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L C Murrin

Publications and source records attributed to L C Murrin.

At least 37 records · Page 2Linked to original sources
PubMed1993

High-affinity choline transport sites: use of [3H]hemicholinium-3 as a quantitative marker.

High-affinity choline transport (HAChT), the rate-limiting and regulatory step in acetylcholine (ACh) synthesis, is selectively localized to cholinergic neurons. Hemicholinium-3 (HC3), a potent and selective inhibitor of HAChT, has been used as a specific radioligand to quantify HAChT sites in membrane binding and autoradiographic studies. Because both HAChT velocity and [3H]HC3 binding change as in vivo activity of cholinergic neurons is altered, these markers are also useful measures of cholinergic neuronal activity. Evidence that [3H]HC3 is a specific ligand for HAChT sites on cholinergic terminals is reviewed. The ion requirements of HAChT and [3H]HC3 binding indicate that sodium and chloride are required for recognition of both choline and [3H]HC3. A common recognition site is also indicated by the close correspondence of the potency of HC3 and choline analogues for inhibiting both HAChT and [3H]HC3 binding. The parallel regional distributions of both markers in adult brain, during development and after specific lesions, all indicate specific cholinergic localization. The close association of HAChT and [3H]HC3 binding sites is also supported by parallel regulatory changes occurring after in vivo drug treatments and in vitro depolarization. Overall, the data indicate a close association between HAChT and [3H]HC3 binding and are consistent with the sites being identical. Methodologic considerations in using [3H]HC3 as a ligand and considerations in interpretation of results are also discussed.

Animals↗
PubMed1992

Development of high-affinity choline transport sites in rat forebrain: a quantitative autoradiography study with [3H]hemicholinium-3.

The development of cholinergic terminals in rat brain has been quantitatively analyzed by [3H]hemicholinium-3 autoradiography. [3H]Hemicholinium-3 binds to high affinity choline transport sites, a specific marker for cholinergic neurons. In neonatal animals, kinetic and pharmacologic binding characteristics and regional distribution of [3H]hemicholinium-3 sites are consistent with specific cholinergic localization, as in the adult. The distribution of cholinergic terminals is described in the adult rat brain and during development, including heterogeneity of binding within several regions such as the striatum, nucleus accumbens, olfactory tubercle, cortex, and hippocampus. Early development and maturation vary greatly between brain regions. At embryonic day E18 and day 0, specific binding density is high only in the medial habenula. Development occurs primarily during the postnatal period in most brain regions examined. Many brain regions exhibit a lull in development between days 5 and 10, although the rate of development is highly region specific. Specific binding increases 2-12-fold between day 5 and adult animals, with adult density being achieved anywhere from day 15 to after day 21. The ontogeny of [3H]hemicholinium-3 binding sites generally occurs in a rostral to caudal direction. In the striatal body the characteristic lateral to medial gradient of binding site density is apparent by day 5, and development is more rapid in the lateral striatum. Patches of dense [3H]hemicholinium-3 binding coincident with acetylcholinesterase are observed on day 5 in the caudal striatum. The various patterns of cholinergic terminal development suggest that factors regulating cholinergic development are regional and complex.

Acetylcholine↗
PubMed1992

High-affinity choline transport regulation by drug administration during postnatal development.

High-affinity choline transport sites specifically bind [3H]hemicholinium-3. Hemicholinium-3 binding sites are regulated by in vivo drug treatments in the same manner as these drugs alter acetylcholine release and high-affinity choline transport. The current study examines regulation of binding sites by in vivo drug administration for adult, day 15, and day 5 rats. Drugs or saline were administered intraperitoneally, and striatal and cortical membrane preparations were assayed. Control [3H]hemicholinium-3 binding increases twofold between postnatal days 5 and 15 only in striatum. After day 15, binding increases 2.7-fold in cortex and striatum. Nicotine treatment increases striatal and cortical hemicholinium-3 binding at all three ages, with greater percent increases at day 5. Haloperidol increases binding only in striatum, again with larger effects at day 5. Both striatal and cortical binding are reduced by oxotremorine; however, the magnitude of this effect is unchanged during development. Pentobarbital reduces binding only in striatum, with no developmental change. Atropine and apomorphine do not change binding from control values. In summary, all drug treatments effective in adults were already effective by day 5. Cholinergic terminals present early in development are regulated by similar nicotinic and muscarinic cholinergic, dopaminergic, and sedative-hypnotic mechanisms as the adult. Changes in magnitude may be due to changes in drug metabolism or to developmental differences in regulation.

