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)

1. Concentrations of neuropeptide Y (NPY)-, neurokinin A (NKA)- and neurotensin (NT)-like immunoreactivity (-LI) were measured in brain tissues of Fawn Hooded (FH) (a model of depression), Wistar (W) (control for depression) and Sprague Dawley (SD) rats (control for strain) with the aim to explore possible associations between neuropeptides and models of depression. 2. In addition, peptides were determined after six electroconvulsive stimuli (ECS) or six sham ECS ("baseline") in order to investigate ECS mechanisms of action. 3. Baseline NPY-LI concentrations were markedly lower in the hippocampus of the "depressed" FH compared to the W and SD animals. 4. Baseline NKA-LI concentrations were higher in the occipital cortex and NT-LI concentrations in the occipital cortex, frontal cortex, and hypothalamus of the FH and W compared to the SD rats. 5. ECS increased NPY-LI in the hippocampus, frontal cortex and occipital cortex of all three strains. In the hippocampus, the increase was significantly larger in the FH compared to the W and SD rats. ECS also increased NKA-LI in the hippocampus. 6. In contrast, ECS decreased NT-LI in the occipital cortex of the FH and W animals. 7. The results indicate that NPY may play a role in depression and that changes in NPY and NKA probably constitute one of the mechanisms of ECT action. More speculatively, NT may also be involved in depression.
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PMID:Neuropeptide Y, neurokinin A and neurotensin in brain regions of Fawn Hooded "depressed", Wistar, and Sprague Dawley rats. Effects of electroconvulsive stimuli. 961 49

Neuropeptides: corticotropin releasing factor (CRF), neuropeptide Y (NPY) and somatostatin (STS) have been associated with depression and anxiety, while neurotensin (NT), calcitonin gene-related peptide (CGRP) and tachykinins [neurokinin A (NKA) and substance P (SP)] are presumed to also play a role in the function of the dopaminergic system. Moreover, investigations in the past decade have shown that psychotomimetics and antipsychotic drugs as well as lithium affect brain synthesis, tissue concentrations, and release of some neuropeptides. In view of the above, experiments were carried out to explore whether changes in neuropeptides constitute one of the mechanisms of action of electroconvulsive treatment (ECT). Human cerebrospinal fluid (CSF) was studied before and after ECT, and brains from healthy and models of depression rats were investigated in electroconvulsive stimuli (ECS)-treated and sham-treated animals. The major findings were that a series of ECTs, in parallel to clinical recovery, increased CSF concentrations of NPY-like immunoreactivity (-LI), STS-LI, and CRF-LI, and in one study endothelin-LI. A series of ECS, but not a single treatment, reproducibly elevated concentrations of NPY-LI, NKA-LI, and STS-LI--but not NT-LI, SP-LI, galanin-LI, or CGRP-LI--in hippocampus, frontal cortex, and occipital cortex. No changes were measured in other regions, e.g., striatum. NPY and STS mRNAs were also increased indicating that ECS affects peptide synthesis. Generalized seizures induced by, e.g., kainic acid or pentylenetetrazole, had similar effects on neuropeptides. The changes persisted for at least 1 week after the last treatment. Pretreatment with compounds reducing seizures, such as benzodiazepines and MK-801; had no effect on magnitude of neuropeptide changes although the seizure duration was decreased by > 50%. On the basis of these findings, it is suggested that neuropeptides are involved in ECT's mechanisms of action. Since ECT is therapeutically efficient in both schizophrenia and depression and, taking into account that antipsychotic drugs and psychotomimetics as well as lithium selectively affect some neuropeptides, it is hypothesized that distinct combinations of neuropeptide and monoamine changes in selected neuronal populations constitute the underpinnings of ECT's effects on specific disease symptoms, conceivably independent of diagnosis.
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PMID:Neuropeptides and electroconvulsive treatment. 1018 19

The aim of this study was to examine whether anorexia and bulimia nervosa are accompanied by lower serum activity of prolyl endopeptidase (PEP;EC 3.4.21.26; post-proline cleaving enzyme), a cytosolic endopeptidase which cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass. Substrates of PEP are, amongst others, neuroactive peptides, such as arginine vasopressin, luteinizing hormone-releasing hormone, thyrotropin releasing hormone,alpha-melanocyte secreting hormone, substance P, oxytocin, bradykinin, neurotensin and angiotensin (Ag) I and II. Serum PEP activity was measured in the serum of 18 normal women, 21 anorexia nervosa and 21 bulimia nervosa women by means of a fluoremetric method. The Bulimic Investigatory Test, Edinburgh (BITE), the Eating Disorder Inventory (EDI) and the Hamilton Depression Rating Scale (HDRS) were scored. Serum PEP activity was significantly lower in patients with bulimia nervosa and anorexia nervosa, irrespective of the restricted or binging subtype, than in normal controls. There were significant and inverse correlations between serum PEP activity and the HDRS and BITE. In anorectic patients, but not in normal or bulimic patients, there was a significant correlation between serum PEP and body mass index. In bulimic patients, but not in normal or anorectic patients, there was a significant correlation between serum PEP and duration of illness. It is concluded that lowered serum PEP activity takes part in the pathophysiology of anorexia and bulimia nervosa. It is hypothesized that a combined dysregulation of PEP and neuroactive peptides, which are substrates of PEP, could be an integral component of eating disorders.
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PMID:Lower serum activity of prolyl endopeptidase in anorexia and bulimia nervosa. 1107 Mar 31

