Showing papers in "Journal of Neural Transmission in 1993"
TL;DR: D dopamine likely contributes significantly to the pathophysiology of depression, however, the role of dopamine in this syndrome must be understood in the context of existing theories involving other neurotransmitters which may act independently, and interact with dopamine and other neurochemicals, to contribute to depression.
Abstract: The dopamine hypothesis of schizophrenia and the emphasis on other neurotransmitters, most notably norepinephirne, serotonin, and acetylcholine, in the pathogenesis of depression, have focused attention away from substantial evidence implicating dopamine in affective disorders. The clinical evidence includes alterations in depressive symptoms with aging (concomitant with possible changes in dopamine metabolism), potential dopaminergic involvement in several subtypes of depression, similarities between some of the symptoms of Parkinson's disease and those of depression (including psychomotor retardation and diminished motivation), and potential dopaminergic abnormalities in seasonal mood disorder. The biochemical evidence in patients with deprission derives from studies of homovanillic acid, a dopamine metabolite, indicating diminished dopamine turnover. In addition, there is a considerable amount of pharmacologic evidence regarding the efficacy of antidepressants with dopaminergic effects in the treatment of depression. We conclude that dopamine likely contributes significantly to the pathophysiology of depression. However, the role of dopamine in this syndrome must be understood in the context of existing theories involving other neurotransmitters which may act independently, and interact with dopamine and other neurochemicals, to contribute to depression.
342 citations
TL;DR: The dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H3 receptors, and simultaneous blockade of dopamine autoreceptors increases the extent of the H3 receptor-mediated inhibition of dopamine release.
Abstract: In superfused mouse striatal slices preincubated with [3H] dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 μmol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [3H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H3 agonist R-(−)-α-methylhistamine; it was not affected by the H1 antagonist dimetindene and the H2 antagonist ranitidine but abolished by the H3 antagonist thioperamide. Tritium overflow evoked by Ca2+ ions (introduced into Ca2+free, K+-rich medium containing tetrodotoxin) was not affected by histamine 10 μmol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H3 receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H3 receptor-mediated inhibition of dopamine release.
333 citations
TL;DR: The influence from the locus coeruleus on midbrain dopamine neurons could be important in behavioural situations involving novelty and reward, and might also be of importance for the actions of psychotropic drugs.
Abstract: Electrical stimulation techniques were employed in the chloral hydrate anaesthetized male rat to evaluate if the pontine noradrenergic nucleus locus coeruleus can influence the activity of midbrain dopamine neurons in the ventral tegmental area and zona compacta, substantia nigra. Single-pulse locus coeruleus stimulation evoked an excitation, followed by an inhibition, of the electrical activity of single midbrain dopamine neurons. Neither of these responses were observed in animals pretreated with reserpine, implicating noradrenaline as a mediator. The α1-adrenoceptor antagonist prazosin decreased the excitation, while other adrenoceptor antagonists were without general effect. Burst-type stimulation produced only a more long-lasting inhibition. The influence from the locus coeruleus on midbrain dopamine neurons could be important in behavioural situations involving novelty and reward, and might also be of importance for the actions of psychotropic drugs.
299 citations
TL;DR: It is suggested that U 99194 A can antagonise a population of postsynaptic dopamine receptors involved in the suppression of some aspects of psychomotor activity that belong to the D 3 receptor subtype.
Abstract: We report on the pharmacological effects of the 20 fold D3 vs. D2 dopamine receptor preferring compound U99194A. It is shown that U99194A increases rat locomotor activity at doses that do not increase release or utilisation of dopamine in the striatum or the nucleus accumbens significantly. The data do not support any direct agonist action of U99194A at dopamine receptors. It is suggested that U99194A can antagonise a population of postsynaptic dopamine receptors involved in the suppression of some aspects of psychomotor activity. These postsynaptic receptors presumably belong to the D3 receptor subtype.
253 citations
TL;DR: The functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease is suggested.
Abstract: The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.