Animals↗
PubMed1991

Autoradiographic localization of dopaminergic and noradrenergic receptors in the bovine pineal gland.

Dopamine and norepinephrine are involved in regulation of melatonin synthesis in the pineal gland. In bovine pineal gland, D1- and D2-dopaminergic and alpha 1-adrenergic receptors have been characterized pharmacologically in several laboratories, while beta 1-adrenergic receptors have been studied using physiological technique. The current study presents a quantitative autoradiographic analysis of these four dopaminergic and noradrenergic receptors in bovine pineal gland. The density order of the receptors is D1 greater than alpha 1 greater than D2 greater than or equal to beta 1. The Bmax of dopamine D1 receptors is about 5 to 6 times higher than the Bmax for alpha 1-adrenergic receptors and about 20 times higher than the Bmax values for beta 1-adrenergic and D2-dopaminergic receptors. Dopamine D1 receptors are significantly denser in the pineal cortex than in the medulla. Both dopamine receptors are more concentrated in the distal area than in the proximal area (close to the habenula), whereas both noradrenergic receptors are homogeneously distributed along the longitudinal axis. Only D1-dopaminergic receptors display a heterogeneous distribution between the superior and the inferior areas, being denser in the inferior area. The observation of a much higher concentration of D1-dopaminergic receptors relative to the other receptors suggests an important role for dopamine in the regulation of bovine pineal physiology.

Animals↗
PubMed1990

Ontogeny of dopamine D1 receptors in rat forebrain: a quantitative autoradiographic study.

The development of dopamine D1 receptors during the early postnatal period is examined in rat forebrain, using quantitative autoradiography and [3H]SCH 23390 as ligand. Dopamine D1 receptors are present in many regions at birth. In general, regions with the highest densities of D1 receptors in adults have the highest densities of receptors in neonates. For most regions in the forebrain there is a steady increase in the density of D1 receptors, as measured in fmol/mg tissue, from day 1 to day 28 of age. This is most obvious in the regions with the greatest number of receptors, such as the caudate-putamen, the nucleus accumbens, and the olfactory tubercles. The more caudal regions examined in this study had a relatively greater portion of their receptors present at day 1 compared to day 28 than more rostral regions. In general they had about 50% of their receptors present at birth, whereas most regions studied had receptor levels at day 1 about 20% of those found at day 28. In the most anterior regions, the development of receptors was somewhat slower. Receptor number in the frontal cortex region did not begin to increase until about 10 days of age. The present studies indicate that dopamine D1 receptors develop in the forebrain of the rat in a steady pattern. There are no dramatic increases or decreases in receptor number throughout the postnatal period.

Aging↗
PubMed1990

Tritium quench in autoradiography during postnatal development of rat forebrain.

Quantitative autoradiography of tritium-labeled brain tissue requires correction for regional and age-dependent changes in tritium quenching. Correction values are determined using chloroform extraction of brain sections labeled with tritiated 2-deoxyglucose ([3H]2DG) in adult rats and rats at postnatal ages of 5, 14 and 21 days. Conditions are described for intraperitoneal injection of [3H]2DG for labeling neonatal animals which maximize the formation of [3H]2-deoxyglucose-6-phosphate. Tritium quench correction coefficients are determined in 65 brain regions at each age. Autoradiographic tritium quench increases during postnatal development in all brain regions, with the rate and extent of change corresponding to the development of myelination in different structures. Quench coefficients range from 6 to 45% in 5 day animals and from 21 to 108% in adult animals. Gray matter structures have a major increase in tritium quenching between postnatal days 5 and 14. Quench coefficients in white matter-containing structures increase throughout postnatal development at region-specific rates. These data may be used to correct regional differences in tritium quenching for autoradiographic studies of postnatal development.

Absorption↗
PubMed1990

Histidine decarboxylase from rat and rabbit brain: partial purification and characterization.

Histidine decarboxylase, the synthetic enzyme for histamine, was partially purified from regions of rat or rabbit brain rich in the enzyme. The enzyme was purified using ion exchange and hydrophobic column chromatography and chromatofocusing. Approximately 70-fold and 110-fold enrichments were attained from rat and rabbit brain, respectively. Rat and rabbit brain histidine decarboxylase had isoelectric points of pH 5.4 and 5.6, Km values of 80 microM and 120 microM histidine and Vmax values of 210 and 625 pmol histamine formed/hr-mg protein, respectively. The partially purified histidine decarboxylase from both sources was dependent on pyridoxal phosphate for maximal activity and was inhibited by alpha-fluoromethylhistidine, nickel chloride and cobaltous chloride but was not inhibited by impromidine, alpha-methyldopa, DTNB, zinc chloride or mercuric chloride. The enzyme had a broad pH optimum between pH 7.2 and 8.0. These studies provide further information on the characteristics of mammalian histidine decarboxylase from brain.

