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Journal ArticleDOI

Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain.

13 Mar 2009-Pharmacology & Toxicology (Acta Pharmacol Toxicol (Copenh))-Vol. 20, Iss: 2, pp 140-144
About: This article is published in Pharmacology & Toxicology.The article was published on 2009-03-13. It has received 2061 citations till now. The article focuses on the topics: Normetanephrine & Norepinephrine (medication).
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Stephan Ripke1, Stephan Ripke2, Benjamin M. Neale2, Benjamin M. Neale1  +351 moreInstitutions (102)
24 Jul 2014-Nature
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

6,809 citations

Journal ArticleDOI
TL;DR: A new attempt at a general theory of addiction is offered, based on the common denominator of the psychomotor stimulants---amphetamine, cocaine, and related drugs---rather than on thecommon denominators of the socalled depressant drugs~opiates, barbiturates, alcohol, and others.
Abstract: The theory is advanced that the common denominator of a wide range of addictive substances is their ability to cause psychomotor activation. This view is related to the theory that all positive reinforcers activate a common biological mechanism associated with approach behaviors and that this mechanism has as one of its components dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Evidence is reviewed that links both the reinforcing and locomotor-stimulating effects of both the psychomotor stimulants and the opiates to this brain mechanism. It is suggested that nicotine, caffeine, barbiturates, alcohol, benzodiazepines, cannabis, and phencyclidine----each ofwhich also has psychomotor stimulant actions--may activate the docaminergic fibers or their output circuitry. The role of physical dependence in addiction is suggested to vary from drug to drug and to be of secondary importance in the understanding of compulsive drug self-administration. Attempts at a general theory of addiction are attempts to isr late--from a variety of irrelevant actionsmthose drug actions that are responsible for habitual, compulsive, nonmedical drug self-administration. The common assumption of addiction theorists is that general principles of addiction can be learned from the study of one drug and that these principles will have heuristic value for the study of other drugs. Thus far, attempts at a general theory of addiction have failed to isolate common actions that can account for addiction across the range of major drug classes. A major stumbling block has been the psychomotor stimulants--amph etamine and cocainemwhich do not readily fit models traditionally based on depressant drug classes. The present article offers a new attempt at a general theory of addiction. It differs from earlier theories (e.g., Collier, 1968; Himmelsbach, 1943; Jaffe & Sharpless, 1968; Jellinek, 1960; Kalant, 1977; Lindsmith, 1947; Solomon & Corbit, 1974) in that it is based on the common denominator of the psychomotor stimulants---amphetamine, cocaine, and related drugs---rather than on the common denominator of the socalled depressant drugs~opiates, barbiturates, alcohol, and others. We take up two topics before presenting the new theory. First, we briefly discuss the heuristic value of a biological approach and suggest that the biologist's distinction between homology and analogy offers a useful insight. Next we discuss the shortcomings of earlier theories--variants of dependence theory. Then we outline the new theory and review the relevant evidence for its three major assertions: (a) that all addictive drugs have psychomotor stimulant actions, (b) that the stimulant actions of these different drugs have a shared biological mechanism, and (c) that the biological mechanism of these stimulant

2,752 citations

Journal ArticleDOI
13 Sep 1990-Nature
TL;DR: The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions, and seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease.
Abstract: A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions It seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease, that were previously thought to interact only with D2 receptors

2,627 citations

Journal ArticleDOI
TL;DR: A heuristic framework for linking the psychological and biological in psychosis is provided and it is proposed that a dysregulated, hyperdopaminergic state, at a "brain" level of description and analysis, leads to an aberrant assignment of salience to the elements of one's experience, at an "mind" level.
Abstract: OBJECTIVE: The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework. METHOD: Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. RESULTS: A central role of dopamine is to mediate the “salience” of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a “brain” level of description and analysis, leads to an aberrant assignment of salience to the elements of one’s experience, at a “mind” level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsyc...

2,359 citations

Journal ArticleDOI
TL;DR: The dopamine hypothesis of schizophrenia-version III is synthesized into a comprehensive framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function.
Abstract: The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

2,311 citations


Cites background from "Effect of chlorpromazine or haloper..."