218 citations
TL;DR: Hydropathicity analysis revealed twelve membrane spanning segments, a topology proposed for other cloned sodium-dependent transporters, and a potential protein kinase C phosphorylation site identified in the rat homolog is not conserved in the human 5-HTT.
Abstract: A cDNA encoding a serotonin transporter (5-HTT) in the human dorsal raphe nucleus was isolated and sequenced using cross-species amplification of human 5-HTT partial cDNA by the polymerase chain reaction (PCR) and the RACE-PCR procedure, designed for rapid amplification of 3′ and 5′ cDNA ends. The cDNA contains an open reading frame encoding a hydrophobic polypeptide of 630 amino acids with a calculated molecular weight of ∼ 70 kDa. The human 5-HTT is ∼ 92% homologous to the rat protein but contains an additional consensus phosphorylation site for cAMP-dependent protein kinase recognition located in the cytoplasmic N-terminal region, while a potential protein kinase C phosphorylation site identified in the rat homolog is not conserved in the human 5-HTT. Hydropathicity analysis revealed twelve membrane spanning segments, a topology proposed for other cloned sodium-dependent transporters.
213 citations
TL;DR: Preliminary methodological studies suggest that [123I]β-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.
Abstract: Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [123I]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane ([123I]β-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamusmidbrain area. Here, we report on the regional kinetic uptake of [123I]β-CIT in the brain of 4 normal volunteers and 2 patients with Parkinson's disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinson's disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only mildly diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinson's disease. Consequently, in Parkinson's disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [123I]β-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.
195 citations
TL;DR: A unique model of DA system regulation is presented, in which tonic steady-state DA levels in the ECF act to down-regulate the response of the system to pulsatile DA released by DA cell action potential generation.
Abstract: A unique model of DA system regulation is presented, in which tonic steady-state DA levels in the ECF act to down-regulate the response of the system to pulsatile DA released by DA cell action potential generation. This type of regulation is similar in many respects to the phenomenon proposed to mediate the action of norepinephrine on target neurons; i.e., an increase in the "signal-to-noise" ratio as measured by postsynaptic cell firing (Freedman et al., 1977; Woodward et al., 1979). However, in this model the signal and the noise are neurochemical rather than electrophysiological. Furthermore, the "noise" (tonic DA in the ECF) actually down-regulates the "signal" (phasic DA release) directly, and thereby provides a "signal" of its own that affects the system over a longer time-course. Therefore, the difference between signal and noise may also depend on the time frame under which such determinations are made.
188 citations
TL;DR: It seems likely that monoaminergic therapies will continue to be necessary to treat behavioral disturbances in both Alzheimer's disease and senescence, and that dysfunction of monoamine neurons is more closely linked to non-cognitive than to cognitive changes in behavior.
Abstract: The integrity of dopaminergic, noradrenergic and serotonergic neurons in normal aging and Alzheimer's disease is reviewed. Loss of dopaminergic innervation of the neostriatum is a prominent age-related change, which corresponds with the age-related loss of dopaminergic cell bodies from the substantia nigra. This change is regionally specific, since dopaminergic innervation of the neocortex and the neostriatum are not affected. Although there is an age-related loss of noradrenergic cell bodies from the locus coeruleus, most studies indicate normal concentrations of noradrenaline in target areas. There is also evidence for reduced serotonergic innervation of the neocortex and, less convincingly, the neostriatum. Alzheimer's disease is associated with more pronounced noradrenergic and serotonergic denervation but, unlike normal aging, dopaminergic innervation of neostriatum is intact; although dopamine neurons are probably dysfunctional in this region. Studies relating neuronal markers to the symptomatology of Alzheimer's disease indicate that dysfunction of monoamine neurons is more closely linked to non-cognitive than to cognitive changes in behavior. In addition, monoaminergic therapies have been successful in ameliorating affective and psychotic behaviors along with sleep disturbances in both Alzheimer's disease and senescence. It seems likely that monoaminergic therapies (developed as we learn more about alterations in dopamine, noradrenaline and serotonin) will continue to be necessary to treat such behavioral disturbances.
