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)

Tricyclic antidepressants revolutionized the treatment of depression. These results and the monoamine-depleting effect of reserpine have contributed to the proposal that an imbalance in monoamines is a causal factor in depression. Most antidepressants act to concentrate monoamines in the synapse either by blocking metabolism via monoamine oxidase or by inhibiting reuptake by plasma membrane transporters. We have used a novel cDNA expression cloning strategy to isolate cDNAs for the antidepressant-sensitive serotonin transporter and for a reserpine-sensitive vesicular monoamine transporter which is critical for packaging serotonin, dopamine, norepinephrine, epinephrine and histamine into synaptic vesicles and secretory granules. In addition, we have isolated a dopamine transporter. The three papers summarized here describe the molecular characteristics of three proteins critical for monoamine neurotransmission and which are targets for antidepressant and psychostimulant drugs. The cloning of the serotonin and dopamine transporters and of the CNS vesicular transporter provide new tools to examine how post-translational and transcriptional regulation of these transporters effect uptake, storage and release of monoamines in normal and disease states. In addition to providing substrates for further drug discovery, isolation of human homologues should be useful for assessing the possible genetic bases of depression.
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PMID:Expression cloning of a serotonin transporter: a new way to study antidepressant drugs. 815 77

Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson's disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal.
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PMID:Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. 1151 69

The intraneuronal uptake of monoamines into brain synaptic vesicles is mediated by the vesicular monoamine transporter (VMAT2). This transporter plays a major role in monoamine storage and quantal release. Recently we demonstrated a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. In the present study we measured the VMAT2 density, using [3H]dihydrotetrabenazine ([3H]TBZOH) as a ligand, in platelets of untreated patients diagnosed with major depressive disorder (MDD) (n=10; three with recurrent depression and seven with first episode depression) compared to sex- and age-matched healthy control subjects (n=23). A significant elevation in the VMAT2 density (B(max)) was observed in the platelets of untreated MDD patients (+24%) compared to healthy control subjects. No significant change was found in the affinity constant (K(d)). The increased platelet VMAT2 density may reflect depression-related enhancement of the capacity to accumulate monoamines in the vesicles in the presence of lower monoamine turnover.
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PMID:Elevated platelet vesicular monoamine transporter density in untreated patients diagnosed with major depression. 1245 Jun 34

Psychopharmacological and neurochemical research suggests that alterations in monoamine transporters may be involved in the etiology of depression. We studied the expression of the brain-type vesicular monoamine transporter (VMAT2) in the Flinders sensitive line (FSL) rats, which represent a genetic animal model for clinical depression in humans. VMAT2 expression at the protein level was assessed by autoradiography using [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding, in the prefrontal cortex, the striatum and its subregions, nucleus accumbens (NAC), ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC). The VMAT2 mRNA level was analyzed by in situ hybridization, in the VTA, SNC and the dorsal raphe (DR) nucleus. Reduced levels of [(3)H]TBZOH binding were detected in the striatum and its subregions, NAC shell but not in the NAC core. A marked reduction of 21% was found in the VTA while only a slight reduction (13%) was observed in the SNC. The reduced levels of VMAT2 protein binding capacity were not accompanied by a parallel alteration in VMAT2 mRNA levels in the VTA, the SNC and the DR. Since the VMAT2 is responsible for the intracellular storage and regulated release of monoamines, the reduced [(3)H]TBZOH binding levels in limbic brain regions of FSL rats may imply a reduced density of vesicular monoamine transporters, which can result in reduced monoamine transmission. Such reduction in the limbic neurotransmission, especially in NAC shell and VTA regions, may be involved in the depressive features of anhedonia and lack of motivation reported in the FSL rats.
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PMID:Decreased limbic vesicular monoamine transporter 2 in a genetic rat model of depression. 1259 Nov 35

We assessed the impact of chronic swim stress in rats (daily for 3 weeks) on vesicular monoamine transporter 2 (VMAT2) in the nucleus accumbens and striatum. Exposure to repeated swim stress resulted in significant reduction in VMAT2 density in nucleus accumbens (20%, p<0.01) and striatum subregions (21-38%, p<0.001). The down-regulation of VMAT2 in this dopaminergic regions may serve as an adaptatory mechanism in the response to prolonged stress, and may be relevant to chronic stress-induced depression.
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PMID:Repeated swim stress leads to down-regulation of vesicular monoamine transporter 2 in rat brain nucleus accumbens and striatum. 1569 65

