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Acheter de la methamphetamine en Saint-Georges

From Wikimedia Commons, the free media repository. DL-amphetamine mescaline amphetamines. National Archives Identifier: Subcategories This category has the following 5 subcategories, out of 5 total. Media in category 'Methamphetamine' The following 99 files are in this category, out of 99 total. Blue Crystal Meth. Crystal Meth Rock. Crystal Meth. Desoxyn methamphetamine 5 mg tablets. Deux pilules de Desoxyn Gradumet 10mg. RS -Methamphetamine structural formulae. Glial ntox review. Homemade Crystal Meth Bong. Illegales Methlab USA. Meth San Ysidro Meth 1. Meth 2. Meth 3. Meth 4. Meth ammonia tank Otley iowa. Meth lab trash central IA. Meth Pathway enum. Meth Pathway V2. Meth Pathway. Meth powder hexagon. Meth synthesis. Methamphetamine enantiomers 1. Methamphetamine enantiomers. Methamphetamine molecule ball. Methamphetamine pills. Methamphetamine PMR. Methamphetamine Shards. Montana Meth Project mural - Drummond Montana. Pervitin MMM Corones. Philopon dependent patient in s. Pound of methamphetamine. Powder meth in foil. Propylhexedrine and methamphetamine. Racemic methamphetamine. HI,P Reduction of Ephedrine. Methamphetamine from ephedrine via chloroephedrine en. Methamphetamine from ephedrine via chloroephedrine ru. Methamphetamine from ephedrine with HI en. Methamphetamine from ephedrine with HI ru. Methamphetamine from P2P en. Methamphetamine from P2P ru. Methamphetamine leuckart synthesis. Methamphetamine reductive amination. Sampling methamphetamine levels. Sintesis Metanfetamina. Namespaces Category Discussion. Views View Edit History. In other projects Wikimedia Commons Wikipedia. This page was last edited on 28 March , at Files are available under licenses specified on their description page. All structured data from the file and property namespaces is available under the Creative Commons CC0 License ; all unstructured text is available under the Creative Commons Attribution-ShareAlike License ; additional terms may apply. By using this site, you agree to the Terms of Use and the Privacy Policy. Upload media.

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Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress

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Methamphetamine is a widely abused drug, which possesses neurotoxic activity and powerful addictive effects. Understanding methamphetamine toxicity is key beyond the field of drug abuse since it allows getting an insight into the molecular mechanisms which operate in a variety of neuropsychiatric disorders. In fact, key alterations produced by methamphetamine involve dopamine neurotransmission in a way, which is reminiscent of spontaneous neurodegeneration and psychiatric schizophrenia. Thus, understanding the molecular mechanisms operated by methamphetamine represents a wide window to understand both the addicted brain and a variety of neuropsychiatric disorders. This overlapping, which is already present when looking at the molecular and cellular events promoted immediately after methamphetamine intake, becomes impressive when plastic changes induced in the brain of methamphetamine-addicted patients are considered. Thus, the present manuscript is an attempt to encompass all the molecular events starting at the presynaptic dopamine terminals to reach the nucleus of postsynaptic neurons to explain how specific neurotransmitters and signaling cascades produce persistent genetic modifications, which shift neuronal phenotype and induce behavioral alterations. A special emphasis is posed on disclosing those early and delayed molecular events, which translate an altered neurotransmitter function into epigenetic events, which are derived from the translation of postsynaptic noncanonical signaling into altered gene regulation. All epigenetic effects are considered in light of their persistent changes induced in the postsynaptic neurons including sensitization and desensitization, priming, and shift of neuronal phenotype. Methamphetamine METH is a widely abused psychostimulant with powerful addictive and neurotoxic properties. This compound rapidly enters and persists within the central nervous system CNS \\\\\\[ 1 , 2 \\\\\\]. In fact, METH has a long half-life, which ranges from 10 to 12 hours \\\\\\[ 3 \\\\\\]. Such acute behavioral effects are due to early neurochemical events produced by METH, which consist in a rapid release of monoamines, mainly dopamine DA , from nerve terminals. This occurs mostly within the striatum, where DA terminals are mostly abundant, though specific limbic