The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids.
TL;DR: These findings corroborate recent reports that GC, via GC—GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5- HT1A-coupled Gi (but not 5-HT2- coupled Go) resulting in altered sensitivity of5-HT 1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-TT1A and 5-ht2 receptor function and a GC—GR—G-protein—effector
Abstract: Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gsα-and decrease Giα-protein subunit expression without affecting Goα.
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TL;DR: It is shown that antidepressants interfere not only with the production and release of catecholamines and indolamines but also with the signal transduction of those neurotransmitters that have long been implicated in the pathogenesis and treatment of depression.
Abstract: I. Introduction PAST studies of antidepressants have focused almost exclusively on their effects on the metabolism and receptors of monoamine neurotransmitters in various brain regions. These studies have been extended to the molecular effects of antidepressants and have led to a profoundly expanded understanding of their actions in the central nervous system. For example, long-term administration of antidepressants decreases the expression of tyrosine hydroxylase, down-regulates cAMP-dependent protein kinase, modulates the mRNA expression of central β-adrenoceptors and serotonin (5-HT) receptors, and alters the functional activity of specific G protein subunits and adenylyl cyclase (1). Taken together, these and many other recent observations clearly indicate that antidepressants interfere not only with the production and release of catecholamines and indolamines but also with the signal transduction of those neurotransmitters that have long been implicated in the pathogenesis and treatment of depression...
859 citations
TL;DR: Biochemical mediators explored in this theoretical review include the hypothalamic–pituitary–adrenal axis, neurosteroids, brain‐derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system.
Abstract: Depression has been likened to a state of "accelerated aging," and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress-related depression may contribute to "accelerated aging," cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic-pituitary-adrenal axis (e.g., hyper- or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain-derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re-conceptualization of depression as a whole body disease rather than just a "mental illness," and to the rational development of new classes of medications to treat depression and its related medical comorbidities.
277 citations
TL;DR: Although definitive controlled trials remain to be conducted, there is a consistent body of evidence indicating that cortisol-lowering treatments may be of clinical benefit in select individuals with major depression and other hypercortisolemic conditions.
Abstract: OBJECTIVE The theoretical and empirical rationales for the potential therapeutic use of antiglucocorticoid agents in the treatment of depression are reviewed. METHOD Individual case reports, case series, open-label, and double-blind, controlled trials of the usage of cortisol-lowering treatments in Cushing's syndrome and major depression are evaluated and critiqued. RESULTS In each of the 28 reports of antiglucocorticoid treatment of Cushing's syndrome, antidepressant effects were noted in some patients; the largest two series document a response rate of 70% to 73%. Full response, however, was at times erratic and delayed. Across the 11 studies of antiglucocorticoid treatment of major depression, some degree of antidepressant response was noted in 67% to 77% of patients. Antidepressant or antiobsessional effects of antiglucocorticoid augmentation of other psychotropic medications have also been noted in small studies of patients with treatment-resistant depression, obsessive-compulsive disorder, and schizoaffective disorder or schizophrenia. CONCLUSIONS These promising results with antiglucocorticoid treatment must be interpreted cautiously because of the small sample sizes and heterogeneity of the studies reviewed, the bias favoring publication of positive results, and the open-label nature of most of the studies. Although definitive controlled trials remain to be conducted, there is a consistent body of evidence indicating that cortisol-lowering treatments may be of clinical benefit in select individuals with major depression and other hypercortisolemic conditions.
176 citations
TL;DR: Investigation of the use of [3H]WAY-100635 as a quantitative autoradiographic ligand in post-mortem human hippocampus, raphe and four cortical regions and compared it with the 5-HT1A receptor agonist, concluded that it is a valuable autoreadiography ligand for the qualitative and quantitative study of 5- HT1A receptors in the human brain.
174 citations
TL;DR: Mechanisms by which hormonal imbalance might contribute to illness are discussed and certain clinical manifestations of such hormonal imbalances are reviewed, and pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology are discussed.
Abstract: Stress is commonly associated with a variety of psychiatric conditions, including major depression, and with chronic medical conditions, including diabetes and insulin resistance. Whether stress causes these conditions is uncertain, but plausible mechanisms exist by which such effects might occur. To the extent stress-induced hormonal alterations (e.g., chronically elevated cortisol levels and lowered dehydroepiandrosterone [DHEA] levels) contribute to psychiatric and medical disease states, manipulations that normalize these hormonal aberrations should prove therapeutic. In this review, we discuss mechanisms by which hormonal imbalance (discussed in the frameworks of "allostatic load" and "anabolic balance") might contribute to illness. We then review certain clinical manifestations of such hormonal imbalances and discuss pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology.