Animals↗
PubMed1990

Pathogenesis and treatment of neuroleptic malignant syndrome.

1. Neuroleptic drugs (antipsychotics) produce numerous side effects which include serious extrapyramidal symptoms consisting of akathisia, dystonia, neuroleptic malignant syndrome, parkinsonian reactions such as postural abnormality, tremor, akinesia or bradykinesia, rigidity, and tardive dyskinesia. 2. Among the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is characterized by extreme hyperthermia, "lead pipe" skeletal muscle rigidity causing dyspnea, dysphagia, and rhabdomyolysis, autonomic instability, fluctuating consciousness, leukocytosis, and elevated creatine phosphokinase. 3. Neuroleptic malignant syndrome should be differentiated from malignant hyperthermia, lethal catatonia, and other pathological states producing some of these same symptoms. 4. In addition to neuroleptics, malignant syndrome has been caused by thymoleptics (antidepressants), metoclopramide (antiemetic), metoclopramide combined with cimetidine, tetrabenazine, overdosage of benzodiazepine, phenelzine, dothiepin and alcohol, and amphetamine. 5. Factors leading to and/or facilitating the emergence of neuroleptic malignant syndromes are reportedly organic brain syndrome, dehydration, exhaustion, external heat load, excessive sympathetic discharge, use of long acting neuroleptics, high doses of neuroleptics, rapid dose titration with neuroleptics, abrupt discontinuation of antiparkinsonism agents, and concurrent lithium therapy. 6. Although, the pathogenesis of neuroleptic malignant syndrome is not understood completely, a blockade of dopaminergic receptors in the hypothalamus, spinal cord and striatum, an alteration of dopaminergic-serotonergic transmission in the body, an enhanced synthesis and action of prostaglandin E1 and E2, and a modification of calcium-mediated signal transduction in the body have been suggested. 7. The treatment of malignant syndrome includes immediate withdrawal of neuroleptic drugs, i.v. infusion of dantrolene, and oral administration of bromocriptine; or alternatively i.v. infusion of dantrolene and the combination of levodopa-carbidopa. 8. Other measures to enhance the therapeutic effectiveness of the aforementioned regimens are to include the use of anticholinergic drugs such as benztropine to enhance the effectiveness of bromocriptine, of lorazepam if catatonic symptoms persist, or of electroconvulsive therapy (ECT) if psychotic symptoms persist. 9. These treatments, however, must be "active" rather than "passive", in order to avert fatalities and/or unfortunate sequelae from this iatrogenic and incompletely understood disease.

Antipsychotic Agents↗
PubMed1990

Hippocampal zinc thionein and pyridoxal phosphate modulate synaptic functions.

The hippocampus, a component of the limbic system, is a prominent subcortical structure, which not only contains high concentrations of zinc, but also exhibits regional variations in this essential element, with concentrations being highest in the hilar region and lowest in the fimbria. For example, the concentration of zinc in the mossy fiber axons has been estimated to approach 300-350 microM. Both zinc and pyridoxal phosphate (PLP) deficiency and excess have been reported to produce epileptiform seizures, which are blocked by gamma-aminobutyric acid (GABA). The proposed mechanism is that at physiological concentrations zinc stimulates the activity of the hippocampal pyridoxal kinase (50% stimulation at 1.7 x 10(-7) M), enhancing the formation of PLP, whereas in pharmacological doses zinc inhibits the activity of glutamate decarboxylase (GAD) directly (50% inhibition at 6.5 X 10(-4) M) by preventing the binding of PLP to HoloGAD. Furthermore, recent studies have shown that two forms of GAD are found in the rat brain. One form (GAD A) does not require PLP for maximal activity, while another form (GAD B) does. Furthermore, the ratio between GAD A and GAD B is nonuniform throughout brain areas, and the hippocampus contains twice as much GAD B (the PLP-requiring GAD) as GAD A. Although the hippocampus is a common target of exogenous neurotoxic agents, "free" zinc in greater than physiological concentrations should be considered an endogenous central neurotoxin. For example, iontophoretically applied zinc in the frontoparietal cortex enhances and prolongs the firing rate of neurons in urethane-anesthetized rat. In addition, zinc (50-500 microM) significantly depresses the paired-pulse potentation in the hippocampal CA3 subfield. Moreover, zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons and enhances the quisqualate receptor-mediated injury. Finally zinc competitively inhibits the calcium-dependent release of transmitter by inhibiting the entry of Ca2+ into the nerve terminals. Since zinc in a concentration of 300-350 microM could not possibly remain "unbound" in the hippocampus, we searched for and identified a metallothionein-like protein (MT) in the bovine hippocampus, which produces two isoforms on reverse-phase HPLC and lacks aromatic amino acids, but possesses metallomercaptide bonds. We believe that the hippocampal metallothionein, by donating zinc to an extensive number of zinc-activated, PLP-mediated biochemical reactions, modulates synaptic functions. Furthermore, by virtue of its inducibility, metallothionein binds additional amounts of zinc, maintains its steady-state concentration, prevents inhibition of an extensive number of sulfhydryl-containing enzymes and receptor sites, and hence averts metal-related neurotoxicity.

