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Journal ArticleDOI

Effect of chronic administration of antidepressant drugs on 5-HT2-mediated behavior in the rat following noradrenergic or serotonergic denervation.

01 Jan 1991-Journal of Neural Transmission (J Neural Transm Gen Sect)-Vol. 84, Iss: 1, pp 19-32
TL;DR: The functional interrelationship of 5-HT2 and Β-adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.
Abstract: Chronic (14 day) administration of several pharmacologically-distinct antidepressant drugs resulted in marked reductions in the serotonin2 (5-HT2)-mediated quipazine-induced head shake response which were accompanied by significant reductions in the density of cortical Β-adrenergic and 5-HT2 binding sites. Noradrenergic (DSP4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine]-induced) and serotonergic (5,7-DHT[5,7-dihydroxytryptamine]-induced) lesions either attenuated or blocked antidepressant-induced reductions in 5-HT2-mediated behavior. DSP4- and 5,7-DHT lesions did not alter the down-regulation of 5-HT2 binding sites produced by imipramine, desipramine, phenelzine or iprindole. To a large extent, the antagonism of antidepressant-induced reductions in 5-HT2-mediated behavior was coincident with the blockade of down-regulation of Β-adrenergic binding sites by both noradrenergic and serotonergic denervation. The functional interrelationship of 5-HT2 and Β-adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.
Citations
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Journal ArticleDOI
TL;DR: Sch schizophrenia is associated with reduced gray matter volume in prefrontal cortex, which affects men and women in the dorsolateral sector and the effects are moderated by sex for dorsomedial and orbital regions and are related to symptom severity and cognitive function.
Abstract: Background Converging neuroanatomic, neurophysiological, and neurobehavioral evidence implicate prefrontal subregions in schizophrenia. Neuroanatomic studies with magnetic resonance (MR) imaging enable regional volume parcellation. Inconsistent reports may relate to variable methods and small samples. We attempted to resolve volume differences within sectors of the prefrontal lobe in a large sample, relating volumes to clinical and neurocognitive features. Methods Magnetic resonance imaging was performed in 70 patients with schizophrenia (40 men and 30 women; 29 neuroleptic naive and 41 previously treated) and 81 healthy controls (34 men and 47 women). Gray and white matter volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were quantified. Symptoms, functioning, and neurocognition were assessed concurrently. Results Reduced prefrontal gray matter volume was observed in patients. The reduction was evident for the dorsolateral area in men (9%) and women (11%), for the dorsomedial area only in men (9%), and for orbital regions only in women (23% and 10% for lateral and medial, respectively). The reduction of orbital volume in women was associated with poorer premorbid functioning, more severe negative symptoms, and depression. Volume of dorsal cortex was positively associated with better performance on abstraction and attention tasks across all groups. Conclusions Schizophrenia is associated with reduced gray matter volume in prefrontal cortex, which affects men and women in the dorsolateral sector. The effects are moderated by sex for dorsomedial and orbital regions and are related to symptom severity and cognitive function. This is not a by-product of treatment, since the differences are evident in neuroleptic-naive patients.

375 citations

Journal ArticleDOI
TL;DR: This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John’s wort and its active constituents with a large body of existing literature.
Abstract: competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John’s wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John’s wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John’s wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John’s wort extract demonstrated significant affinity for adenosine, GABAA, GABAB and glutamate receptors. In vivo St John’s wort extract leads to a downregulation of β-adrenergic receptors and an upregulation of serotonin 5-HT2 receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John’s wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John’s wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John’s wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John’s wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids.