164 citations
TL;DR: Evidence suggests that negative modulation of glutamatergic neurotransmission has antiparkinsonian effects in a variety of rodent and primate models of parkinsonism, and the pronounced synergism between dopaminergic agents and glutamate receptor antagonists may provide a means of using very low doses of the two drug classes in concert to treat Parkinson's disease effectively and minimize dose-related drug side effects.
Abstract: Current antiparkinsonian therapies focus on either replacing dopamine via precursor (L-DOPA) administration, or directly stimulating post-synaptic dopamine receptors with dopamine agonists. Unfortunately, this approach is associated with numerous side effects and these drugs lose efficacy with disease progression. This article reviews recent evidence which suggests that negative modulation of glutamatergic neurotransmission has antiparkinsonian effects in a variety of rodent and primate models of parkinsonism. The pronounced synergism between dopaminergic agents and glutamate receptor antagonists may provide a means of using very low doses of the two drug classes in concert to treat Parkinson's disease effectively and minimize dose-related drug side effects.
141 citations
TL;DR: The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) on the firing pattern of midbrain dopamine neurons were studied with single cell recording techniques in male albino rats anaesthetized with chloral hydrate to shed some light on the mechanisms involved in psychotic symptoms induced by phencyclidine.
Abstract: The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) on the firing pattern of midbrain dopamine neurons were studied with single cell recording techniques in male albino rats anaesthetized with chloral hydrate. The extracellularly recorded electrical activity of single, identified dopamine neurons was studied with respect to firing rate, burst firing and regularity of firing. MK-801 (0.01–1.0 mg/kg IV) induced different effects in different subgroups of midbrain dopamine neurons. In the substantia nigra, firing rate was increased while the pattern was regularized and burst firing slightly increased. In the ventral tegmental area, firing rate and regularity of firing was also increased while effects on burst firing were bidirectional. Histological inspections revealed that neurons which responded with an increase in burst firing were mainly located in the nucleus paranigralis subdivision of the ventral tegmental area, while cells responding with a decrease were predominantly found in the nucleus parabrachialis pigmentosus subdivision. The effects of MK-801 were similar to previously described effects of phencyclidine, another non-competitive NMDA antagonist. The present effects of MK-801 might shed some light on the mechanisms involved in psychotic symptoms induced by phencyclidine and other non-competitive NMDA antagonists.
TL;DR: Results indicate that estrogen may have a protective effect against methamphetamine-induced dopamine depletions and may relate to the fact that males are more likely to incur Parkinson's disease than females.
Abstract: Male and female mice were treated with methamphetamine (10.0 mg/kg/injection for four injections) and sacrificed two weeks later. It was observed that the methamphetamine treatment caused depletions in striatal dopamine which were significantly greater in males (74%) than in females (56%). These results indicate that estrogen may have a protective effect against methamphetamine-induced dopamine depletions and may relate to the fact that males are more likely to incur Parkinson's disease than females.
TL;DR: The ability of non-competitive NMDA antagonists and of the D1 or D2 antagonists to protect against m-AMPH-induced striatal DA terminal injury can be accounted for by their attenuation of m- AMPH-evoked DA overflow.
Abstract: Repeated administration of methamphetamine (m-AMPH) to rats induces dopamine (DA) terminal damage, and coadministration of antagonists of the N-methyl-D-aspartate (NMDA) or dopamine D1 or D2 receptors are protective. Striatal microdialysis of rats given a neurotoxic regimen of 4 × m-AMPH (4 mg/kg, s.c.) treatments revealed a dramatic and prolonged elevation of extracellular DA after the final m-AMPH administration. Neuroprotective regimens of MK-801, SCH 23390, or eticlopride greatly attenuated the overflow of DA resulting from the fourth m-AMPH treatment. By itself, MK-801 had no significant influence on striatal DA overflow, whereas either DA antagonist given alone elevated dialysate DA concentrations. A significant correlation was found between the magnitude of the m-AMPH-induced DA overflow of individual microdialyzed rats and their striatal DA content at sacrifice one week later.