135 citations
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TL;DR: This paper presents a meta-analysis of G Protein Interactions and its Foundations, which states that G Proteins are Law-Regulated and G Protein-Effector Interactions are Nonvolatile.
Abstract: PERSPECTIVES AND SUMMARY .............................................................. 615 HISTORY ............................................................................................... 616 INDIVIDUAL G PROTEINS: FUNCTIONS AND MOLECULAR ENTITIES .......... 617 Criteria .for Involvement of a G Protein ..................................................... 618 Functions Regulated by G Proteins ........................................................... 619 Molecular Entities and Structure .............................................................. 622 LIGAND-G PROTEIN TERACTIONS ........................................................ 631 LIGAND-REGULATED PROTEIN-PROTEIN TERACTIONS ........................... 634 Receptor-G Protein Interactions ............................................................... 634 G Protein-Effector Interactions ................................................................ 638 G PROTEII~I-MEMBRANE INTERACTIONS .................................................. 643 COVALENT MODIFICATION F G PROTEINS ............................................ 644
6,160 citations
"The 5-HT receptor--G-protein--effec..." refers background in this paper
...G-proteins, a family of guanine nucleotide-binding regulatory components appear to play a key role in coupling neurotransmitter receptors to various types of intracellular effector system (Gilman, 1987)....
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TL;DR: The goal in the study of aging is not to halt the aging process, because we can no more be cured of aging than of birth as mentioned in this paper, but to slow and soften the sharpest edges of the biological unraveling that constitutes aging.
Abstract: AS RECENTLY as 1900, tuberculosis, influenza, and pneumonia were the leading causes of death in our country (1). For the most part, however, these infectious diseases, as well as those of poor hygiene or undernutrition, no longer plague us. Instead, we succumb most frequently to heart disease and cancer, diseases of slow degeneration (1). Most of all, unlike so many in the generations before us, we are in a position to age. Regardless of what else occurs, we age, we become more constrained by the discrepancy between what we were and what we have become, and each step becomes harder. The goal in the study of aging is not to halt the process, because we can no more be cured of aging than of birth. The goal, instead, is to slow and soften the sharpest edges of the biological unraveling that constitutes aging. Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stress to...
2,122 citations
Journal Article•
TL;DR: The goal in the study of aging is not to halt the process, because the authors can no more be cured of aging than of birth, but to slow and soften the sharpest edges of the biological unraveling that constitutes aging.
Abstract: Over the past 5 yr, we have examined some of the sharpest edges of the pathology of aging. We have studied the capacity of aged organisms to respond appropriately to stress and the capacity of stre...
2,084 citations
"The 5-HT receptor--G-protein--effec..." refers background in this paper
...are decreased by elevation in circulating GC concentrations and may mediate some of the neurotoxic effects of GC (Sapolsky et al., 1986)....
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...during the depressive state may contribute to a sustained vulnerability or abnormality of the 5-HT system after clinical remission (Sapolsky et al., 1986)....
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1,245 citations
Additional excerpts
...5-HT receptors, G-proteins, and effector units (Van Loon et al., 1981; McEwen et al., 1986; Malbon et al., 1988)....
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TL;DR: In situ hybridization and RNA blot analysis indicate that the 5HTlc receptor is expressed in neurons in many regions of the central nervous system and suggest that this subclass of receptor may mediate many of thecentral actions of serotonin.
Abstract: Neurons that release serotonin as a neurotransmitter project to most regions of the central and peripheral nervous system and mediate diverse neural functions. The physiological effects of serotonin are initiated by the activation of multiple, distinct receptor subtypes. Cloning in RNA expression vectors was combined with a sensitive electrophysiological assay in Xenopus oocytes in order to isolate a functional cDNA clone encoding the 5HTlc serotonin receptor. Injection of RNA transcribed in vitro from this clone into Xenopus oocytes elicits serotonin sensitivity. Mouse fibroblasts transformed with this clone bind serotonin agonists and antagonists and exhibit an increase in intracellular Ca2+ concentrations in response to serotonin. The sequence of the 5HTlc receptor reveals that it belongs to the family of G protein-coupled receptors, which are thought to traverse the cytoplasmic membrane seven times. Moreover, in situ hybridization and RNA blot analysis indicate that the 5HTlc receptor is expressed in neurons in many regions of the central nervous system and suggest that this subclass of receptor may mediate many of the central actions of serotonin.
705 citations