Development of β-adrenergic receptor subsensitivity by antidepressants
TL;DR: The purpose of the experiments described here was to explore the molecular basis for antidepressant-induced noradrenergic subsensitivity by examining the kinetic properties of the β-ADrenergic receptors in the microsomal suspension of rat brain by using a potent β- adrenergic receptor antagonist 3H-dihydroalprenolol as a radiolabelled ligand, and results indicate that the main mechanism is a reduction in the number of receptors.
Abstract: CONSIDERABLE evidence exists that the tricyclic antidepressant drugs are selective inhibitors of monoamine uptake into monoaminergic nerve terminals1,2. These drugs also potentiate pharmacological responses to the monoamines in both the peripheral and central nervous systems3–6. These effects do not explain the discrepancy between the time-course of the biochemical and pharmacological responses which are elicited by these antidepressant drugs within minutes or hours and their clinical antidepressant action which requires treatment for weeks for efficacy to be reached. Furthermore, desipramine, an antidepressant drug, can potentiate neuronal responses to noradrenaline and dopamine in the caudate nucleus7, although it does not block the catecholamine uptake in this area of the brain1,2. Finally the antidepressant iprindole does not influence noradrenaline turnover8 or metabolism9,10 or its uptake into catecholaminergic neurones11, but is effective in potentiating the responses of single cortical and caudate neurones to monoamines12. Vetulani and his associates13 suggested that the therapeutic action of tricyclic antidepressants may be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events. The purpose of the experiments described here was to explore the molecular basis for antidepressant-induced noradrenergic subsensitivity by examining the kinetic properties of the β-adrenergic receptors in the microsomal suspension of rat brain by using a potent β-adrenergic receptor antagonist 3H-dihydroalprenolol as a radiolabelled ligand14–19. Our results indicate that the main mechanism is a reduction in the number of receptors.
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TL;DR: These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons.
Abstract: Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.
2,029 citations
TL;DR: The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.
Abstract: Antidepressants compete at several neurotransmitter receptor binding site, but drug affinities do not correlate with clinical efficacy. Long-term, but not short-term, antidepressant treatment decreases the numbers of both serotonin and beta-adrenergic receptors. The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.
832 citations
TL;DR: It is concluded that drug dependence and depression may be associated with alterations in some of the same neurotransmitter systems and, in particular, with alterations of neurotransmitter function in limbic-related brain structures, and may be linked by some shared neurobiology.
737 citations
TL;DR: The effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function are evaluated to provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies ofAmine receptor function in patients.
Abstract: • Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.
642 citations
TL;DR: The evolutionary process involved in the discovery of the selective 5-HT uptake inhibitor, fluoxetine, is described and some of the large body of scientific research performed on fluoxettine in the 20 years since the first publication is summarized.
614 citations
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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
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
TL;DR: Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made, and confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness.
Abstract: The studies discussed here have shown a fairly consistent relationship between the effects of drugs on biogenic amines, particularly norepinephrine, and affective or behavioral states. Those drugs which cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioral stimulation or excitement and generally have an antidepressant effect in man (Table 1). From these findings, a number of investigators have formulated the concept, designated the catecholamine hypothesis of affective disorders (6), that some, if not all, depressions may be associated with a relative deficiency of norepinephrine at functionally important adrenergic receptor sites in the brain, whereas elations may be associated with an excess of such amines. It is not possible either to confirm or to reject this hypothesis on the basis of currently available clinical data. Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression. Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect. Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors. Although in this review of the relationship of biogenic amines to affective state relatively little has been said concerning the intricate set of environmental and psychological determinants of emotion, the importance of these factors must be stressed. The normally occurring alterations in affective state induced by environmental events is well known to all, from personal experience. The interactions between such environmental determinants of affect, various physiological factors, and the complexity of psychological determinants, including cognitive factors derived from the individual's remote and immediate past experiences, have received only limited study under adequately controlled conditions. It may be anticipated, however, that this will prove to be a particularly fruitful area for future research, for only within such a multifactorial framework may one expect to understand fully the relationship of the biogenic amines to emotional state.
855 citations
TL;DR: It appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.
Abstract: The response of the norepinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electroconvulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after the administration of a single dose or short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.
401 citations
TL;DR: Data suggest that beta-adrenergic catecholamines are able to regulate catechlamine sensitivity of tissues in vivo, by regulating the properties of the beta- adrenergic receptor binding sites.
Abstract: Injection of frogs with beta-adrenergic catecholamines for 1-24 hr produces marked subsensitivity of the erythrocyte membrane adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1.] to in vitro stimulation by isoproterenol. The subsensitization is specific for catecholamine stimulation, since basal and fluoride-stimulated enzyme activity are unaffected. Maximum isoproterenol-stimulated adenylate cyclase activity declines by 75% in the isoproterenol-treated animals (P less than 0.001). The concentration of isoproterenol causing one-half maximal activation of adenylate cyclase, however, is unaltered. (-)[3H]Alprenolol, a potent competitive beta-adrenergic antagonist, was used to study directly the beta-adrenergic receptor binding sites in the erythrocyte membranes from control and subsensitized animals. A highly significant (P less than 0.005) 60% fall in the number of the beta-adrenergic receptor binding sites ("specific"(-)[3H]alprenolol binding sites) in the treated animals was found. The binding affinity of the sites was not markedly altered. These data suggest that beta-adrenergic catecholamines are able to regulate catecholamine sensitivity of tissues in vivo, by regulating the properties of the beta-adrenergic receptor binding sites.
375 citations