regions and isocortical areas are involved as well \\\\\\[ 7 — 11 \\\\\\]. The cellular effects induced by METH may be roughly summarized by its interaction with three molecular targets: 1 the synaptic vesicles and vesicular monoamine transporter type-2 VMAT-2 Figure 1. Both isoforms are responsible for the selective recognition and transport of cytosolic monoamines DA, norepinephrine NE , and serotonin 5-hydroxytryptamine 5-HT within synaptic vesicles \\\\\\[ 12 \\\\\\]. It is noteworthy that a combined effect of METH as a weak base to tone down the pH gradient needs to be accompanied by a selective effect on VMAT-2 since alkalinization per se may be nonsufficient to fully produce the typical redistribution of vesicular DA \\\\\\[ 16 \\\\\\]. This is confirmed by administering bafilomycin, which acts as a proton pump inhibitor only, with no effects on VMAT In the absence of such a compartmentalized physiological oxidative deamination, DA autooxidation produces a high amount of reactive aldehyde DOPALD, which owns a dramatic oxidative potential and quickly interacts with surrounding proteins, by targeting oxidation-prone domains \\\\\\[ 25 , 26 \\\\\\]. Autooxidative DA metabolism leads to the generation of toxic quinones and highly reactive chemical species such as hydrogen peroxide H 2 O 2 and superoxide radicals, which in turn react with sulfhydryl groups and promote structural modifications of proteins, lipids, and nucleic acids within the DA axon terminals and surrounding compartments Figure 5 \\\\\\[ 15 , 27 — 39 \\\\\\]. On the one hand, these effects drive a powerful oxidative stress for presynaptic DA terminals, which is key in producing nigrostriatal toxicity \\\\\\[ 27 — 31 , 34 , 40 — 43 \\\\\\]. On the other hand, elevated cytosolic presynaptic DA diffuses in the extracellular space either by passive diffusion or via the reverted direction of DAT, another molecular effect which is promoted by METH Figures 1 — 5 \\\\\\[ 14 , 16 , 33 , 44 \\\\\\]. All these effects also cause peaks of extracellular DA concentration, which produce synaptic effects at short distance. At striatal level, this paracrine environment encompasses medium-sized spiny neurons MSNs. Nonetheless, due to the propensity of extracellular DA to diffuse at considerable distance from the DA terminals according to a volume transmission \\\\\\[ 45 — 47 \\\\\\], other extrasynaptic sites may be affected as well. This produces unusually high extracellular and mostly striatal DA levels which reach out nonneuronal targets including the neurovascular unit, which is also affected by METH administration \\\\\\[ 48 , 49 \\\\\\]. In fact, although they occur outside DA cells, mainly within glia Figures 3 — 5 , they do not influence much the amount of extracellular DA \\\\\\[ 25 , 50 — 53 \\\\\\]. This pulsatile pattern of extracellular DA concentrations magnifies the slight variations produced by physiological release, such that, METH produces an abnormal stimulation all and none of postsynaptic neurons. For instance, pulsatile activation of postsynaptic DA receptors triggers noncanonical transduction pathways, which, along with the diffusion of abnormal reactive oxygen ROS and nitrogen RNS species, alter the response of postsynaptic neurons as mainly studied at the level of GABA MSNs \\\\\\[ 57 — 59 \\\\\\] Figure 6. The impact of such a nonphysiological in time, amount, and place DA release is largely to blame when considering both the behavioral syndrome occurring immediately after METH intake and long-term behavioral changes including addiction, craving, relapse, and psychotic episodes, which reflect mainly the persistent alterations in postsynaptic DA brain regions following chronic METH exposure. As we shall see, overstimulation of postsynaptic DA receptors alternating with a lack of stimulation within an abnormal redox context drives most epigenetic effects. After mentioning the presynaptic effects of METH to understand the role of redox species in causing the loss of integrity of DA axon terminals , the present review discusses the postsynaptic changes in relationship with epigenetics, DNA alterations, and persistent phenotypic changes produced by METH. As thoroughly revised by Moratalla et al. At first, such a toxicity was considered to be relevant only for DA axon terminals. Such neurotoxicity is documented by the following markers: i a steady decrease in striatal DA levels and striatal DA uptake sites \\\\\\[ 54 , 60 — 63 \\\\\\], ii loss of tyrosine hydroxylase TH -activity, TH immunoblotting and TH immunohistochemistry \\\\\\[ 64 — 71 \\\\\\], and most directly, iii the occurrence