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)

The pathophysiology of depression remains unclear, but involves disturbances in brain monoaminergic transmission. Current antidepressant drugs, which act by enhancing this type of transmission, have limited therapeutic efficacy in a number of patients, and not rarely serious side-effects. Increasing evidence suggests that neuropeptides, including galanin, can be of relevance in mood disorders. Galanin is coexpressed with and modulates noradrenaline and serotonin systems, both implicated in depression. Pharmacological and genetic studies have suggested a role for galanin in depression-like behaviour in rodents, whereby the receptor subtype involved appears to play an important role. Thus, stimulation of GalR1 and/or GalR3 receptors results in depression-like phenotype, while activation of the GalR2 receptor attenuates depression-like behaviour. These findings suggest that galanin receptor subtypes represent targets for development of novel antidepressant drugs.
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PMID:Galanin, galanin receptor subtypes and depression-like behaviour. 1850 Jun 40

Neuropeptide galanin modulates a variety of central nervous system functions by signaling through three G-protein-coupled receptor subtypes, GalR1 through GalR3. Galanin and its receptors are expressed at high levels in the limbic structures of the rodent brain. Intracerebroventricular injection of galanin has been shown to modulate depression and anxiety-like behaviors in the rat. We have previously shown that chronic antidepressant treatments increase the binding of a GalR2-preferring ligand, galanin (2-11), to the dorsal raphe nucleus (DRN) of the rat, which, along with the finding that intra-DRN infusion of galanin (2-11) increases the release of serotonin in the hippocampus, suggests that GalR2 signaling might exert antidepressant-like actions by modulating ascending serotonergic outflow. Recently, two research groups reported their phenotypic analysis of a GalR2 knockout (GalR2KO) mouse line, produced by gene-trapping method and maintained on a 129S1/SvImJ genetic background. The only positive finding in that GalR2KO mouse line was an anxiogenic-like phenotype specific to the elevated plus-maze. Because it is known that genetic background can affect the outcome of behavioral tests, in the present study, we analyzed a separate GalR2KO line, which was produced by targeted deletion and maintained on a C57BL/6 background, using a different set of depression- and anxiety-related tests. GalR2KO mice exhibited a more persistent depressive-like phenotype in the learned helplessness paradigm as well as increased immobility in the tail suspension test when results from the present studies were combined by fixed effect meta-analysis with that reported by Gottsch and colleagues. GalR2KO mutants showed anxiety-like behavior comparable to wild-type littermates in the elevated plus-maze, open-field, and light-dark transfer tests. The present findings are consistent with a predicted antidepressant-like effect of GalR2 signaling, suggesting that GalR2 might be a valid drug target for depressive disorders.
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PMID:Phenotypic analysis of GalR2 knockout mice in anxiety- and depression-related behavioral tests. 1855 14

One of the first neurobiological theories of major depression was the monoamine deficiency hypothesis. The classic monoamine theory of depression suggested that a deficit in monoamine neurotransmitters in the synaptic cleft was the main and primary cause of depression. Recent and newer versions and modifications of the primary classic theory also mainly included this postulate, while other theories of depression preferred departing from the monoamine-based model altogether. Unfortunately, the clear neurobiology of major depression remains an elusive issue, despite intense research. It is clearly held that most, if not all, antidepressant pharmacotherapies treatments produce their therapeutic antidepressant effects, at least in part, by modulating monoamine systems (noradrenergic, serotonergic, and dopaminergic) by a selective or a multi-acting way; however, much less is known about the neurobiological pathology of these monoamine systems in depression. Much of the past 10-15 years of research in the biology of mood disorders has led to considerable evidence in depression implicating multiple system pathology, including abnormalities of monoamine as well as other neurotransmitter systems. These approaches and findings have led researchers to propose broader theories regarding the neurobiology of depression, just like a spreading disorder of specific neuronal networks in the brain. A model for the pathophysiology of depression ill be discussed in the next pages, after describing the main components of depression pathogenesis. Suggestion is that the primary defect emerges in the cross-regulation and vulnerability of special monoaminergic and non-monoaminergic neural networks, which leads to a decrease in the tonic release of neurotransmitters in their projection areas, altering postsynaptic sensitivity, and following, overexaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the primary defect should be involved, in the noradrenergic innervation spreading from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to malfunction of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Consecutive deficits in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Malfunction and dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptive ability to stressful stimuli. The new SNRI antidepressants seem to be more superior and effective in the treatment of major depression and in the prophylaxis of recurrent depressive episodes because of their coexistent noradrenergic activity.
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PMID:[Domino principle--monoamines in bottom-view]. 1895 17

G-protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors and are the major drug targets for the treatment of various human diseases. The lack of sensitive and selective antibodies capable of recognizing endogenous GPCRs, however, hampers the progress of research on this class of receptors. GalR1 through GalR3, GPCRs for the neuropeptide galanin, are potential drug targets for seizure, Alzheimer's disease, depression and anxiety, as well as pain and metabolic syndrome; therefore, determining the cellular and subcellular localization of galanin receptors is of high interest. Several Antibodies raised against galanin receptors are currently available from commercial or academic sources. We have tested several antibodies to GalR1 and GalR2 on tissues from respective knockout mice. Unexpectedly, the immunoreactivity patterns are the same in wild-type and in knockout mice, suggesting that current GalR1 and GalR2 antibodies, under standard immunodetection conditions, might not be suitable for mapping the receptors. These findings argue for taking precaution when using antibodies to galanin receptors.
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PMID:Analyzing the validity of GalR1 and GalR2 antibodies using knockout mice. 1915 18