339 citations

Book ChapterDOI
TL;DR: The role of the serotonergic system in the neuroplastic events that create, repair, and degenerate the brain has been explored but the mechanisms for their therapeutic efficacy are still unclear.
Abstract: The role of the serotonergic system in the neuroplastic events that create, repair, and degenerate the brain has been explored. Synaptic plasticity occurs throughout life and is critical during brain development. Evidence from biochemical, pharmacological, and clinical studies demonstrates the huge importance of an intact serotonergic system for normal central nervous system (CNS)function. Serotonin acts as a growth factor during embryogenesis, and serotonin receptor activity forms a crucial part of the cascade of events leading to changes in brain structure. The serotonergic system interacts with brain-derived neurotrophic factor (BDNF), S100beta, and other chemical messengers, in addition to ts cross talk with the GABAergic, glutamatergic, and dopaminergic neurotransmitter systems. Disruption of these processes may contribute to CNS disorders that have been associated with impaired development. Furthermore, many psychiatric drugs alter serotonergic activity and have been shown to create changes in brain structure with long-term treatment. However, the mechanisms for their therapeutic efficacy are still unclear. Treatments for psychiatric illness are usually chronic and alleviate psychiatric symptoms, rather than cure these diseases. Therefore, greater exploration of the serotonin system during brain development and growth could lead to real progress in the discovery of treatments for mental disorders.

310 citations


Cites background from "Effect of chronic administration of..."

  • ..., 1981), some selective serotonin reuptake inhibitors (SSRIs) (Eison et al., 1991; Nelson et al., 1989; Stolz et al., 1983), 5-HT1A receptor partial agonists (Lafaille et al....

    [...]

  • ...…and Kellar, 1980; Wajda et al., 1986), monoamine oxidase inhibitors (Kellar et al., 1981), some selective serotonin reuptake inhibitors (SSRIs) (Eison et al., 1991; Nelson et al., 1989; Stolz et al., 1983), 5-HT1A receptor partial agonists (Lafaille et al., 1991; Yocca et al., 1991), and…...

    [...]

Journal ArticleDOI
TL;DR: Results suggest that discrete domains of the receptor structure are important for ligand binding, G-protein coupling, and internalization, as well as a model for regulation of 5-HT2-family receptors by receptor-mediated endocytosis.

281 citations

Journal ArticleDOI
TL;DR: Observation of serotonin receptor alterations, before and following effective treatments, may yield important insights into the aetiology of these psychiatric disorders and may ultimately lead to more selective and effective therapies.
Abstract: Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide variety of physiological functions by activating multiple receptors, and abnormalities of these receptor systems has been implicated in many psychiatric disorders including anxiety, depression, psychosis, migraine, disorders of sexual functioning, sleep, cognition, and feeding. Many of the currently used treatments for these disorders act by affecting the serotonergic system. Observation of serotonin receptor alterations, before and following effective treatments, may yield important insights into the aetiology of these psychiatric disorders and may ultimately lead to more selective and effective therapies. Copyright © 2000 John Wiley & Sons, Ltd.

251 citations

References
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Journal ArticleDOI
TL;DR: The number and variety of known compounrjs between proteins and small molecules are increasing rapidly and make a fascinating story as discussed by the authors, and there are many compounds of serum albumin, which was used during the war by many chemists, most of whom found at least one 6ew compound.
Abstract: The number and variety of known compounrjs between proteins and small molecules are increasing rapidly and make a fascinating story. For instance, there are the compounds of iron, which is carried in our blood plasma by a globulin, two atoms of iron to each molecule of globulin held in a rather tight salt-lie binding? which is stored as ferric hydroxide by ferritin much as water is held by a sponge? and which functions in hemoglobin, four iron atoms in tight porphyrin complexes in each protein molecule. Or, there are many compounds of serum albumin, which was used during the war by many chemists, most of whom found at least one 6ew compound. This molecule, which has about a hundred carboxyl radicals, each of which can take on a proton, and about the same number of ammonium radicals, each of which can dissociate a proton, has one single radical which combines with mercuric ion so firmly that two albumin molecules will share one mercury atom if there are not enough to go a r ~ u n d . ~ At the present stage of rapid growth of known compounds, it seems more profitable for me to make no attempt to catalogue the various classes of compounds, but to discuss the general principles involved, in the hope that this will make more useful the information which is accumulating so rapidy from so many laboratories. We want to know of each molecule or ion whicb can combine with a protein molecule, /‘How many? How tightly? Where? Why?” The answer to the first two questions, and sometimes to the third, can be furnished by the physical chemist, but he will often need to team with an organic chemist to determine the effect of altering specified groups to find if they are reactive. The determination of function iç a complicated problem which may be the business of the physiologist or physiological chemist. But the answers to both of the more complicated problems will depend on the answers to the simpler questions, “HOW many?” and “How tightly bound?” If the various groups on a protein molecule act independently, we can apply the law of mass action as though each group were on a separate molecule,4 and the strength of binding can be expressed as the constant for each group. Often, a single constant will express the behavior of severa1 groups. If the constants are widely spread, as those for the reaction of hydrogen ion with carboxylate ions, with imidazoles and with amines, the interpretation is simple. If the separation is less, it is very difficult to distinguish the case of different intrinsic affinities from the case of interaction among the groups. We know that such interaction occurs in simple moleculeç in which a reac-