The monoamine theory is one of the major hypotheses about the biological etiology of major depressive disorders. Recent pharmacological and postmortem investigations suggest that depressed patients have alterations in function of serotonergic neuronal system. However, the exact sites of alterations and the association between these alterations and the etiology of the disorder are still unclear. To elucidate these issues, we immunohistochemically examined vesicle monoamine transporter 2 (VMAT2), serotonin receptor type 1a (5HT1a), and serotonin transporter (5HTT) in the hippocampal region of reserpine-treated rats, an animal model of depression. The results showed more VMAT2-immunoreactive varicose fibers in the pyramidal cell layer of hippocampus and parahippocampal cortexes, and more intense 5HTT-immunoreactivity in the pyramidal cell layer and the area CA4 of hippocampus in the animal models compared to those of the controls. On the other hand, lower density of 5HT1a-immunoreactive deposits in the pyramidal cell layer of hippocampus and the parahippocampal cortex was observed in the animal models compared to those of the controls. These results suggest that a deficit of monoamines induces the alterations in the expression of the storage protein, the receptor and the transporter that are involved in the serotonergic neurotransmission in the hippocampal region. These alterations may underlie the changes of serotonergic system observed in the brains of patients with the depressive disorder.
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PMID:Immunohistochemical study of the serotonergic neuronal system in an animal model of the mood disorder. 1667 34

Monoamine transporters play key roles in controlling monoamine levels and modulating monoamine reuptake. The objective of the present study was to identify monoamine transporter inhibitors from herbal sources. We discovered that bakuchiol analogs isolated from Fructus Psoraleae inhibited monoamine transporter uptake to differing degrees. The bakuchiol analog, Delta3,2-hydroxybakuchiol was the most potent and efficacious reuptake blocker and was thus selected as the candidate target. Monoamine transporter inhibition by Delta3,2-hydroxybakuchiol was more selective for the dopamine transporter (DAT) (IC50=0.58+/-0.1 microM) and norepinephrine transporter (NET) (IC50=0.69+/-0.12 microM) than for the serotonin transporter (SERT) (IC50=312.02+/-56.69 microM). Delta3,2-Hydroxybakuchiol exhibited greater potency (pEC50 for DAT and NET) than bupropion and exhibited similar efficacy (E(max) for DAT and/or NET) to bupropion and GBR12,935. Pharmacokinetically, Delta3,2-hydroxybakuchiol competitively inhibited DAT and NET with partial reversibility and occupied cocaine binding sites. Moreover, Delta3,2-hydroxybakuchiol counteracted 1-methyl-4-phenylpyridinium-induced toxicity in cells expressing DAT with similar efficacy to GBR12,935. In vivo studies showed that Delta3,2-hydroxybakuchiol increased the activity of intact mice and improved the decreased activity of reserpinized mice. In the conditioned place preference test, preference scores in intact mice were unaffected by Delta3,2-hydroxybakuchiol treatment. Bakuchiol analogs, especially Delta3,2-hydroxybakuchiol, are monoamine transporter inhibitors involved in regulating dopaminergic and noradrenergic neurotransmission and may have represented potential pharmacotherapies for disorders such as Parkinson's disease, depression, and cocaine addiction.
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PMID:Bakuchiol analogs inhibit monoamine transporters and regulate monoaminergic functions. 1832 2

The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.
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PMID:Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease. 1843 76

The identification of genetic variants regulating antidepressant response would allow for more individualized, rational, and successful drug treatments. We previously identified a region of mouse chromosome 19 that strongly influences citalopram response in an antidepressant model, the tail suspension test. By virtue of their location in this loci, expression in brain, and involvement in monoamine neurotransmission, we nominated SLC18A2 (encoding vesicular monoamine transporter 2, a.k.a. VMAT2) and ADRB1 (encoding beta-1 adrenergic receptor) as candidate genes for a human pharmacogenetic study. This study tested for an association between SLC18A2 and ADRB1 and treatment outcome in 873 major depressive disorder patients treated with the antidepressant citalopram in the Sequenced Treatment Alternatives to Relieve Depression study. Haplotype-tagging single nucleotide polymorphisms (four in SLC18A2 and two in ADRB1) were chosen to detect the common genetic variation. We failed to detect any significant association between treatment outcome and genotypes or allele frequencies at any of the markers studied. We did, however, detect ethnic differences in the allele frequencies of five out of six markers. These data do not rule out the possible involvement of SLC18A2 or ADRB1 in antidepressant treatment response as these genes may contribute a small effect size or interact epistatically with other genes.
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PMID:Variation in the genes encoding vesicular monoamine transporter 2 and beta-1 adrenergic receptor and antidepressant treatment outcome. 1879 99

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.
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PMID:Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity. 1982 98


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