  • ...drugs increased the metabolism of dopamine when administered to animals.(2) Further evidence came from observations that reserpine, which is effective for treating (1)To whom correspondence should be addressed; PO Box 053, Institute of Psychiatry, King’s College London, De Crespigny Park, London, SE5 8AF, UK; tel:þ44-20-7848-0593, fax:þ44-207848-0287, e-mail: shitij....

    [...]

References
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Journal ArticleDOI
TL;DR: A method for chemical assay of small amounts of adrenaline and noradrenaline in tissues is described, utilizing the difference in the activation spectra of the fluoro-phores to identify the two amines.
Abstract: Summary. A method for chemical assay of small amounts of adrenaline and noradrenaline in tissues is described. The catechol amines are extracted with perchloric acid. The extracts are passed through a cation exchange column (Dowex 50) which takes up the catechol amines. Elution of the amines from the column is performed by hydrochloric acid. Estimation of the two amines in the eluates is made fluorimetrically after oxidation and rearrangement in alkali. Differentiation between adrenaline and noradrenaline is performed by utilizing the difference in the activation spectra of the fluoro-phores.

993 citations

Journal ArticleDOI
TL;DR: A fluorimetric method for the determination of dopamine using differences in fluorescence characteristics at pH about 5.3, microquantities of dopainine can be determined in the presence of at least equal amounts of adrenaline or noradrenaline.
Abstract: Summary. A fluorimetric method for the determination of dopamine is described. The principle is similar to that employed in the tri-hydroxyindole method for estimating adrenaline and noradrenaline. Utilizing differences in fluorescence characteristics at pH about 5.3, microquantities of dopainine can be determined in the presence of at least equal amounts of adrenaline or noradrenaline.

618 citations

Journal ArticleDOI
TL;DR: In this paper, α-Methyl DOPA (DOPA = 3,4-dihydroxyphenylalanine) and α-methyl metatyrosine were injected to mice (400 mg/kg intraperitoneally).
Abstract: α-Methyl DOPA (DOPA = 3,4-dihydroxyphenylalanine) and α-methyl metatyrosine were injected to mice (400 mg/kg intraperitoneally). The former amino acid was also injected to rabbits (200 mg/kg intravenously). At varying intervals after the injection the brains were examined for monoamines (5-hydroxytryptamine, noradrenaline, dopamine, and α-methyl analogues). A transient decrease in 5-hydroxytryptamine and dopamine and a prolonged and more marked decrease in noradrenaline were observed. The α-methyl amino acids were found to undergo decarboxylation and subsequent β-hydroxylation in vivo. The drop in noradrenaline and dopamine levels in brain caused by the α-methyl amino acids appears to be largely due to displacement by these decarboxylation products, which may possibly also take over the functions of the physiological amines.

498 citations

Journal ArticleDOI
TL;DR: F fluorimetric method for the determination of small amounts of 3-methoxytyramine in tissues indicates a role of catecholO-methyl transferase in the degradation of DA in this tissue.
Abstract: : A fluorimetric method for the determination of small amounts of 3-methoxytyramine, (MT), in tissues is described. After separation on ion-exchange column, MT is converted to a strongly fluorescent compound. Interference of dopamine (DA), is eliminated either by column separation or differential oxidation. MT is demonstrated in brain of some mammals indicating a role of catecholO-methyl transferase in the degradation of DA in this tissue. (Author)

54 citations

Journal ArticleDOI
TL;DR: The iproniazid-induced inhibition of the amine depleting effect of reserpine could also be abolished by chlorpromazine, and a potentiation of the isle depleting action of Reserpine by chlor Promazine could not be found in the authors' experiments.
Abstract: 1. The catecholamine (CA) and 5-hydroxytryptamine (5-HT) content of the rat's brain has been examined after treatment with various drugs. The mean values for untreated animals were 0.43 μg./g. wet tissue for CA and 0.46 μg./g. for 5-HT.

26 citations