TL;DR: The results indicate a loss of central D2 receptors in PMS, which is consistent withperiodic movements in sleep disturbances.
Abstract: Periodic movements in sleep (PMS) can cause severe sleep disturbances. We investigated the central dopamine D2 receptor density in patients with PMS with 123I-IBZM and single photon emission tomography (SPET). In PMS there was a lower 123I-IBZM binding in the basal ganglia compared to the control group. The results indicate a loss of central D2 receptors in PMS.
TL;DR: It is suggested that extracellular dopamine in the neostriatum is not stimulated locally by endogenous excitatory amino acids, as suggested by the classical process of impulse-evoked exocytosis.
Abstract: It has been suggested that dopamine release can be evoked by excitatory amino acids acting on dopaminergic terminals, as well as by the classical process of impulse-evoked exocytosis. We used in vivo microdialysis to examine whether endogenous excitatory amino acids locally evoked dopamine efflux under basal conditions. Infusion of N-methyl-d-aspartate (NMDA) or kainate into the neostriatum increased extracellular dopamine, and this effect was blocked by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. However, neither these antagonists nor kynurenate decreased extracellular dopamine when administered alone. In contrast, infusion of tetrodotoxin into the medial forebrain bundle reduced extracellular dopamine to below the limit of detection of our assay. These and other findings reviewed in this report suggest to us that extracellular dopamine in the neostriatum is not stimulated locally by endogenous excitatory amino acids.
TL;DR: The prominence of accumbens-evoked and morphine-sensitive neurons within the ventral pallidum corroborates the density of Accumbens and opioid input to this brain region, and demonstrates that opioids serve as an important influence on neuronal activity and information processing in the ventRAL-striatopallidal pathway.
Abstract: The principle output of the nucleus accumbens innervates the ventral pallidum and rostral substantia innominata. GABA and opioid peptides are among the neurotransmitter candidates for this projection. The goal of the present experiments was to delineate further the physiology and pharmacology of the accumbens projection to the ventral pallidum. The trans-synaptic responsiveness of ventral pallidal and rostral substantia innominata neurons to electrical stimulation of the nucleus accumbens was examined concurrently with the ability of microiontophoretically applied morphine (an opioid agonist), naloxone (an opioid antagonist) and bicuculline (a GABA antagonist) to modulate evoked responses. Accumbens stimulation altered the firing rate in 60% of the 132 neurons tested. Fifty-two percent of responding neurons exhibited simple excitations or inhibitions in response to accumbens stimulation, while 48% exhibited complex response sequences with two or more evoked components. Predominant responses consisted of a short latency ( 80%) of neurons evoked by accumbens stimulation also exhibited a current-dependent and naloxone-sensitive increase in spontaneous firing to microiontophoretically applied morphine. Morphine shortened the duration of the accumbens-evoked, short latency excitation and attenuated the magnitude of the long-latency inhibition. Evoked responses in the presence of morphine were opposite to those observed with naloxone, but similar to bicuculline. Thus, opioid receptor activation may be functionally antagonistic to GABAergic neurotransmission in the ventral pallidum. The prominence of accumbens-evoked and morphine-sensitive neurons within the ventral pallidum corroborates the density of accumbens and opioid input to this brain region, and demonstrates that opioids serve as an important influence on neuronal activity and information processing in the ventral-striatopallidal pathway.
TL;DR: An organization of corticostriatal glutamatergic neurons impinging on the so-called “direct” striato-thalamic pathways appear to act as a driving force with respect to psychomotor functions could explain some of the behavioural differences between competitive and un-competitive NMDA antagonists.
Abstract: Corticostriatal glutamatergic neurons impinging on the so-called “direct” striato-thalamic pathways appear to act as a driving force with respect to psychomotor functions, whereas corticostriatal glutamatergic neurons projecting to the “indirect” striato-thalamic route appear to mediate inhibition of the thalamus and thus act as a “brake” with respect to psychomotor functions. The GABAergic striatal projection neurons pertaining to the “direct” pathway mediating behavioural stimulation appear to be phasically activated, whereas GABAergic striatal projection neurons pertaining to the “indirect” pathway mediating suppression of behaviour must be assumed to display a high tonic activity. Such an organization could explain some of the behavioural differences between competitive and un-competitive NMDA antagonists, since the binding of competitive NMDA antagonists is inhibited by glutamate, whereas the binding of un-competitive NMDA antagonists is enhanced by the presence of NMDA receptor agonists, a phenomenon called use/agonist dependence.