of silver-stained Fink-Heimer method \\\\\\[ 61 , 62 \\\\\\] or amino-cupric silver-stained de Olmos procedure degenerating nerve fibers within the striatum \\\\\\[ 72 \\\\\\]. Some studies also indicate the occurrence of METH-induced toxicity at the level of neuronal cell bodies in the substantia nigra pars compacta SNpc. This was firstly reported by Sonsalla et al. Further studies confirmed a loss of mesencephalic DA neurons even within the ventral tegmental area \\\\\\[ 67 \\\\\\], but again, no stereological count was carried out. In a recent manuscript by Ares-Santos et al. These inclusions start as multilamellar whorls, which further develop as cytoplasmic inclusions reminiscent of PD-like Lewy bodies. Remarkably, most of these proteins are substrates of ubiquitin proteasome- UP- and autophagy- ATG- clearing systems, which are markedly affected during METH toxicity Figure 5 \\\\\\[ 38 , 79 — 81 , 83 , 86 \\\\\\]. METH effects on postsynaptic compartment are multifaceted. Even neurotoxicity may extend to postsynaptic neuronal cell bodies throughout the striatum, hippocampus, and frontal cortex \\\\\\[ 72 , 73 , 87 — 94 \\\\\\]. A pioneer manuscript by Jakel and Maragos \\\\\\[ 95 \\\\\\] discussed very well how activation of DA receptors on striatal neurons as well as DA-derived oxidative species and oxyradicals might all converge to accelerate striatal neuronal cell loss in a specific striatal neurodegenerative disorder such as Huntington disease HD. As we shall see, the interaction between DA and GLUT, as well as the convergence of signaling cascades placed downstream plasma membrane receptors, may be enhanced under chronic METH intake. Along with diffusion of free radicals, which fuel oxidative damage, the striatal compartment challenged by METH is filled with DA acting on its receptors. It is well known that overstimulation of D1-like DA receptors mainly D1 DA receptors DRD1 leads to a switch in the transduction pathway towards noncanonical signaling, which, in turn, generates a number of adaptive biochemical events \\\\\\[ 96 — \\\\\\]. In extreme conditions, this may produce excitotoxicity within striatal GABA neurons \\\\\\[ — \\\\\\]. Thus, following METH administration, GLUT synergizes with DA to produce oxidative stress, mitochondrial dysfunction, and inflammatory reactions, which synergistically interact to promote neuronal damage Figure 6 \\\\\\[ 34 , 42 , 43 , \\\\\\]. Such an effect is expected to significantly alter DNA stability \\\\\\[ 29 , — \\\\\\]. Even the occurrence of striatal cytoplasmic inclusions within MSNs is likely to be due to combined mechanisms. In summary, the various effects of DRD1 receptor overstimulation and prooxidative processes produced by excessive DA release are likely to assemble and cooperate to produce long-lasting neurochemical changes following METH. A number of papers explored the mechanisms operating at postsynaptic level to modify neuronal phenotype, in an effort to unravel potential strategies to counteract addiction. To such an aim, in the last decades, a number of studies focused on specific transduction pathways and genes activated by METH. Remarkably, studies of the last decade indicated a key role for epigenetic mechanisms in modulating the transcription of a number of genes, which underlie long-lasting behavioral alterations and biochemical events induced by METH abuse. A gap still exists concerning the signaling cascades through which METH may induce epigenetic changes via mechanisms going beyond a mere effect of DA-related oxidative stress. In the present section, studies focused on METH-induced epigenetic changes in both experimental models and human abusers are discussed. In Sections 4. At last, in Section 4. DA canonical signaling in the brain is mediated by five DRD1—DRD5 G-protein-coupled receptors, which are grouped into two classes depending on which G-protein they are coupled to. Again, these receptors target voltage-dependent ion channels through a mechanism, which operates at the level of plasma membrane and phospholipase C PLC \\\\\\[ \\\\\\]. All five DA receptors are expressed in the striatum, but DRD1 and DRD2 are the most abundant, with the former being placed specifically within postsynaptic neurons and the latter being placed both presynaptically and postsynaptically Figure 7. For such a reason, DRD1 and DRD2 represent a cue investigation topic in the context of behavioral effects underlying drug addiction. However, the disruption of canonical DRD1 signaling is more important \\\\\\[ 57 , 99 , \\\\\\]. In fact, peaks and drops of DA stimulation generate the switch from canonical