About 25 years ago the observation that neuropeptides serve as signalling molecules in the nervous system generated great expectations for drug industry. In this article the progress made since then in exploiting neuropeptide systems pharmacologically in psychiatry is highlighted. In affective disorders a number of neuropeptides seem to be causally involved in development and course of illness, especially corticotropin releasing hormone (CRH), vasopressin (AVP) and substance P, whose receptors are now targeted with small molecules designed to reduce depressive and anxiety symptoms. Although not exactly neuropeptides, also neurotrophins, may have a distinct role in antidepressant action and possibly also in causation of depression. Schizophrenia-like symptoms are caused by neurotensin (NT), supporting the notion that drugs interfering with NT systems are potential antipsychotics. Finally, sleep disorders, currently treated with hypnotics, that have serious adverse effects can be targeted with neuropeptides. According to the work by Axel Steiger several neuropeptides even if peripherally administered produce improvements of quality of sleep. All these observations call for intensified application of novel research tools necessary to exploit the potential of neuropeptide systems as psychopharmaceutical targets.
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PMID:The role of peptides in treatment of psychiatric disorders. 1283 Sep 27

In this article we show some recent findings that constitute a great progress in the molecular knowledge of synaptic dynamics. To communicate, neurons use a code that includes electrical (action potentials) and chemical signals (neurotransmitters, neuromodulators). At the moment a great variety of molecules are known, whose neurotransmitter function in brain and the peripheral nervous system are out of question. Monoamines like acetylcholine, dopamine, noradrenaline, adrenaline, histamine, serotonin, glutamate, aspartate, glycine, ATP and GABA are good examples. Opioid neuropeptides, vasoactive intestinal peptide (VIP), neurokinines (substance P), somatostatin, neurotensin, neuropeptide Y, cholecystokinine, vasopressin or oxitocin have been related to the control of the stress response, sexual behaviour, food intake, pain, learning and memory, qualities that are also related to nitric oxide (NO). A great part of the molecular structure of the secretory machinery is known to be responsible for fast neurotransmitter release at the synapse, in response to action potentials. Proteins like sinaptobrevin (located in the membrane of the synaptic vesicle), sintaxin and SNAP-25 (both located at the presynaptic plasma membrane) constitute a trimeric complex which is responsible of the vesicular docking at the active sites for exocytosis. From this strategic location, vesicles release their neurotransmitter within few milliseconds, when the action potential invades the nerve terminal and activates the opening of the different subtypes of voltage-dependent Ca2+ channels. The asymmetric geographical distribution of each type of channel, in different neurons, rose the hypothesis that Ca2+ that enters through each subtype of channel is compartmentalised, thus favouring the generation of Ca2+ microdomains, in the cytosol and the nucleus, involved in different cellular functions. This great biochemical synaptic heterogeneity is facilitating the selection of many biological targets to develop drugs with potential therapeutic applications in neuropsychiatric diseases i.e. Alzheimer's, Parkinson, epilepsies, stroke, vascular dementia, depression, schizophrenia, anxiety and so on.
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PMID:[Neurotransmitters, calcium signalling and neuronal communication]. 1515 88

The main families of psychotropic drugs have been almost fortuitously discovered, from investigations carried out directly in humans. The burst of studies triggered by these discoveries and the considerably strengthened ethical guidelines for clinical trials have allowed remarkable developments in preclinical studies performed in animals, and especially in rodents. The corresponding models may be classified as follows: homologous models mimicking the aetiology of the disease against which one attempts to develop drugs; isomorphic models mimicking specific symptoms of a disease but involving different aetiological mechanisms; predictive models, which assess the effect of a drug on behavioural or other functional signs/symptoms unconnected to the psychiatric disease but involving the same type of biological targets as those affected by the disease; and theoretical or explanatory models that aim to elucidate the mechanism of action of agents producing psychotropic effects. Among the latter, the following can be cited: the knock out of genes coding for a specific biological target; the neutralisation of a specific ARNm by antisense oligodeoxynucleotides, which also aims to prevent the synthesis of a specific biological target; use of controlled reproduction to achieve a concentration of genes, the association of which leads to the development of a disease. Each one of these approaches has been illustrated by an example developed within the Rouen Neuropsychopharmacology Unit: the psychobehavioural spectrum of mice with invalidation of the gene coding for adenosine A2A receptors; the abolition of either nociceptin ORL1 receptors or neurotensin NTR2 receptors in order to characterise their functions; the concentration, by controlled breeding in mice, of a phenotype corresponding to that of depression. These developments illustrate several recent developments in neuropsychopharmacology with the aim of emphasising the vitality of this discipline.
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PMID:[The importance of in vivo pharmacology in fundamental research on psychotropic drugs and their biological targets]. 1519 68

