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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Until recently it appeared that lithium carbonate possessed a unique spectrum of clinical action in the acute and prophylactic treatment of manic and depressive episodes. It is now increasingly apparent that the anticonvulsants carbamazepine and valproate also share components of this spectrum of efficacy in the affective disorders but, in addition, are clinically effective in some lithium nonresponders. This clinical convergence can now drive a reexamination of the potential mechanisms of action of these compounds in the affective disorders. In spite of intensive study over several decades, the mechanism of action of lithium has remained elusive. A basic conundrum in the consideration of the actions of lithium has also been to explain how a simple ion could have such complex effects on multiple neurotransmitter systems and, in particular, have bimodal actions in the treatment of both manic and depressive phases of the illness. We suggest that a fundamental reconceptualization of both mania and depression as overactivated neural systems (either excitatory or inhibitory) could facilitate this conceptualization. Given the recent evidence linking lithium's effects to uncoupling receptor-mediated activity at the level of G-proteins or attenuating it at the level of second messenger systems mediated by adenylate cyclase or phosphoinositide turnover, these mechanisms become ideal candidates for considering how the drug could dampen overactivated systems potentially relevant to either depression or mania. The lag in onset of maximum therapeutic action of lithium, carbamazepine, and valproate further suggests that biologic effects associated with chronic compared with acute administration are the prime candidates for psychotropic effects. Comparison of the acute and chronic effects of carbamazepine with those of valproate is also offered to focus on the most likely receptor, second-messenger, and ion channel mechanisms involved in their anticonvulsant and psychotropic actions. It is hoped that better understanding of the comparative actions of lithium, carbamazepine, and valproate will allow better targeting of individual drugs for individual patients as well as, ultimately, the development of new and more selective treatments for the recurrent affective disorders.
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PMID:Mechanisms of action of anticonvulsants in affective disorders: comparisons with lithium. 154 15

Advances in neuropeptide neurobiology in the last decade are illustrated by studies of corticotropin-releasing factor (CRF), the 41 amino acid-containing peptide that controls the anterior pituitary secretion of adrenocorticotropin and other pro-opiomelanocortin products. Corticotropin-releasing factor is synthesized in both hypothalamic and extrahypothalamic perikarya in a large prohormone form, (186 amino acids), then it is processed and transported to nerve terminals where it is released in its active form by a calcium-dependent mechanism. Corticotropin-releasing factor biosynthesis can now be measured by in situ hybridization because of the elucidation of the CRF gene sequence. Once released, CRF acts on high-affinity CRF receptors, and signal transduction is mediated by activation of adenylate cyclase in certain brain areas, and perhaps by phosphoinositide hydrolysis. In other brain areas CRF is inactivated by peptidases that degrade the hormone, though these are not well characterized. A CRF binding protein has been identified in plasma, and perhaps in brain. Considerable evidence exists from cerebrospinal fluid studies, postmortem tissue receptor measurements, and CRF stimulation test studies to support the hypothesis that CRF is hypersecreted in depression, resulting in both pituitary-adrenal axis hyperactivity and certain signs and symptoms of depression, e.g., decreased libido, insomnia, and decreased appetite. There is also evidence for an involvement of CRF in the pathophysiology of anxiety disorders and in the mechanism of action of benzodiazepines. The development of selective CRF-receptor antagonists will permit direct testing of the hypothesis that CRF hypersecretion is responsible for certain of the cardinal features of affective and anxiety disorders.
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PMID:New vistas in neuropeptide research in neuropsychiatry: focus on corticotropin-releasing factor. 161 Apr 87

Thirty-three years ago, Gaddum and Picarelli classified the serotonin receptors in the guinea pig ileum into D and M types based on the activity of dibenzyline and morphine to block contractions of intestinal smooth muscle caused by serotonin. The subsequent location of specific ligand binding sites for serotonin in the brain has led to the identification of at least eight serotonin receptor sub-types in rat brain. While there is some controversy over the functional importance of many of these receptor sub-types, there is evidence that they fall into two major groups according to the nature of their coupling to secondary messengers or ion channels. Thus the 5-HT1 and 5-HT2 receptors appear to occupy the G protein receptor sub-family which may be coupled either to adenylate cyclase (most 5-HT1 sub-types) or phosphatidyl inositol (5-HT2 sub-types). The central "M" receptors (now termed 5-HT3) appear to occupy a ligand gated ion channel super-family. The cloning of three of the serotonin receptor sub-types in 1989 (5-HT1A, 5-HT1C and 5-HT2) has been of importance in enabling the receptor sub-types to be classified as specific protein molecules encoded by specific genes. The problem now arises with regard to the linking of the changes in the cellular activity of the various receptor sub-types with the plethora of behavioural changes that arise as a consequence of the actions of serotonin in the brain. The present review summarizes the evidence implicating the role of specific serotonin receptor sub-types in eating disorders, sleep, sexual activity, anxiety states, aggression, schizophrenia and depression. A summary of the relationship between these receptor sub-types and their possible involvement in the aetiology of these diseases is shown in Table 2.
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PMID:Sub-types of serotonin receptors: biochemical changes and pharmacological consequences. 162 53

