Receptor activity and turnover of dopamine and noradrenaline after neuroleptics.
TL;DR: The most potent and specific neuroleptics seemed to influence mainly the brain DA mechanisms, both functionally and chemically.
About: This article is published in European Journal of Pharmacology.The article was published on 1970-08-01. It has received 1010 citations till now. The article focuses on the topics: Fluspirilene & Chlorpromazine.
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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
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
Cites background from "Receptor activity and turnover of d..."
...The dopamine hypothesis of antipsychotic medications can be traced to the early observation that antipsychotics increase the turnover of monoamines (4), more specifically, dopamine (5), and this observation anticipated the discovery of the “neuroleptic receptor” (6–8), now called the dopamine D2 receptor, providing a mechanistic basis for the dopamine hypothesis of antipsychotic action....
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TL;DR: In this article, the effect of L-DOPA and the dopamine receptor stimulating drug apomorphine was studied in rats after unilateral degeneration of the nigrostriatal DA system by intracerebral injection of 6-hydroxydopamine.
Abstract: The effect of L-DOPA and the dopamine (DA) receptor stimulating drug apomorphine was studied in rats after unilateral degeneration of the nigrostriatal DA system by intracerebral injection of 6-hydroxydopamine. Both apomorphine and L-DOPA induced a strong rotational behaviour which was registered in a specially designed “rotameter”. The direction of the rotation indicated that the denervated striatum was more sensitive to DA receptor stimulating drugs than the innervated striatum. This supersensitivity probably corresponded to the decentralisation type of supersensitivity in the peripheral nervous system although it developed faster. The action of L-DOPA was inhibited by pretreatment with the DOPA-decarboxylase inhibitor Ro4–4602 which indicated that L-DOPA must be converted to DA in order to stimulate the supersensitive postsynaptic cells. Pretreatment with a single dose of reserpine also induced supersentitivity to apomorphine which reached its maximum on the 3rd day and then decreased on the 4th day. Postsynaptic supersensitivity after degeneration of the nigro-striatal DA system is probably an important reason for the effectiveness of the L-DOPA therapy against Parkinson's disease.
1,895 citations
01 Jan 1982
TL;DR: This paper is a rough precis of a recent book concerned with the question: what are the brain structures which mediate the psychology as well as the neurology of anxiety?
Abstract: This paper is a rough precis of a recent book (GRAY, 1982). It is concerned with the question: what are the brain structures which mediate the psychology as well as the neurology of anxiety? It is clear that, once you start asking questions about the brain, you have to work with animals for reasons that are familiar to everybody. But it is very difficult to start studying emotions in animals, because it is difficult to know what emotions animals experience and whether these are the same as the human emotions. So the first thing one has to look for is a kind of crutch or bridge to get you across from the human domain on one side to the animal domain on the other. Now in the case of anxiety we are quite fortunate in that there are certain drugs which are clinically very effective in controlling anxiety in human subjects. So one can take those drugs and apply them to animals to study their behavioral effects.
1,810 citations
TL;DR: This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia of drug-treated schizophrenic patients and demonstrates that clozapine is also "atypical" with respect to the central D1 occupancy in patients.
Abstract: • Positron emission tomography and selective radioligands were used to determine D,and D2dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2occupancy than those without side effects. This finding indicates that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D,occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1occupancy was 38% to 52%. The D,occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.
1,357 citations
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TL;DR: In this article, the reaction between formaldehyde and phenylalanine and phenylethylamine derivatives has been studied under mild conditions and it has been shown that the amines primarily condense with formaldehyde to 1,2,3,4-tetrahydroisoquinolines which are involved in a secondary reaction to become highly fluorescent and at the same time insoluble.
Abstract: The reaction under mild conditions between formaldehyde and phenylalanine and phenylethylamine derivatives has been studied. When the amines included in a dried protein film were exposed to formaldehyde vapour a very intense green to yellow fluorescence was give only by those that as well as being primary amines also have hydroxyl groups at the 3 and 4 positions (3,4-dihydroxyphenylalanine, dopamine, noradrenaline). The 3-OH group seems to be esssential for the reaction. The catechol amines, which are secondary amines (adrenaline, epinine), gave a much weaker fluorescence that developed more slowly.The results obtained on further examination of the reaction favour the view that the amines primarily condense with formaldehyde to 1,2,3,4-tetrahydroisoquinolines which are involved in a secondary reaction to become highly fluorescent and at the same time insoluble. This secondary reaction may be a binding to protein, and oxidation with the formation of double bonds in the heterocyclic ring, or both.
2,583 citations
2,061 citations
Journal Article•
TL;DR: A good case can be made for the concept that the physiological activity of the brain dopamine is quite different from that of brain norepinephrine, although there are as yet no experiments to positively show that dopamine is a true neuro-transmitter substance in the brain.
Abstract: The whole body of evidence discussed in this article shows that brain dopamine can be regarded as a strong candidate for a physiologically active substance, regulating the functioning of some extrapyramidal centers, especially substantia nigra, striatum and pallidum. The following findings provide strong support for this view: The dopamine is mainly confined to the extrapyramidal regions mentioned; in these regions, the amine is localized in specific neurons and nerve terminals; its rate of turnover is of a high order of magnitude; is there a correlation between itsconcentration in the brain and the functional state of the extrapyramidal centers following administration of certain drugs; there is a striking relationship between some extrapyramidal disorders (drug-induced and genuine parkinsonism) and the lack of the amine in the substantia nigra, the striatum and the pallidum; and, finally, that substantia nigra exerts a direct influence on the concentration of the amine in the striatum by virtue of the nigro-striatal dopamine-containing fibers.
In the extrapyramidal centers, dopamine may have either inhibitory or excitatory activity. Neurophysiological evidence obtained in different species points to a predominantly inhibitory activity of dopamine on single neurons of the brain.
Evidence showing that in the retina and in the median eminence (including the pituitary stalk) dopamine may be the predominant catecholamine argues in favor of a specific function of the amine in these brain structures, although there are at present no direct findings to prove this suggestion.
From the evidence discussed in this article a good case can be made for the concept that the physiological activity of the brain dopamine is quite different from that of brain norepinephrine. There are as yet., however, no experiments to positively show that dopamine is a true neuro-transmitter substance in the brain. All central dopamine effects could equally well be explained by assuming that the amine is a modifier of synaptic transmission.
Therefore, in order to establish dopamine unequivocally as a central neurotransmitter substance, there is still one crucial experiment to be done: to demonstrate that upon stimulation of the relevant parts of the brain, dopamine is in fact released at synapses to exert by itself an effect on the neurons standing in synaptic relationship with the stimulated dopamine-containing terminals. It is to be hoped that we shall not have to wait too long for this experiment to be performed.
1,379 citations
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