TL;DR: The results suggest that L-DOPA and 5-HTP, the precursor amino acids for catecholamines and indoleamines, could affect mutually each other neuronal activity through the inhibition of their rate-limiting enzymes.
Abstract: Using a microdialysis technique, the rat striatum was perfused with NSD-1015, an inhibitor of aromatic L-amino acid decarboxylase, and the amount of L-3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytrytophan (5-HTP) accumulating in dialysate was measured as an index of in vivo activities of tyrosine hydroxylase and tryptophan hydroxylase. NSD-1015 increased the concentration of L-DOPA much higher than that of 5-HTP in a dose-related manner (1–100 μmol/L). In order to examine the relationship between dopaminergic and serotonergic neurons in the striatum, either 5-HTP or L-DOPA was injected intraperitoneally to rats pretreated with benserazide, an inhibitor of peripheral decarboxylase. 5-HTP administration increased 5-HTP, but decreased L-DOPA in a dose-dependent manner. Conversely, 5-HTP concentration decreased in an association with the increased content of L-DOPA following L-DOPA administration. The decrease of 5-HTP caused by L-DOPA administration was not as remarkable as that of L-DOPA by 5-HTP injection. These results suggest that L-DOPA and 5-HTP, the precursor amino acids for catecholamines and indoleamines, could affect mutually each other neuronal activity through the inhibition of their rate-limiting enzymes.
TL;DR: Because of their selective action on the specific forms ofMAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.
Abstract: The “cheese effect”, potentiation of sympathomimetic action of indirectly acting amines such as tyramine, the main side effect of irreversible nonselective and selective monoamine oxidase (MAO) A inhibitors, has largely been eliminated in the new generation of reversible selective MAO-A and B and irreversible MAO-B inhibitors. These selective inhibitors are demonstrating unique pharmacology and initial controlled clinical studies are providing evidence to support their action as anti-depressants and anti-Parkinson's disease drugs and possibly as neuroprotectors. Thirty years of experience with nonselective MAO inhibitors has resulted in a better understanding and management of the new generation of MAO inhibitors. Because of their selective action on the specific forms of MAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.
TL;DR: These observations support the glutamate hypothesis of schizophrenia which suggests that reduced glutamatergic transmission causes a relative dopaminergic excess in the basal ganglia and the limbic system.
Abstract: Amantadine was introduced for the pharmacological management of neuroleptic malignant syndrome (NMS) because of its beneficial effects in Parkinson's disease which were attributed to dopaminomimetic properties. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of the glutamate receptor. Amantadine has psychotomimetic properties in patients with Parkinson's disease and normal controls. Two of four patients who received amantadine for NMS suffered an exacerbation of their psychiatric illness. Our observations support the glutamate hypothesis of schizophrenia which suggests that reduced glutamatergic transmission causes a relative dopaminergic excess in the basal ganglia and the limbic system.
TL;DR: Observations provide further evidence of a regulatory role for neural cell adhesion molecule sialylation state in information storage processes in hippocampal immunoprecipitates.