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 Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. 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 of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC-GR/5-HT1A-G-protein--effector system-related abnormality in depression.
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PMID:The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids. 164 69

Infection of beagles with an opossum-derived strain of Trypanosoma cruzi (Tc-O) results in features of early and chronic chagasic cardiomyopathy, that is, increases in PR interval, atrioventricular block, and frequent ventricular premature contractions, ventricular tachycardia, and decreased left ventricular ejection fraction. These signs are not observed in animals infected with a canine strain of T. cruzi (Tc-D). To understand the biochemical basis for these early cardiac effects, we examined the beta-adrenergic adenylate cyclase complex in myocardial membranes prepared from animals infected with either of the two strains. In animals infected with Tc-O (symptomatic), the maximum velocity (Vmax) decreased and concentration of agonist resulting in 50% of Vmax (Kact) increased for isoproterenol-dependent adenylate cyclase activity; in animals infected with Tc-D (asymptomatic), Vmax and Kact for isoproterenol were unchanged from control, uninfected animals. beta-Receptor density decreased by 20% in symptomatic animals with no change in affinity, whereas no differences were observed between uninfected and infected asymptomatic animals. A complex pattern of changes was apparent in the guanine nucleotide binding protein, Gs, in the setting of infection. Alterations in cholera toxin-dependent ADP-ribosylation patterns as well as immunochemical detection with anti-G alpha s antisera suggested a change in the biochemical nature of the Gs species and not necessarily a physical loss of this protein. Reconstitution of adenylate cyclase activity in cyc- membranes demonstrated a decrease in hormone-sensitive Gs activity in membranes prepared from symptomatic animals without a change in activity demonstrable in the presence of Gpp(NH)p. Collectively, the results suggest that the depression in beta-adrenergic adenylate cyclase activity associated with symptomatic infection of beagles with T. cruzi occurs primarily as a result of changes in the Gs protein complex, most likely resulting in an uncoupling of the beta-adrenergic receptor from the Gs protein.
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PMID:Myocardial beta-adrenergic adenylate cyclase complex in a canine model of chagasic cardiomyopathy. 164 78

1. After blocking K+ currents with 10 mM-tetraethylammonium (TEA) or TEA plus 250 microM-3,4-diaminopyridine (3,4-DAP). motor nerve terminal Ca2+ currents were recorded using focal extracellular electrodes. Two transmitters released from the terminal. ATP and acetylcholine (ACh), were then applied, and the effects on the nerve terminal Ca2+ current were measured. 2. ATP (50 microM) reduced the Ca2+ current by 34%, but this action is prevented when hydrolysis to adenosine is blocked by alpha,beta-methyladenosine 5'-diphosphate (200 microM). Thus, inhibition by ATP presumably occurs subsequent to ATP hydrolysis to adenosine. 3. Adenosine (50 microM) inhibited the terminal Ca2+ current by 29%. This was mimicked by the adenosine analogue L-phenylisopropyl adenosine (L-PIA) and blocked by theophylline (100 microM), which antagonizes adenosine receptors at micromolar concentrations. 4. ACh (100 microM) or the anticholinesterase methane sulphonyl fluoride (MSF; 1 mM) also depressed the terminal Ca2+ current. This response was mimicked by muscarine (100 microM) and antagonized by atropine (100 microM) or pirenzipine (4 microM), which is generally specific for M1 receptors. 5. Addition of Ba2+, which blocks adenosine-mediated K+ currents, had no effect on the inhibitory effects of either adenosine or ACh; similarly, neither adenosine nor ACh in the bath affected K+ current records obtained after blocking all inward currents with 10 mM-Co2+ and focal application of tetrodotoxin. 6. Incubation of the muscle for 4 h in pertussis toxin (10(-5) g ml-1) eliminated both adenosine- and ACh-induced inhibition of the terminal Ca2+ current. This result indicates the possible involvement of a G protein in the transduction of the feedback pathway. 7. Neither cyclic AMP analogues, the adenylate cyclase activator forskolin (10 microM), the phorbol ester phorbol 12-myristate 13-acetate (PMA; 3 microM) nor the diacylglycerol analogue 1,2-oleoylacetylglycerol (OAG; 3 microM) had any effect on adenosine- or ACh-induced depression of the terminal Ca2+ current. Therefore, pathways involving these particular second messengers are most probably not involved. 8. The effects of adenosine and ACh are non-additive. 9. These results indicate that ATP and ACh, which are released during exocytosis, may inhibit their own release through attenuation of the terminal Ca2+ current via autoreceptors coupled to a G protein.
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PMID:Autoreceptor-mediated purinergic and cholinergic inhibition of motor nerve terminal calcium currents in the rat. 165 22