Whereas the cerebellum contains 22 different types of neuropeptides as presently known, their expression is generally weak and diffusely dispersed in cerebellar tissues, which often makes their functional significance doubtful. Nevertheless, our knowledge about certain neuropeptides has advanced to the extent that we can figure out their unique functional roles in cerebellar circuits. Throughout the cerebellum, CRF is contained in climbing fibers and its spontaneous release is required for the induction of cerebellar long-term depression (LTD), a cellular mechanism of motor learning. Corticotropin-releasing factor (CRF) is also expressed in the paraventricular nucleus-pituitary system and amygdala-lower brainstem system, both of which are involved in coping responses to stress. In view that motor learning requires stressful efforts for correcting errors in repeated trials, CRF in climbing fibers may imply that the olivocerebellar system is part of a large CRF-operated functional system that acts to cope with various stressors. Orexin, on the other hand, is contained in beaded fibers, which, originating from the hypothalamus, project to various brainstem nuclei and also to the cerebellum, exclusively the flocculus. Currently available evidence suggests that, in fight-or-flight situations, orexinergic neurons switch the state of cardiovascular control systems including the flocculus to secure blood supply to working muscles. Considerable knowledge has also been accumulated about angiotensin II, galanin, and cerebellin, but there is still a gap in defining their unique functional roles in cerebellar circuits.
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PMID:Functional roles of neuropeptides in cerebellar circuits. 1936 75

Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.
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PMID:Neuropeptide and sigma receptors as novel therapeutic targets for the pharmacotherapy of depression. 1968 66

The etiology and pathophysiology of both depression and anxiety remain unclear, but involve dysfunctional monoaminergic neurotransmission and function. The currently available antidepressant medications that work through optimizing the monoaminergic system are often limited by their lack of efficacy or their adverse effects. There is increasing evidence that some neuropeptides, including substance P, corticotropin-releasing factor, neuropeptide Y, vasopressin and galanin, may have relevance in both depression and anxiety. Integration of anatomical, physiological and clinical evidence suggests that modulation of monoaminergic transmission is the most likely mechanism by which neuropeptides may work in these disorders. These neuropeptides and their receptors may serve not only as potential therapeutic targets for treatment of depression and anxiety, but may also help enhance our understanding of the psychopathology of these two major psychiatric disorders.
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PMID:Neuropeptides: relevance in treatment of depression and anxiety disorders. 1977 21

In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.
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PMID:Behavioral effects of neuropeptides in rodent models of depression and anxiety. 2002 11

Despite effective and safe therapies for major depressive disorder (MDD), the current arsenal of antidepressant therapies does not fully satisfy the needs of patients or physicians. Many patients are only partial responders or are treatment resistant and side effects interfere with compliance. The majority of antidepressants directly affect monoamine neurotransmission within the central nervous system. Moving beyond this mechanism has been a challenge because of the lack of knowledge about the underlying etiology and pathophysiology of MDD. Provided in this report is a review of some of the major new advances in MDD research that suggest the possibility of novel and improved future therapeutic options. Emphasis is placed on studies of unipolar, but not bipolar, depression. New therapies include dual and triple monoamine uptake inhibitors, non-conventional antidepressants such as tianeptine, and a number of augmentation strategies. In addition, studies are underway on a number of mechanisms of action that might yield the next therapeutic advance. These include agents that interact with endocannabiniod systems, examination of natural products, and compounds that influence neuropeptide systems such as galanin and melanin-concentrating hormone, and growth and neurotrophic factors. Epigenetic mechanisms involving histone modification are also being explored. An area of intensive investigation is glutamate neurotransmission. Data support the hypothesis that NMDA receptor antagonists are effective in MDD individuals resistant to conventional therapies. The potential of metabotropic glutamate receptors as novel targets is also discussed. Accumulating evidence supports the idea that amplification of AMPA receptor function is a critical link in the transduction processes involved antidepressant effects.
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PMID:New approaches to the pharmacological management of major depressive disorder. 2023 Jul 66

Galanin (GAL) is an estrogen-inducible neuropeptide, highly expressed in brain regions reported to be involved in regulation of mood and anxiety. GAL possibly has a direct modulatory effect on hypothalamic-pituitary-adrenal (HPA)-axis regulation. Recent data from pharmacological and genetic studies indicate a significant function of GAL in stress-related disorders. By using a tag SNP approach covering the locus encoding preprogalanin (PPGAL), earlier findings of female-specific associations of polymorphisms in this locus with panic disorder were expanded to a larger sample of 268 outpatients with anxiety disorders (ADs). Within a larger sample of 541 inpatients with major depressive disorder (MDD), we then tested associations of one PPGAL tag SNP with specific depression symptom clusters and HPA-axis activity assessed by the combined dexamethasone-suppression/CRH-stimulation test both at inpatient admission and discharge (n=298). Gender specificity as well as dependence of the association on levels of circulating estrogens was analyzed. Genotyping revealed high linkage disequilibrium in the promoter area of the PPGAL gene, which includes several estrogen-response elements. Confirming earlier results, rs948854, tagging this promoter region, was associated with more severe anxiety pathology in female AD patients, but not in males. In premenopausal female MDD patients, the same allele of rs948854 was associated with more severe vegetative but not cognitive depressive symptoms at discharge and worse treatment response on antidepressant medication. Furthermore, this allele was associated with higher HPA-axis activity at admission. No significant case-control associations could be observed. However, because of power limitations of both patient samples, small effects cannot be excluded. The reported associations in independent samples of AD and MDD support an estrogen-dependent function of GAL in pathophysiology of anxiety and depression, affecting response to antidepressant treatment.
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PMID:Gender-specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity, and antidepressant treatment response. 2023 60


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