Abstract: The influence of cholinergic and dopaminergic agents on the acquisition of a passive avoidance response in the rat is demonstrated. Trifluoperazine (0.12 mg/kg), a dopamine antagonist, inhibited task acquisition when present during training or later, during consolidation, at the 10-12 h post-training period and at no other intervening time point. Induction of amnesia was dose-dependent and was not apparent when the dose exceeded 0.12 mg/kg. This effect appears to be due to an increase in dopamine release through presynaptic receptor antagonism as similar results could be obtained by the administration of apomorphine (0.5 mg/kg), a dopamine agonist, and this effect could be antagonized by the D1 receptor selective antagonist SCH-23390. Scopolamine (0.15 mg/kg), a muscarinic antagonist, impaired acquisition of the passive avoidance response when administered during training and, separately, at the 6 h post-training period. This could not be attributed to presynaptic antagonism as oxotremorine (0.2 mg/kg), a muscarinic agonist, had no amnesic action. Administration of apomorphine or scopolamine during training and at the appropriate post-training period prevented subsequent paradigm-specific increases of neural cell adhesion molecule sialylation state in hippocampal immunoprecipitates obtained at 24 h after task acquisition and 4 h following intraventricular infusion of the labelled sialic acid precursor - N-acetyl-D-mannosamine. Oxotremorine alone did not influence neural cell adhesion molecule sialylation state. These observations provide further evidence of a regulatory role for neural cell adhesion molecule sialylation state in information storage processes.
Journal Article•
TL;DR: The material and data on aging and dementia, collected by the Netherlands Brain Bank in the past six years will serve in the present paper to illustrate the wide variety of potentialities and pitfalls in the use of post-mortem human brain tissue.
Abstract: The number of sophisticated neurobiological techniques which can be applied on human brain has rapidly increased and causes an increased demand for post-mortem human brain tissue for research purposes. Brain banks, which collect post-mortem tissue from patients who suffered from neurological and psychiatric disorders, have become an important link between clinicians, scientists and neuropathologists involved in aging and dementia research. Due to the large variability of the material, there are many drawbacks in the use of post-mortem brains. Therefore, collecting human brain tissue for research should include matching for several factors, both ante-mortem and post-mortem. Some of the most important ante-mortem factors include age, sex, agonal state, seasonal alterations, circadian variation and clock time of death. The post-mortem factors which should be matched for include the post-mortem delay, fixation and storage time and lateralization. The material and data on aging and dementia, collected by the Netherlands Brain Bank in the past six years will serve in the present paper to illustrate the wide variety of potentialities and pitfalls in the use of post-mortem human brain tissue. Brain Bank organizations for various neurological diseases form at present an important clinico-pathological link in aging and dementia research and the availability of post-mortem human brain tissue makes it possible to investigate those diseases for which no animal model is available. In order to provide research groups with post-mortem brain tissue from Alzheimer's disease (AD) patients and controls, a brain bank was established by the end of 1985 in The Netherlands Institute for Brain Research. This brain bank is based upon research projects submitted in advance, specifying a variety of requirements such as: total number of brains needed, kind of fixation, agonal state, post-mortem delay, exact anatomical boundaries of the brain region, kind of fixation and other treatment requirements of the tissue. This Brain Bank has got two unique features: 1. Human brain tissue is obtained by means of rapid autopsies with a very short post-mortem delay, ranging between 2-4 hour. 2. Fresh brain dissection procedure is used, which is a difficult regime to establish, requiring qualified staff at inconvenient times. This dissection procedure is necessary for the immediate use of fresh tissue and advantageous in increasing the range of morphological, neurochemical, immunocytochemical, metabolic and other procedures which can be applied to tissues fixed in a different way or rapidly frozen brain tissue free of freezing artifacts.
TL;DR: 6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinolines and their N-methylated derivatives were found to inhibit type A and B monoamine oxidase isolated from human brain synaptosomal mitochondria.
Abstract: 6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline (norsalsolinol) and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), and their N-methylated derivatives were found to inhibit type A and B monoamine oxidase isolated from human brain synaptosomal mitochondria. N-Methyl-norsalsolinol, (R) and (S) enantiomer of salsolinol, and N-methyl-salsolinols inhibited type A monoamine oxidase competitively to the substrate, kynuramine, andR enantiomers were more potent inhibitors thanS enantiomers. The inhibition was reversible. Norsalsolinol induced positive cooperativity toward kynuramine. Both norsalsolinol and N-methyl-norsalsolinol inhibited type B oxidase non-competitively to the substrate, and their K1 values were much higher than those to type A. Types of inhibition of type A monoamine oxidase depended on the enzyme sources. Inhibition of monoamine oxidase by 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines is discussed in relation to their chemical structures.