Corticotropin-releasing factor (CRF) plays an important role in mediating central and peripheral responses to stress. Alterations in CRF system activity have been linked to a number of psychiatric disorders, including anxiety and depression. Aim of this study was to elucidate homeostatic mechanisms induced by lifelong elevated CRF levels in the brain. We therefore profiled gene expression in several brain areas of transgenic mice overexpressing CRF (CRF-OE), a model for chronic stress. Several genes showed altered expression levels in CRF-OE mice when compared to their wild type littermates and were confirmed by quantitative PCR. Differences in gene expression profiles revealed the presence of previously unrecognized homeostatic mechanisms in CRF-OE animals. These included changes in glucocorticoid signaling, as exemplified by changes in 11beta-hydroxysteroid dehydrogenase type 1, FK506 binding protein 5 and serum/glucocorticoid kinase. Alterations in expression of genes involved in myelination (myelin, myelin-associated glycoprotein), cell proliferation and extracellular matrix formation (Edg2, Fgfr2, decorin, brevican) suggest changes in the dynamics of neurogenesis in CRF-OE. Pronounced changes in neurotensin (NT) receptors 1 and 2 mRNA were identified. Overall downregulation of NT receptors in CRF-OE animal was substantiated by receptor binding studies. Pronounced neurotensin receptor downregulation was observed for NT type 1 receptors in limbic brain areas, suggesting that NT could be implicated in some of the effects attributed to CRF overexpression. These data show that lifelong exposure to excessive CRF leads to adaptive changes in the brain which could play a role in some of the behavioral and physiological alterations seen in these animals.
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PMID:Gene expression profiles highlight adaptive brain mechanisms in corticotropin releasing factor overexpressing mice. 1546 90

Neurotensin (NT) is a peptide that is widely distributed throughout the brain. NT is involved in locomotion, reward, stress and pain modulation, and in the pathophysiology of drug addiction and depression. In its first part this review brings together relevant literature about the neuroanatomy of NT and its receptors. The second part focuses on functional-anatomical interactions between NT, the mesotelencephalic dopamine system and structures targeted by dopaminergic projections. Finally, recent data about the actions of NT in processes underlying behavioral sensitization to psychostimulant drugs and the involvement of NT in the regulation of the hypothalamo-pituitary-adrenal gland axis are considered.
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PMID:Brain neurotensin, psychostimulants, and stress--emphasis on neuroanatomical substrates. 1693 69

Neuropeptides play a crucial role in the normal function of the central nervous system and peptide receptors hold great promise as therapeutic targets for the treatment of several CNS disorders. In general, the development of peptide therapeutics has been limited by the lack of drug-like properties of peptides and this has made it very difficult to transform them into marketable therapeutic molecules. Some of these challenges include poor in vivo stability, poor solubility, incompatibility with oral administration, shelf stability, cost of manufacture. Recent technical advances have overcome many of these limitations and have led to rapid growth in the development of peptides for a wide range of therapeutic indications such as diabetes, cancer and pain. This review examines the therapeutic potential of peptide agonists for the treatment of major CNS disorders such as schizophrenia, anxiety, depression and autism. Both clinical and preclinical data has been accumulated supporting the potential utility of agonists at central neurotensin, cholecystokinin, neuropeptide Y and oxytocin receptors. Some of the successful approaches that have been developed to increase the stability and longevity of peptides in vivo and improve their delivery are also described and potential strategies for overcoming the major challenge that is unique to CNS therapeutics, penetration of the blood-brain barrier, are discussed.
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PMID:Peptide therapeutics for CNS indications. 2205 Oct 78

Neurotensin (NT), a neuropeptide abundant in the ventral midbrain, is known to act as a key regulator of the mesolimbic dopamine (DA) system, originating in the ventral tegmental area (VTA). NT activates metabotropic receptors coupled to Gq heterotrimeric G proteins, a signaling pathway often triggering endocannabinoid (EC) production in the brain. Because ECs act as negative regulators of many glutamate synapses and have also been shown recently to gate LTP induction in the VTA, we examined the hypothesis that NT regulates glutamate-mediated synaptic inputs to VTA DA neurons. We performed whole cell patch-clamp recordings in VTA DA neurons in TH-EGFP transgenic mouse brain slices and found that NT induces a long-lasting decrease of the EPSC amplitude that was mediated by the type 1 NT receptor. An antagonist of the CB1 EC receptor blocked this decrease. This effect of NT was not dependent on intracellular calcium, but required G-protein activation and phospholipase C. Blockade of the CB1 receptor after the induction of EPSC depression reversed synaptic depression, an effect not mimicked by blocking NT receptors, thus suggesting the occurrence of prolonged EC production and release. The EC responsible for synaptic depression was identified as 2-arachidonoylglycerol, the same EC known to gate LTP induction in VTA DA neurons. However, blocking NT receptors during LTP induction did not facilitate LTP induction, suggesting that endogenously released NT is not a major source of EC production during LTP inducing stimulations.
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PMID:Neurotensin inhibits glutamate-mediated synaptic inputs onto ventral tegmental area dopamine neurons through the release of the endocannabinoid 2-AG. 2288 66


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