to noncanonical DRD1 signaling. This kind of perturbation of DRD1 is the authentic drive to switch the DRD1 transduction pathway \\\\\\[ 59 , 99 , , \\\\\\]. Thus, in the presence of abnormal stimulation, DRD1 moves towards noncanonical signaling which makes MSNs supersensitive to DA stimulation despite that the number of DA receptors is not increased \\\\\\[ 99 \\\\\\]. In fact, a chain of events follows DRD1 overstimulation, which involves metabolic transduction and transcriptional pathways, eventually switching gene expression and neuronal phenotype underlying addictive behavior in PD and METH \\\\\\[ 57 , 59 , 96 — 99 , , , , — \\\\\\]. Although precise signaling changes and substrates underlying this shift remain to be fully elucidated, a prominent role for AC \\\\\\[ \\\\\\] and PKA \\\\\\[ , \\\\\\] is well established Figure 8. In fact, in its canonical pattern, PKA phosphorylates cellular targets, including voltage-dependent ion channels, GLUT receptors, TFs, and epigenetic enzymes involved in physiological synaptic plasticity and synaptic strength as naturally occurring in a normal striatum. TFs, in turn, may either induce or suppress a number of downstream target genes. In summary, ERK plays a primary role in mediating long-lasting effects of psychostimulants within the striatum especially dorsal striatum and NAc. In line with this, the activity of CDK5 is implicated in motor- and reward-related behaviors following drug abuse including METH \\\\\\[ , , , \\\\\\]. This is coupled with activation of a calmodulin-dependent kinase II CaMKII , which translocates in the nucleus to regulate gene expression \\\\\\[ — \\\\\\]. In response to neurotransmitter receptor activation and enhanced oxidative stress, specific TFs are recruited to regulate gene transcription. These TFs are often present within large protein complexes, which bind to a specific DNA sequence corresponding to promoter or enhancer regions of target genes. In the next paragraph, we will focus on those TFs and genes recruited during METH administration according to the biochemical pathways we just described. By definition, IEGs undergo early synthesis and they can associate to form a variety of homo- and heterodimers binding to common DNA sites to regulate further gene expression. This leads to a variety of plastic effects ranging from neuronal metabolism to neuromorphology. In line with this, METH alters the expression of a multigene machinery coding for proteins involved in signal transduction, metabolic pathways, and transcriptional regulation. This alters protein expression and alters the amount of inflammatory cytokines, neuropeptides, and trophic factors mainly brain-derived neurotrophic factor BDNF , as well as oxidative-, mitochondrial-, and endoplasmic reticulum stress-related events and proapoptotic cascades \\\\\\[ 91 , , , — \\\\\\]. On the one hand, DA per se and its metabolites provide a powerful source of radical species, which in turn interact with DNA and TFs to modulate gene expression \\\\\\[ , , \\\\\\]. AP-1 is mainly known for its role in cell proliferation, while it plays a compensatory effect on redox stress and DNA damage \\\\\\[ \\\\\\]. Several studies demonstrate that METH causes an early increase in IEG expression belonging to Jun and Fos families \\\\\\[ 91 , , — , — , , , , , — \\\\\\]. Those simple phenomena occurring in specific sites and critical time windows generate the remarkable diversity and specificity in the epigenetics of METH. This is achieved by diverse effects on a number of genes. In line with this, METH activates and overexpresses several members of the Egr family, especially Egr1 and Egr2 \\\\\\[ 91 , , , , , , — \\\\\\]. Again, METH causes substantial increases in the expression of nuclear TF families including nuclear receptor 4a Nr4a , nuclear factor erythroid 2- NFE2- related factor 2 Nrf2 , and NFAT, which regulate genes involved in metabolism, development, and axonal growth within the mammalian brain \\\\\\[ 91 , , , \\\\\\]. A critical point to decipher the effects of METH upon the activity of all these TFs is the pattern of drug administration. Again, early time intervals compared with late time intervals from METH exposure i. This early effect is short lived, which makes it unlikely to produce behavioral sensitization. In fact, the effects of a single dose of METH on specific genes are markedly different depending on the existence of a previous METH exposure \\\\\\[ , \\\\\\]. These differences appear to be related to the occurrence of a previous epigenetic switch \\\\\\[ , \\\\\\]. Dynamic epigenetic remodeling allows perpetual