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Personality Traits and Identity Styles in Methamphetamine-Dependent Women: A Comparative Study

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The vesicular monoamine transporter VMAT is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters — such as dopamine , serotonin , norepinephrine , epinephrine , and histamine — into the vesicles , which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. Pharmaceutical drugs that target VMATs have possible applications for many conditions, leading to a plethora of biological research, including hypertension , drug addiction , psychiatric disorders, Parkinson's disease , and other neurological disorders. Many drugs that target VMATs act as inhibitors and alter the kinetics of the protein. Much research regarding the effects of altered VMATs on biological systems is still ongoing. Monoamines transported by VMATs are mainly noradrenaline , adrenaline , dopamine , serotonin , histamine , and trace amines. In the s, scientists like Arvid Carlsson recognized the need to understand how transport systems and ion gradients work in different organisms in order to explore new treatment options such as reserpine RES. Researchers discovered inhibitors that blocked the uptake of neurotransmitters into vesicles, suggesting the existence of VMATs. Scientists have used these tools to analyze DNA and amino acid sequences, and discovered that transporters in bacteria and humans were very similar, which emphasized the importance and universality of transporters. VMAT1 may be found in neuroendocrine cells , particularly chromaffin and enterochromaffin granules, which are primarily found in the medulla of the adrenal glands. VMAT2 favors expression in a variety of monoaminergic cells of the central nervous system , such as the brain, sympathetic nervous system , mast cells , and cells containing histamine in the gut. VMATs function by loading monoamines—dopamine, serotonin, histamine, norepinephrine, and epinephrine—into transport vesicles. VMATs also function in sorting, storing, and releasing neurotransmitters, and are believed to participate in protecting these neurotransmitters from autoxidation. Vesicle packing requires a large energy source to store large quantities of neurotransmitters into a small vesicular space at high concentrations. Studies indicate that the amino acid residue His, located on the domain between TMDs X and XI of rat VMAT1, plays a role in energy coupling to the amine transport by assisting the first proton-dependent conformational change. VMAT1 has a lower turnover number and a lower affinity for most monoamine substrates than VMAT2, which may be because of VMAT2's location in the central nervous system, which demands fast recovery from neurotransmitter release in order to prepare for subsequent releases. The uptake efficiencies of each VMAT substrate can be ranked in order of efficiency as: serotonin, dopamine, epinephrine, and norepinephrine. Methamphetamines decrease V max , while cocaine increases V max reversibly in rat brain. The effects of VMAT inhibition have been studied in-depth in animal models. More specifically, inhibition of VMAT2 may cause an increase in cytosolic catecholamine levels, which can result in an increase in efflux of catecholamines through the cell membrane , depleting catecholamine concentrations and causing increased oxidative stress and oxidative damage to the neuron. Heterozygous VMAT mutants display hypersensitivity to amphetamine , cocaine, and MPTP 1-methylphenyl-1,2,3,6-tetrahydropyridine , the latter being a substance causally linked to Parkinson's disease PD in rodents. Some evidence suggests these two sites may overlap or exist as two separate conformations of the same binding site. Inhibitor affinity varies among VMAT isoforms. The residues asp33 and ser, , and are believed to be involved in substrate recognition, and interact with the protonated amino group and hydroxyl group on the catechol or indole rings. Cocaine and methylphenidate MPD, also known as Ritalin and Concerta are believed to interact with VMAT2 to cause a shift in VMAT2 'from a plasmalemmal membrane-associated fraction to a vesicle-enriched, nonmembrane-associated fraction. The current working model proposes that RES and the substrate bind to a single site in a pH-gradient modulated conformational structure of the transporter. Two of the glycosylation sites, the N -linked glycosylation terminal and C -linked terminal , are located in the cytosolic portion of the vesicle. Over-expression of VMAT2 results in increased secretion of neurotransmitter upon cell stimulation. Data suggests that deletion of the VMAT2 genes does not affect the size of small clear-core vesicles. VMATs may be regulated by changes in transcription , post-transcriptional modifications such as phosphorylation and mRNA splicing of exons , and vesicular transport inactivation facilitated by heterotrimeric G-proteins , which are thought to be possessed by chromaffin granules, and have shown to regulate small clear-core vesicles. VMAT2 has been shown to contribute to many clinical neurological disorders including drug addiction, mood disorders, and stress, \[ 28 \] as well as Parkinson's disease \[ 29 \] and Alzheimer's disease. VMAT2 presence does not independently protect neurons from PD, but a decrease in VMAT2 expression has been shown to correlate with susceptibility to the disease, \[ 32 \] which may be due to a ratio between the dopamine transporter and VMAT2. Based on the understanding the increased cytosolic dopamine levels lead to dopaminergic cell death in PD, it has been proposed that regulatory polymorphisms in VMAT2 affect VMAT2 quantitative expression, and may serve as a genetic risk factor for PD. Studies using a genetic rodent model to understand clinical depression in humans suggest that VMAT2 genetic or functional alterations may be involved in depression. Based on these findings, it has been proposed that VMAT2 activity is not altered at the level of genetic expression, but may be altered at the functional level in ways that may correlate with clinical depression. Many psychostimulants , including substituted amphetamines and cocaine, are known to interact with VMAT2. Studies indicate that both amphetamines and cocaine act to increase