra, and limbic areas, whereas much low...
Using a rapid, simple and sensitive radioreceptor assay, a Ca2+-dependent K+-evoked release of endogenous GABA was demonstrated from rat cortical and hippocampal slices in vitro. This evoked-release of endogenous GABA was similar to that of [3H]GABA release (in its Ca2+ dependency) but differed from the latter in having a higher signal to noise lev...
Acetylcholinesterase staining was examined in the substantia innominata of 3 normal human brains. Large intensely stained neurones were seen within the region of the basal nucleus of Meynert which is believed to be the origin of the cholinergic projection to the neocortex in animals. On the basis of the acetylcholinesterase staining pattern, the su...
Benzodiazepine tranquillizers such as diazepam and chlordiazepoxide interact with high-affinity binding sites in nervous tissue1,2. The correlation between the affinities of various benzodiazepines for these sites with their clinical potencies and activity in behavioural and electrophysiological tests in animals suggests that the sites represent th...
The ability of various related peptides and substance P analogues to compete for the binding of 3H-labelled substance P to rat brain membranes corresponds with their known biological activities, providing a simple model for studies of peptide receptors in the central nervous system. In salivary gland and brain slices substance P and related peptide...
The metabolic activity of the neural lobe of the rat pituitary gland was measured by autoradiographic estimation of the rate of accumulation of 1-[3H]-2-deoxy-D-glucose ( [3H]-2DG). Replacement of drinking water by 2% saline for 5 days resulted in a 300% increase in [3H]-2DG accumulation in the neural lobe. Morphine (8 mg/kg s.c.) increased [3H]-2D...
A metabolically protected analog of substance P, [pGlu5-MePhe8-MeGly9]SP(5-11) (DiMe-C7), was approximately equipotent with substance P in causing increased locomotor activity after microinfusion into the ventral tegmental area of rat brain, but the effects of DiMe-C7 on behavior were considerably prolonged. There was little metabolic degradation o...
1.
The possible existence of multiple receptors for substance P (SP) was investigated by examining the relative pharmacological potencies of SP and related peptides in contracting guinea pig ileum, in potentiating electrically evoked contractions of rat vas deferens preparations and in competing for 3H-SP receptor binding in rat brain membranes, an...
During the last two decades many new techniques have been developed to measure neurotransmitters and neurotransmitter-related enzymes and receptor sites in the central nervous system. The application of such neurochemical techniques, together with histochemical staining methods, has greatly expanded our knowledge of transmitter-specific pathways in...
Volume 15 of Handbook of Psychopharmacology represents the first of a new series of volumes whose aim is to bring earlier sections of the work up to date by describing the latest developments in the field. It is now seven years since the first Handbook volumes on Basic Neuropharmacology were published, and there have been many important advances. A...
The noradrenergic innervation to the cerebellum was lesioned by intracerebroventricular 6-hydroxydopamine and the effects on GABA and benzodiazepine receptors followed by radiolabelling experiments. This lesion produced a 20% decrease in benzodiazepine receptor labelling in the cerebellum with no change in the labelling of GABA receptors. This prov...
3-Mercaptopropionic acid (3MP) (1 mM) inhibited the potassium-evoked release of endogenous GABA from slices of rat hippocampus and cerebral cortex in vitro. This did not appear to be due to an inhibition of GABA biosynthesis, since 3MP failed to affect the basal rate of GABA release or to accelerate the decline in the GABA content of tissue slices...
The specific binding of [3H]spiperone and [3H]domperidone, as defined by 1 microM-(+)butaclamol, was compared in homogenates of bovine retina and caudate nucleus. Scatchard analyses of saturation data for [3H]spiperone binding yielded dissociation constants (Kd) of 0.35 nM in the retina and 0.64 nM in the caudate nucleus. Comparison of the maximum...
Thirty three synthetic analogues of GABA were tested for their ability to act as inhibitors of neuronal or glial uptake sites for GABA and β-alanine, using [3H]GABA uptake by synaptosome preparations from rat cerebral cortex, and [3H]β-alanine uptake by cortical slices as test systems for neuronal and glial uptake sites, respectively. The results c...
Administration of a single dose of capsaicin (50 mg/kg; sc) to two-day-old rats resulted in a loss of between 85 to 95% of the small diameter unmyelinated primary afferent fibres from lumbar dorsal roots. The numbers of myelinated fibres in the dorsal roots were not significantly affected. The substance P and somatostatin contents of the dorsal roo...
Fifty synthetic analogues of GABA were tested for their ability to interact with GABA receptors, using [3H]GABA binding to human cerebellar membranes as an in vitro model. The most active compounds were found to be aliphatic and heterocyclic aminosulphonic acids. Compounds with highly substituted nitrogen atoms were only weakly active unless a long...
Citations
... In the neuron, VIP is synthesized in the soma, exported to the axons and dendrites (Iversen et al., 2012) and synaptically released in a K+-sensitive, Ca2+-dependent mechanism (Giachetti et al., 1977;Emson et al., 1978). VIP belongs to a family of structurally related neuropeptides and hormones that includes secretin, glucagon, growth hormone releasing factor, glucagon-like peptide-1 and -2, helodermin, gastric inhibitory peptide and pituitary adenylate cyclase-activating polypeptide (PACAP) (Delgado and Ganea, 2013). ...
... Data analysis showed that AQP had a significant higher heart rate before and during surgery compared to the other treatment groups. Administration of capsaicin produces complex or mixed effects (bradycardia or tachycardia) on the cardiovascular system Iversen [20]. Chahl, Lynch [21] even stated a triphasic effect on blood pressure after intravenous injection of capsaicin in rats. ...
... Recent studies also revealed that DRLC prevented intervertebral disc degeneration induced by annular puncture in rabbits (Ogunlade et al., 2019). However, a low level of GSH in the brain has been implicated in the pathogenesis of neurodegenerative diseases (Koji et al., 2006;Rossor & Iversen, 1986;Tiwari & Soni, 2014) and increased production of GSH on the other hand, has been reported to elicit neuroprotective property (Koji et al., 2006;Koji & Toshio, 2013). Previous study has shown that neuronal GSH deficiency correlated with age-dependent neurodegeneration in the cysteine transporter deficient mouse (Koji et al., 2006), suggesting its beneficial effect in age-related memory deficits. ...
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... This is a likely explanation because the NMDA receptor is known to be critically involved in the imprinting process in 2-day-old chicks13141516. However, the pharmacology of ketamine is complex and is not limited to actions on the NMDA receptor system [17]. In Experiment 3, we therefore sought to determine whether treatment with MK-801, a more specific NMDA receptor antagonist, could replicateFig. ...
... However, most studies of susceptibility in genetics focus on analysis of 'common variants' (Goldstein and Chikhi, 2002). An association between cholecystokinin (CCK) and PD was observed in 1979 by one of us, who noted that an intravenous bolus injection of CCK-4 (the bioactive C-terminus of CCK peptides) precipitated panic-like attacks in normal controls (Rehfeld, 1992Rehfeld, , 2000). It is now well established that exogenous CCK-4 provokes panic attacks both in normal controls and in patients with PD (DeMotigny, 1989). ...