Although often not considered, the heart is one of the targets of multiple organ failure in sepsis and septic shock, with myocardial depression being a prominent component of this "acute septic cardiomyopathy". Hypotheses concerning the etiology of this depression are increasingly elucidated on a cellular level, including dysfunction of the beta-adrenoceptor/G protein/adenylate cyclase system, calcium channel blockade by cardiodepressant factor, contractile impairment by activated leucocytes, as well as inhibition of protein synthesis by Pseudomonas exotoxin A. In the search for "mechanisms of myocardial depression in sepsis", isolated cardiomyocytes may play a role as research tools with respect to: a) discrimination between direct and indirect cardiodepressant effects; b) identifying not only the acute, but also chronic toxin- and mediator-induced cardiodepression; c) clarification of the mechanism of action of cardiodepressant bacterial toxins and sepsis mediators; d) establishment of in vitro models of leucocyte-mediated cardiodepression in sepsis.
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PMID:Mechanisms in acute septic cardiomyopathy: evidence from isolated myocytes. 166 46

The response of the beta-adrenoceptor transduction system to global ischemia for 40 min was investigated in isolated working heart of rat. The enhancement of beta-adrenoceptors was not observed in the ischemic myocardium. A depression of forskolin-stimulated adenylate cyclase enzyme occurred with global ischemia, but no change in Gs or Gi2 was detected. Thus, the present in vitro ischemic heart model may not necessarily reflect the identical milieu induced by the in vivo myocardial ischemia.
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PMID:Prolonged period of global ischemia causes no change in the GTP-binding proteins in the isolated perfused rat heart. 166 54

The role of prenatal beta-receptor stimulation in development of adrenergic reactivity was examined by administering the beta-agonist, terbutaline, to pregnant rats on gestational days 17, 18 and 19. On gestational day 20, liver membrane beta-receptor binding capabilities showed the depression characteristic of down-regulation, but heart and kidney receptor binding were essentially normal. Basal adenylate cyclase activity in the fetal liver membrane preparation was unchanged by terbutaline exposure and enzymatic reactivity to beta-adrenergic stimulation showed only a slight lowering; forskolin stimulation, however, was markedly increased in the terbutaline group. By postnatal day 2, receptor binding had returned to normal in the liver and remained at control levels in the other two tissues. Responsivity of adenylate cyclase to beta-receptor stimulation was markedly elevated in heart and kidney membranes; the effect represented an alteration at the level of the cyclase itself, rather than the receptor, since both basal activity and forskolin stimulation of the enzyme showed equivalent enhancement. These data thus suggest that early beta-adrenergic stimulation promotes cellular reactivity by fostering the development of membrane transduction mechanisms, rather than through effects on the receptor ligand binding site per se.
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PMID:Prenatal terbutaline treatment: tissue-selective dissociation of perinatal changes in beta-adrenergic receptor binding from regulation of adenylate cyclase activity. 167 19

1. The intracellular mechanism of heterosynaptic facilitation (HSF) formation in identified neurons from the snail Planorbis corneus has been studied. 2. Facilitation of excitatory postsynaptic currents (EPSC) were induced by (a) stimulation of pallial nerve, and (b) addition to extracellular saline of serotonin, NaF, papaverine, theophylline, caffeine or dibutril-cAMP. 3. A depression of EPSC in solutions containing tolbutamide, a cAMP-dependent protein kinase inhibitor was observed. 4. In some cases the similar facilitation or depression of the current induced by acetylcholine application (ACh-current) was found in the same neuron. 5. The effects on ACh-current were distorted in solutions containing caffeine, a well-known activator of calcium ions release from the intracellular depot. 6. According to our findings, we suggest that adenylate cyclase activity of postsynaptic cells could underlie the formation of HSF and it is likely that this activity was modulated by intracellular concentration of calcium ions.
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PMID:Analysis of heterosynaptic facilitation in identified giant neurons from cerebral ganglion of the pond snail Planorbis corneus. 167 48


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