non-exocytotic release of dopamine in specific regions of the brain by interacting directly with VMAT2 function. VMAT is a main target of methamphetamine. Methamphetamine alters the subcellular location of VMAT2, which affects the distribution of dopamine in the cell. Treatment with methamphetamine relocates VMAT2 from a vesicle-enriched fraction to a location that is not continuous with synaptosomal preparations. Repeated amphetamine exposure may increase VMAT2 mRNA in certain brain regions with little or no decline upon withdrawal from the drug. A study performed by Sonsalla et al. Unlike methamphetamine, cocaine interacts with VMAT2 by mobilizing VMAT2-expressing vesicles, causing a shift in VMAT2 proteins from a plasmalemmal synaptosomal membrane fraction to a vesicle-enriched fraction that is not associated with the synaptosomal membrane and not retained in synaptosomal preparations. Short-term exposure to cocaine increases VMAT2 density in the prefrontal cortex and striatum of mammalian brains. This is theorized to be a defensive mechanism against the depletive effects cocaine has on cytosolic dopamine through increasing monoamine storage capacity. Research suggests a decline in VMAT2 protein through prolonged cocaine use could play an important role in the development of cocaine-induced mood disorders. MDMA is known to affect serotonergic neurons, but has been shown to inhibit synaptosomal and vesicular uptake of serotonin and dopamine \[ 4 \] to roughly the same extent in vitro. Genetic research models have shown that polymorphisms in SLC18A1 and SLC18A2 , the genes that encode for VMAT1 and 2 proteins, respectively, may confer risk for some neuropsychiatric disorders; \[ 4 \] \[ 33 \] \[ 35 \] however, no specific diseases have been identified yet as directly resulting from a genetic mutation in an SLC18 gene, which codes for VMAT proteins. Much of the current research related to VMAT explores the genetic underpinnings of neuropsychiatric disorders as they may be affected by SLC18A family mutations. The dopaminergic neuron is known to play a central role in drug addiction and abuse and the potential role of the dopamine transporter has been well-explored as a target for amphetamine and cocaine. Current research looks toward VMAT2 as a target for such psychostimulants. A combination of imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence has been compiled to provide the most current comprehensive understanding of the role the VMAT2 plays in amphetamine and cocaine abuse and addiction through aminergic neurotransmission. As VMATs are membrane proteins, structural information is limited and researchers have yet to completely understand the structure of both isoforms. Further studies are needed in order to determine the structure and therefore complete function of these proteins. There is preliminary evidence that the gene for VMAT1 may be linked to susceptibility to schizophrenia , bipolar disorder , and various anxiety disorders. Studies have shown that at the synaptic membrane, enzymes responsible for the synthesis of dopamine, tyrosine hydroxylase and amino acid aromatic decarboxylase are physically and functionally coupled with VMAT2. VMAT2 knockouts are known to be lethal as homozygotes, but heterozygote knockouts are not lethal and are used in many studies as a durable animal model. From knockout and knockdown mice, researchers have discovered that it is good to have over-expression or under-expression of the VMAT genes in some circumstances. Drugs that inhibit VMATs may have use in addiction but further studies are needed. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. Download as PDF Printable version. In other projects. Family of transport proteins. This article's lead section may be too short to adequately summarize the key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. May Monoamines \[ edit \]. Discovery \[ edit \]. Location \[ edit \]. Structure and function \[ edit \]. Kinetics \[ edit \]. Inhibition \[ edit \]. Binding site structures \[ edit \]. Ligand-binding affinities and structures \[ edit \]. RES binding site \[ edit \]. TBZ binding site \[ edit \]. Glycosylation sites: N- and C-linked terminals \[ edit \]. C-terminus and VMAT trafficking cycle \[ edit \]. Genetic expression and transporter regulation \[ edit \]. Clinical significance \[ edit \]. Parkinson's disease \[ edit \]. Mood disorders \[ edit \]. Drug addiction \[ edit \]. Pharmacology \[ edit \]. Methamphetamine \[ edit \]. Cocaine \[ edit \]. MDMA \[ edit \]. Current research \[ edit \]. Clinical research \[ edit \]. Animal research \[ edit \]. References \[ edit \]. PMC PMID Edinburgh: Churchill Livingstone. ISBN S2CID Med Res Rev. J Exp Biol. Regulation of vesicular monoamine and glutamate transporters by vesicle-associated trimeric G-proteins: new jobs for long-known signal transduction molecules. Handbook of Experimental Pharmacology. Evidence for autoregulation of vesicular transmitter uptake'. Journal of Biological Chemistry. Medicinal Research Reviews. Sinauer Associates. J Biol Chem. Bibcode : PNAS Trends in Pharmacological Sciences. Annu Rev Pharmacol Toxicol. ISSN X. Vesicular neurotransmitter transporters: Pharmacology, Biochemistry and Molecular Analysis. Neurotransmitter Transporters; Structure, Function, and Regulation, pp. Cell Mol Neurobiol. Amino Acids. Brain Res. Molecular Aspects of Medicine. Proteins interacting with monoamine transporters: Current state and future challenges. External links \[ edit \]. Further reading \[ edit \]. Membrane transport protein : neurotransmitter transporters TC 2. Monoamine reuptake inhibitors. Others: Antihistamines e. Others: A Amoxapine Antihistamines e. Amiodarone Amphetamines e. Monoamine releasing agents. Oxazolines: 4-Methylaminorex Aminorex Clominorex Fluminorex. Others: Indeloxazine Viqualine. Hidden categories: Articles with short description Short description matches Wikidata Wikipedia introduction cleanup from May All pages needing cleanup Articles covered by WikiProject Wikify from May All articles covered by WikiProject Wikify All articles with unsourced statements Articles with unsourced statements from October Articles with unsourced statements from November Articles with unsourced statements from November

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