Animals↗
PubMed1990

Characterization of D1 dopamine receptors in the bovine pineal gland with [3H]SCH 23390.

Previous studies from this laboratory have shown that bovine pineal glands not only contain D2 dopamine receptors, but also that dopamine has dual effects on the activity of pineal serotonin N-acetyltransferase, inhibiting the basal activity at 0.1 microM and stimulating it at 10 microM. We report here that the bovine pineal gland also possesses D1 dopamine receptors, which were characterized by using [3H]SCH 23390, the selective D1 dopamine receptor antagonist. SCH 23390 bound to bovine pineal membranes in a stereoselective, saturable and reversible manner. The receptor density (Bmax) was 974 fmol/mg protein and the dissociation constant (KD), as determined by saturation studies, was 0.56 nM, which is in good agreement with the KD calculated from kinetic studies (0.40 nM). Dopaminergic receptor agonists and antagonists inhibited [3H]SCH 23390 binding in a concentration-dependent and stereoselective fashion, demonstrating a pharmacology characteristic of D1 dopamine receptors. On the other hand, serotonin and serotonin receptor antagonists had a very low potency in inhibiting [3H]SCH 23390 binding. Studies involving dopamine receptor agonists revealed a low density, high affinity binding site (10%) and a high density, low affinity binding site (90%) in the bovine pineal gland. The results of this study are interpreted to indicate that the effects of dopamine in the pineal gland are modulated through mechanisms that involve both D1 and D2 dopamine receptors.

Animals↗
PubMed1989

AF64 depletes hypothalamic high-affinity choline uptake and disrupts the circadian rhythm of locomotor activity without altering the density of nicotinic acetylcholine receptors.

Ethylcholine aziridinium ion (AF64) was synthesized from acetylethylcholine mustard hydrochloride and 5 nmol was infused into the third ventricle of rats. Seven days after AF64 treatment, sodium dependent high-affinity choline (HACU) uptake was decreased by 54% in the hypothalamus. The density of hypothalamic (-)-[3H]nicotine binding sites and [alpha-125I]bungarotoxin sites in AF64-treated animals did not differ significantly from controls. A second experiment was performed to elucidate the effect of AF64 treatment on HACU and determine the effect of AF64 on entrained circadian rhythms. Animals were infused with artificial CSF or 5 nmol AF64. Locomotor activity and body temperature were recorded for 3 weeks before and 3 weeks after treatment. Ten of 14 AF64-treated animals showed a decrease in the ratio of dark cycle:light cycle locomotor activity. The decrease in dark-cycle activity was correlated with a disruption of a predominant circadian rhythm. The circadian rhythm (CR) of core body temperature was disrupted only transiently, but the CR of locomotor activity remained disrupted for the duration of the experiment in several AF64-treated animals. HACU was decreased by 48% in animals with disrupted rhythms in comparison with controls but was not significantly decreased in AF64-treated animals with normal dark-cycle activity and circadian activity. These data suggest that the AF64-treated animal may be a good model for studying the role of acetylcholine in maintaining the integrity of certain circadian rhythms.

Animals↗
PubMed1989

Histamine synthesis in rat hypothalamus is not acutely regulated via histidine decarboxylase.

There is considerable support for histamine acting as a neurotransmitter in the central nervous system. Since the synthesis of many biogenic amine neurotransmitters is highly regulated on a short-term basis, we investigated whether a similar regulation exists for histamine synthesis. Previous studies have indicated that histidine transport into nerve terminals is not a regulatory step in histamine synthesis. In this study we examined histidine decarboxylase activity as a possible regulatory point. Using a variety of depolarization methods and hypothalamic and striatal tissue slices and/or synaptosomes, we found no alterations in histidine decarboxylase activity. Based on these and previous studies we conclude that histamine synthesis in the hypothalamus, and perhaps throughout the CNS, does not have mechanisms for rapid short-term regulation. These data support the idea that histamine acts as a neuromodulator and does not play a critical role in acute regulation of CNS function at least in some brain regions.