TL;DR: The results strongly suggest that tryptophan hydroxylation is involved in the control of the 5-HT biosynthesis circadian Rhythm, suggesting that the circadian factors affecting serotonin metabolism can be different among brain areas.
Abstract: The in vivo rate of brain tryptophan hydroxylation was determined through 5-hydroxytryptophan accumulation (5-HTPacc) following the administration of NSD 1015, a L-aromatic amino-acid decarboxylase inhibitor. This measurement was performed every 4 h throughout a 24 h hour period in 10 discrete brain areas of rats maintained on a regular 12 h/12 h light-dark cycle. The concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were also determined in untreated rats. Daily variations in 5-HTPacc were found in all the areas studied, the 5-HTPacc being higher during the dark period in most structures. These results strongly suggest that tryptophan hydroxylation is involved in the control of the 5-HT biosynthesis circadian rhythm. However, various patterns of 5-HT and 5-HIAA daily variations were observed, suggesting that the circadian factors affecting serotonin metabolism can be different among brain areas.
TL;DR: The results suggest that the effect of RS-8359 on behavioral and biochemical changes by stress may be mainly due to its effects on norepinephrine and serotonin systems, presumably by the inhibition of type A monoamine oxidase.
Abstract: As a stress model, a forced swimming test was applied to mice; and a typical behavioral change, an immobile posture, was recognized. This affected the brain monoamine levels significantly. The norepinephrine concentration was reduced, while that of its product was increased; and in the case of dopamine, both the amount of the amine and its product were increased. Stress increased the levels of serotonin and its product in the brain. The effects of RS-8359, (+/-)-4-(4-cyanophenyl)amino-6,7-dihydro-7-hydroxy-5H-cyclopenta[d ]- pyrimidine, a new inhibitor of type A monoamine oxidase, on the behavioral and biochemical changes caused by forced swimming were also investigated. RS-8359 significantly improved the immobile posture elicited by the forced swimming test. It reduced the increased turnover of norepinephrine and serotonin systems caused by swimming. These results suggest that the effect of RS-8359 on behavioral and biochemical changes by stress may be mainly due to its effects on norepinephrine and serotonin systems, presumably by the inhibition of type A monoamine oxidase.
TL;DR: The present findings suggest that an imbalance of second messengers via G protein function may be involved in the pathophysiology of depression.
Abstract: The amounts of various G protein subunits in postmortem brain samples from the parietal and temporal cortices were the same in controls and depressive patients as demonstrated by immunoblotting. However, photoaffinity GTP labeling (AAGTP) of Gi/oα, but not Gsα, was significantly increased in depressives in both cortex regions. Furthermore, the ratio of Gs/Gi/o AAGTP incorporation revealed a significant reduction in depressives in these regions. The present findings suggest that an imbalance of second messengers via G protein function may be involved in the pathophysiology of depression.
TL;DR: Haloperidol was found to increase prolactin release from GH4C 1 cells transfected with the D 2 receptor cDNA and from wild-type (untransfected) GH 3 cells, but not fromWild-type GH4 C 1 cells, and stimulated cAMP formation in GH3 cells.
Abstract: Haloperidol (30 nM, 3 μM) was found to increase prolactin release from GH4C 1 cells transfected with the D 2 receptor cDNA (GH4ZR 7) and from wild-type (untransfected) GH 3 cells, but not from wild-type GH4C 1 cells. In addition, haloperidol (3 μM) stimulated cAMP formation in GH 3 cells. It is suggested that haloperidol may act as an inverse agonist rather than as a neutral antagonist at dopaminergic D 2 receptors.
TL;DR: The results suggest that the binding characteristics of the central and peripheral serotonin2 receptor are similar, and that the platelet receptor activity may be regulated by blood levels of serotonin.
