Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term potentiation (LTP) is probably the most widely studied form of synaptic plasticity in the mammalian central nervous system. In the early descriptions, the term referred to a sustained increase in synaptic response following a brief high-frequency electrical tetanus. Apparently unique properties of the phenomenon triggered considerable excitement in the field: for many, LTP offered the promise of a potential substrate for learning and/or memory. In the more than 20 years since LTP was first discovered, investigators motivated by this promise have described a vast array of molecules and processes that may be involved in LTP induction and maintenance. And yet, the mechanisms by which LTP occurs have not been resolved. Instead, the compiled results have uncovered layer upon layer of intricacy, including multiple LTP forms and multiple molecular cascades involved in LTP expression. The generally stated thesis that LTP equates to learning and/or memory at a synaptic level has not faced a serious challenge despite the fact that workers in the field have not provided an unambiguous correlation of LTP with either. A number of investigators have now shifted their attention to a newer form of synaptic modification, long-term depression (LTP). Whatever studies of LTD reveal, it is clear that the fundamental questions about LTP remain unanswered: what is it really and what, if anything, is it used for? In this review, we summarize the data concerning putative LTP mechanisms and the evidence for LTP's role in learning and memory. We show that extant models are not sufficient to account for the various forms of LTP and that the experimental evidence does not justify the view that LTP equates to learning and memory. Instead, we suggest that LTP can be related to other forms of synaptic modification, e.g., LTD and kindling, in a neuroplasticity/pathology continuum of events. In particular, we suggest that neurotransmitter receptor regulation may be a key element leading to synaptic modification: in the adult nervous system, homeostatic receptor regulation normally compensates for alterations in synaptic input, while in the developing nervous system a form of 'homeodynamic' receptor regulation prevails. Our model proposes that homeodynamic receptor regulation leading to an LTP-like effect triggers, or acts in concert with, synaptogenesis to allow young neurons to modify response characteristics in response to altered input. In contrast, some forms of LTP in adult neurons may represent a 'failed' form of receptor regulation whose final outcome is neural death. The model suggests a series of experimentally verifiable hypotheses.
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PMID:An alternative to the LTP orthodoxy: a plasticity-pathology continuum model. 887 85

Milnacipran (Ixel) is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake and its lack of affinity for neurotransmitter receptors. It inhibits virtually equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo, as demonstrated by the antagonism of centrally acting monoamine displacers. It has no effect on dopamine reuptake. In addition, milnacipran has been shown by intracerebral microdialysis to increase the extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor or ion channel. In particular, and unlike tricyclic antidepressants, it does not act at noradrenergic, muscarinic or histaminergic receptors. Contrary to tricyclic antidepressants, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. This pharmacological profile, associated with an excellent bioavailability in man, was predicted to be that required for a powerful and well-tolerated antidepressant. Subsequent clinical development has shown this prediction to be well founded.
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PMID:Preclinical pharmacology of milnacipran. 892 22

Abnormalities of hypothalamus-pituitary-adrenal axis regulation are common in the elderly and excess glucocorticoids have been implicated in the loss of neural function in aging. In the current study, we examined cell signaling mediated through adenylyl cyclase in brain regions, heart and liver of young and aged rats given continuous infusions of dexamethasone (10 or 50 micrograms/kg/day) for 26 days. Aged control animals showed significant deficits in total adenylyl cyclase activity (assessed with forskolin-Mn++) in the brain regions and the heart; superimposed on this change, the striatum and the heart displayed interference with the response mediated either at the level of G-protein coupling to cyclase (striatum) or neurotransmitter receptor coupling to G-proteins (heart). Administration of dexamethasone to young rats did not reproduce the effects of aging on any of the measures of adenylyl cyclase, despite the fact that the higher dose produced Cushingoid effects. The same dexamethasone regimens given to aged rats produced alterations in G-protein coupling mechanisms in the cortex and in serotonergic-mediated cyclase responses in the striatum, and also decreased basal enzyme activity in the heart. In contrast to the brain regions and the heart, the liver showed unique effects of aging and dexamethasone. Total adenylyl cyclase activity, the enzymatic response to beta adrenergic stimulation and the number of beta adrenergic receptors were all elevated in aged animals as compared to the younger cohort. Dexamethasone decreased both hepatic beta receptor numbers and isoproterenol responsiveness in young animals, but increased receptor binding in aged animals. These data indicate that the defects associated with aging in the central nervous system and the cardiac cell signaling mediated through adenylyl cyclase are not a result of glucocorticoid excess; however, central and peripheral tissues respond differently to glucocorticoids in aged vs. young animals. Given the high incidence of hypothalamus-pituitary-adrenal axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disruption of cell function and to hypo- or hyper-reactivity to drugs, such as antidepressants, that act by altering synaptic transmission.
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PMID:Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase. 893 Jan 49

Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.
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PMID:Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability. 921 45