20,127 citations

Book
01 Jan 1969
TL;DR: This chapter discusses research strategies and the Control of Nuisance Variables, as well as randomly Randomized Factorial Design with Three or More Treatments and Randomized Block Factorial design, and Confounded Factorial Designs: Designs with Group-Interaction Confounding.
Abstract: Chapter 1. Research Strategies and the Control of Nuisance Variables Chapter 2. Experimental Designs: an Overview Chapter 3. Fundamental Assumptions in Analysis of Variance Chapter 4. Completely Randomized Design Chapter 5. Multiple Comparison Tests Chapter 6. Trend Analysis Chapter 7. General Linear Model Approach to ANOVA Chapter 8. Randomized Block Designs Chapter 9. Completely Randomized Factorial Design with Two Treatments Chapter 10. Completely Randomized Factorial Design with Three or More Treatments and Randomized Block Factorial Design Chapter 11. Hierarchical Designs Chapter 12. Split-Plot Factorial Design: Design with Group-Treatment Confounding Chapter 13. Analysis of Covariance Chapter 14. Latin Square and Related Designs Chapter 15. Confounded Factorial Designs: Designs with Group-Interaction Confounding Chapter 16. Fractional Factorial Designs: Designs with Treatment-Interaction Confounding

8,397 citations

Journal ArticleDOI
TL;DR: The "catecholamine hypothesis of affective disorders" as discussed by the authors suggests that depression is associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites.
Abstract: The "catecholamine hypothesis of affective disorders" proposes that some, if not all, depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines. Evidence supporting this hypothesis was reviewed. Data from pharmacological studies, mainly in animals, suggest that the actions of both major classes of antidepressant drugs are mediated through the catecholamines. The monoamine oxidase inhibitors increase brain concentrations of norepinephrine while imipramine-like agents potentiate the physiological effects of norepinephrine. Reserpine, a drug which can cause clinical depression, depletes catecholamines, but other amines may also be involved in its mechanism of action. A rigorous extrapolation from pharmacological studies to pathophysiology clearly cannot be made. Clinical studies relevant to the catecholamime hypothesis are limited and the ...

3,012 citations

Journal ArticleDOI
TL;DR: The weight of evidence suggests that biochemical changes are most important in the aetiology of affective disorders, and that psychological and environmental events may precipitate and maintain the biochemical events which in turn lead to the affective disorder.
Abstract: In this paper I want to summarise what seems to me to be the most important aspects of the biochemistry of depression and mania. To do so in the brief time allocated for this paper will be difficult for this field is one of the most rapidly expanding areas of psychiatry. My summary, will therefore, have to be selective and dogmatic and I will be unable to do justice to the various controversies that surround nearly every aspect of the subject. I hope to show in this talk that the biochemical changes are of primary aetiological importance but I should like to emphasise that, as a psychiatrist, I recognize that other factors — social and psychological are also of great importance. I think one of our tasks in the future will be to show how these environmental events can interact with the biochemistry of the nervous system to produce the syndromes of depression and mania. In other words I think the affective disorders can be described as a truly psychosomatic disorder.

1,128 citations