Animals↗
PubMed1989

Dopamine D1 receptor development in the rat striatum: early localization in striosomes.

The development of dopamine D1-receptors in rat striatum during the early postnatal period is examined, using autoradiography and [3H]SCH 23390 as ligand. Dopamine D1-receptors are present in striatum at birth and are more dense than in any adjacent region. The receptors are preferentially localized in striosomes and to some extent in a subcallosal streak. The density of D1-receptors in the matrix increases with age so that by two weeks postnatally the striosomal pattern is no longer evident, and the overall dense labelling is the same as seen in adults. Dopamine D1-receptor development seems to take place earlier than that of dopamine terminals but at the same time as or somewhat later than that of acetylcholinesterase. The D1-defined striosomes move from ventrolateral towards dorso-medial striatum with increasing age and from anterior to posterior striatum. This direction is nearly perpendicular to the direction of development of several other markers, including dopamine terminals and D2-receptors. The present studies indicate that for markers appearing in the striosomal compartment there are different patterns of development with respect to time and spatial pattern. Regulation of striatal development by interaction of neuronal systems with one another and with other factors is complex and will require extensive study to clarify the mechanisms involved.

Aging↗
PubMed1988

Ontogeny of dopamine D1 receptors in rat striatum.

The development of dopamine D1 receptors in rat striatum during the early postnatal period is described, using [3H]piflutixol as ligand. Dopamine D1 receptors increase in number from day of birth until about 21 days of age, when they reach adult levels. This increase in number parallels the increase in several other dopamine markers in striatum during the same time period. The increase is reflected in an increase in Bmax of ligand binding to D1 receptors. All other properties of D1 receptors that were examined do not change throughout this developmental period and are essentially the same as those found in adult tissue. These include association and dissociation rates, affinity for piflutixol as determined by kinetic and saturation studies, and pharmacology. These studies provide a biochemical and pharmacological basis for further studies on the ontogeny of dopamine receptors and of striatum and on factors regulating development of this region.

Aging↗
PubMed1987

Nicotine administration to rats: methodological considerations.

The effects of nicotine on normal physiological function are of increasing concern. Preliminary to studies on the effects of prenatal exposure to nicotine, we examined methods of administering nicotine to rats. Drinking water containing nicotine was not palatable to rats and was an unsatisfactory method in our hands, producing weight loss and large decreases in fluid intake. Administration of nicotine in a complete liquid diet produced better results but the data suggest that oral administration of nicotine may interfere with absorption of some nutrients. Osmotic mini-pumps were found to be the best mechanism of nicotine delivery of those tried. There were no significant effects on food or water intake nor on weight gain, particularly when using a short term anesthetic for pump implantation. Plasma nicotine and cotinine levels were directly correlated to dose of nicotine delivered. Plasma nicotine levels similar to levels reported in humans were obtained.

Administration, Oral↗
PubMed1987

Nigrostriatal dopamine neurons: modulation of impulse-induced activation of tyrosine hydroxylation by dopamine autoreceptors.

The role of dopamine autoreceptors on nerve terminals in controlling the activity of tyrosine hydroxylase in the striatum was examined using a model involving supramaximal electrical stimulation of the nigro-neostriatal fibers and accumulation of 3,4-dihydroxyphenylalanine (DOPA) as a measure of the activity of tyrosine hydroxylase in vivo. In this way effects of drugs on impulse flow in these neurons could be negated and the effects on dopamine autoreceptors evaluated. Electrical stimulation, haloperidol, pimozide and clozapine increased the activity of tyrosine hydroxylase in vivo while trivastal, a dopamine agonist, had no significant effect. Combination of electrical stimulation with haloperidol or pimozide produced an additive effect on the activity of tyrosine hydroxylase, consistent with blockade of autoreceptors on nerve terminals. The combination of stimulation with clozapine (a drug shown to have minimal blocking action on autoreceptors in this model) produced an effect equivalent to stimulation alone, consistent with a lack of effect on autoreceptors. Trivastal reduced the effect of electrical stimulation, indicating a stimulatory action on dopamine autoreceptors on nerve terminals. These data are consistent with the theory of regulation of the activity of tyrosine hydroxylase in dopaminergic nerve terminals of the striatum by means of dopamine autoreceptors.

Animals↗