Metabotropic glutamate receptors are thought to be important regulators of synaptic transmission and plasticity in the hippocampus. The metabotropic glutamate receptor subtype mGluR5 is expressed in hippocampal pyramidal neurons but its function remains unknown due to the lack of selective pharmacological blockers. We inhibited the synthesis of mGluR5 with antisense oligonucleotides injected into the hippocampus in vivo. The functional effects of altered mGluR5 expression were measured electrophysiologically in the CA1 region of the hippocampus during applications of the metabotropic agonist 1S,3R-ACPD (50 microM) to hippocampal slices from injected animals. The results show a concomitant reduction of the mGluR5 receptor protein and physiological effects in the hippocampus. The major effect found in the antisensetreated animals was the lack of an excitatory action normally produced by 1S,3R-ACPD. Another effect attributed to metabotropic glutamate receptors, depression of synaptic transmission, had a more rapid onset, but unchanged magnitude, while long-term potentiation remained unchanged. The specificity and effectiveness of the antisense treatment were confirmed using mismatched oligonucleotides and immunoblotting. We conclude that the metabotropic glutamate receptor subtype mGluR5 plays a major role in the regulation of cell excitability in the hippocampus without directly affecting synaptic transmission or long-term potentiation. Moreover, in vivo applications of antisense deoxynucleotides are a useful approach in studies of neurotransmitter receptor subtypes.
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PMID:Down-regulation of mGluR5 by antisense deoxynucleotides alters pharmacological responses to applications of ACPD in the rat hippocampus. 929 2

Lithium remains a first-line approach for the treatment of acute mania and the prophylactic management of manic-depressive illness, yet the underlying neurobiological mechanisms remain as yet undefined. In this paper we critically examine the accumulated preclinical and clinical evidence for the action of lithium in the brain and suggest areas that may be most productive for future investigation, i.e., membrane transport systems, neurotransmitter receptor regulation, second messenger generating systems, protein kinase C (PKC) regulation, and gene expression. In their experimental design, preclinical investigations have often jeopardized the physiologic relevance of their studies by a relative lack of attention to issues such as therapeutic concentrations, acute versus chronic exposure, and a lack of adequate cation and/or psychotropic controls. Future studies should account for the established prophylactic efficacy of lithium, the higher risk for relapse into mania after abrupt discontinuation, the ability of lithium to stabilize recurrent depression associated with unipolar disorder, and the efficacy of lithium in the treatment of refractory major depressive disorder in the presence of an antidepressant. Studies of the action of lithium in receptor mediated phosphoinositide signaling in the brain over the past several years have opened up heuristic lines of investigation that stem from lithium's uncompetitive inhibition of the enzyme inositol monophosphatase. Subsequent studies involving regulation of inositol transport, PKC isozymes and activity, and the expression of the major PKC substrate MARCKS (myristoylated alanine-rich C-kinase substrate) have offered potential avenues for understanding the complexity of the action of long-term lithium in the brain. These studies will offer us a better understanding of the neuroanatomical sites of action of lithium and together with ongoing clinical investigations using brain imaging in patients with manic-depressive illness a more complete understanding of the pathophysiology of this disease.
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PMID:Neurobiology of lithium: an update. 967 36

Interleukin-1beta (IL-1beta), a polypeptide immune mediator, is induced within the central nervous system in response to a variety of pathological stimuli, including systemic infection, hypoxia, brain trauma, and seizure. IL-1beta action on the gamma-aminobutyric acid type A (GABA(A)) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1beta at concentrations encountered in pathophysiological conditions (1-10 ng/ml; 59-590 pM) irreversibly decreased the peak magnitude of current elicited by 30 microM GABA. Current inhibition was IL-1beta concentration- and time-dependent and was prevented by a specific IL-1beta type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1beta depression of GABA current was inhibited by high concentrations of nonspecific kinase inhibitors staurosporine (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 microM), but not by a protein kinase C selective inhibitor calphostin C (5 microM). We conclude that IL-1beta inhibits GABA(A) receptor function in hippocampal neurons by the involvement of an unidentified kinase. This blockade of the GABA(A) inhibitory neurotransmitter receptor may underlie the central nervous system hyperexcitability seen in many pathophysiological conditions.
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PMID:Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. 1064 Feb 85

Milnacipran is a new antidepressant which inhibits equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo with no effect on dopamine reuptake. Microdialysis studies have shown increased extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor. In particular, and unlike tricyclic antidepressants (TCAs), it has no activity at noradrenergic, muscarinic or histaminergic receptors. Contrary to TCAs, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. Milnacipran has a high bioavailability, low plasma protein binding, and is largely eliminated in the urine as the parent drug or as a glucuronide. These features suggest that interactions with other drugs given concurrently are unlikely. Studies in patients with liver dysfunction and in the elderly suggest that dose adjustment is not necessary. In patients with renal impairment, decreased elimination of milnacipran is correlated to the degree of renal impairment allowing an easy dosage adjustment. An intermediate half-life of approximately 8 h is compatible with twice-daily administration. Clinical studies comparing milnacipran, placebo and other antidepressants provide evidence of its efficacy in moderate to severe depression in both hospitalized and outpatient settings. Meta-analyses of the original data of controlled trials comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs) show that milnacipran provides antidepressant efficacy similar to that of TCAs and significantly superior to that of SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of TCAs with notably less cholinergic side effects. The tolerance of milnacipran was comparable to that of SSRIs with a higher incidence of dysuria with milnacipran but a higher frequency of nausea and anxiety with the SSRIs. Milnacipran represents an interesting new therapeutic option in depression, being as well tolerated as the SSRIs but offering clinical efficacy similar to the TCAs.
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PMID:Milnacipran, a new specific serotonin and noradrenaline reuptake inhibitor. 1498 77

Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABAA neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA-related proteins are functional candidates to influence risk of alcohol dependence. Two genome-wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABAA receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABAA receptor alpha-2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 bp in the middle and 3'-portion of the GABRA2 gene (range of P-values = 0.008-0.03). When the subset of the alcohol-dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P-values = 0.002-0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol-dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co-morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence.
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PMID:Allelic and haplotypic association of GABRA2 with alcohol dependence. 1527 50

Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect approximately 17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.
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PMID:Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways. 1568 30


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