Abstract: Changes in the central and peripheral serotonergic receptor activity have been reported to be involved in depression and suicidality. To elucidate the interdependence between central and peripheral receptor sites and their regulation by serotonin, we estimated intra-individual serotonin2 receptor binging characteristics in porcine cortex synaptosomes and in platelet membranes using3H-LSD as ligand and ketanserin as competitor and quantified the relevant serotonin concentrations. A positive correlation between the apparent half maximal saturation concentration, KD, of the receptor in cortex synaptosomes and platelet membranes (r=0.65, p=0.0046, n=18), and between the apparent maximal binding capacity, Bmax, of the receptor in cortex synaptosomes and platelets (r=0.52, p=0.027, n=18) was observed. The blood serotonin concentrations correlated negatively with the maximal binding capacity, Bmax, in platelets (r=−0.77, p=0.0002, n=18). These results suggest that the binding characteristics of the central and peripheral serotonin2 receptor are similar, and that the platelet receptor activity may be regulated by blood levels of serotonin.
TL;DR: The density of the mu opioid receptor subtype relative to the location of the dopaminergic neurons in the retrorubral field, substantia nigra, and ventral tegmental area and related nuclei in the rat was mapped and quantified to indicate that mu opioid receptors are located in certain regions occupied by all three midbrain DA nuclei, but in a highly heterogeneous fashion.
Abstract: Several lines of evidence indicate that an interaction exists between opioid peptides and midbrain dopaminergic neurons The purpose of this study was to map and quantify the density of the mu opioid receptor subtype relative to the location of the dopaminergic (DA) neurons in the retrorubral field (nucleus A8), substantia nigra (nucleus A9), and ventral tegmental area and related nuclei (nucleus A10) in the rat Sections through the rostral-caudal extent of the midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the mu-selective ligand,3H-Tyr-D-Ala-N-MePhe-Gyl-ol enkephalin In the nucleus A8 region, there were low levels of mu binding In the rostral portion of nucleus A9, there was prominent mu binding both in the ventral pars compacta, which contains numerous DA neurons, and in regions that correspond to the location of the DA dendrites which project ventrally into the underlying substantia nigra pars reticulata In the caudal portion of nucleus A9, mu binding was greatest in the substantia nigra pars reticulata, but also in the same region that contains DA neurons In nucleus A10, mu receptor densities differed depending upon the nucleus A10 subdivision, and the rostral-caudal position in the nucleus Low receptor densities were observed in rostral portions of the ventral tegmental area and interfascicular nucleus, and there was negligible binding in the parabrachial pigmented nucleus and paranigral nucleus at the level of the interpeduncular nucleus; all regions where there are high densities of DA somata Mu binding was relatively high in the central linear nucleus, and in the dorsal and medial divisions of the medial terminal nucleus of the accessory optic system, which has been shown to contain DA dendrites These data indicate that mu opioid receptors are located in certain regions occupied by all three midbrain DA nuclei, but in a highly heterogeneous fashion
TL;DR: The results point to immunostimulatory actions of the pineal indoles MEL and MTA in rendering the macrophages responsive to lymphokines.
Abstract: Male C57 mice kept under a 14:10 (L:D) photoperiod received vehicle (VEH), melatonin (MEL) and methoxytryptamine (MTA) in the drinking water for 2 weeks. Splenocytes from MEL-treated mice showed an augmented mitogenic response to concanavalin A and lipopolysaccharide (LPS) while splenocytes from MTA-treated mice demonstrated an enhanced mitogenic response to LPS when compared to the VEH-treated control. Splenocytes from MEL-treated and MTA-treated mice also produced higher levels of gamma interferon and interleukin-2. Lymphokines prepared from splenocytes of MEL-treated mice stimulated peritoneal macrophages to produce more nitrite than those from splenocytes of MTA-treated and control mice, suggesting that MEL had a stronger stimulating effect on the lymphocytes than MTA. Understimulation of lymphokines from MEL-treated mice, peritoneal macrophages from MTA-treated mice produced a greater inhibition of the growth of murine mastocytoma P815 cells than that produced by macrophages from control and MEL-treated mice, suggesting that MTA was more potent than MEL in rendering the macrophages responsive to lymphokines. The results point to immunostimulatory actions of the pineal indoles MEL and MTA.