alterations in gene readout within cells, and within the CNS, it may have a crucial impact on neuronal function. Posttranslational modifications of histone proteins, changes in the binding of TFs at gene promoters, and covalent modifications of DNA bases represent the main mechanisms through which gene expression is regulated. In recent years, METH was shown to induce epigenetic modifications, which underlie persistent changes in gene expression and long-lasting behavioral responses to the drug \\\\\\[ , , , , — \\\\\\]. Histone acetylation and deacetylation are a dynamic process balanced by histone acetyltransferase HAT and histone deacetylase HDAC , a subset of enzymes, which carry out reversible histone modifications by adding or removing acetyl groups. These enzymes physically interact with sequence-specific TFs and target-specific promoters, to modify acetylation patterns of core histones, thus manipulating the functional state of chromatin and orchestrating the transcriptional machinery \\\\\\[ \\\\\\]. HDACs are widely implicated in synaptic plasticity and long-term memory, which is key in drug addiction \\\\\\[ \\\\\\]. This associates with increased gene expression detected at early time intervals following METH \\\\\\[ , \\\\\\]. In detail, such an increase mainly concerning IEGs such as Egr1, Egr2, c-Fos, JunB, Nr4a3, and corticotrophin releasing factor Crf correlates with increased binding of H4K5ac to the promoters of these very same genes \\\\\\[ , , \\\\\\]. In , Krasnova et al. Remarkably, at 1 month of METH withdrawal, c-Fos protein was found to be decreased compared with controls. Renthal et al. McCoy et al. This occurs along with decreased CREB expression. Remarkably, chronic pretreatment with METH suppresses the stimulatory effects on these IEGs when elicited by an acute challenge with the drug. This paradoxical response occurs along with a greater decrease in CREB levels compared with those measured during chronic administration \\\\\\[ \\\\\\]. Similar findings were produced by Cadet et al. These effects were related to decrease H4K5Ac binding. A causal relationship is strengthened by the opposite effects produced by the HDAC inhibitor valproate, which prevents METH-induced alterations at the very same receptor subunits \\\\\\[ \\\\\\]. This confirms a dose dependency for METH-induced epigenetic alterations. In fact, depending on the dose of METH being administered, sometimes, opposite phenotypic changes occur. Histone methylation is regulated by enzymes that add methyl groups acting as writers, namely, methyltransferases KMTs and enzymes that remove methyl groups, acting as erasers, namely, demethylases KDMTs. KMTs are involved in mono-, di-, and trimethylation of histone lysine residues K , which carry specific regulatory switches \\\\\\[ \\\\\\]. In fact, histone methylation regulates both repression and activation of gene expression, depending on the specific K being modified. For instance, methylation of histone H3 at K4 H3K4me is associated with increased transcriptional activity whereas methylation of H3 at K9 H3K9me and K27 H3K27me is associated with repression of gene expression \\\\\\[ \\\\\\]. For instance, the study of Renthal et al. This effect correlates with increased expression levels of KMT1A. More recently, epigenetic mechanisms contributing to METH-associated memories were explored in the NAc and dorsal striatum, given their role as a hub for drug craving. While investigating such a phenomenon, Aguilar-Valles et al. Again, METH craving was shown to be related with epigenetic changes occurring only in Fos-expressing neurons of the dorsal striatum \\\\\\[ \\\\\\]. DNA methylation refers to the classic chemical covalent modification of DNA, which results from the addition of a methyl group at the 5 position of a cytosine base via enzymes of the DNA cytosine-5 -methyltransferases DNMTs family \\\\\\[ \\\\\\]. CpG sites are unevenly distributed throughout the human genome both as interspersed CpG regions and as CpG clusters representing the so-called CpG islands. In line with the concept that promoters are the most sensitive to epigenetic changes, CpG islands occur mainly within promoter regions \\\\\\[ \\\\\\]. DNA hypermethylation of CpG within promoters represses transcription while DNA hypomethylation is often associated with increased gene expression \\\\\\[ \\\\\\]. It is worth mentioning that stability and activity of DNMTs depend on posttranslational mechanisms phosphorylation, acetylation, and methylation carried out by several kinases, such as CDK5 \\\\\\[ \\\\\\] and histone remodeling enzymes, especially HDACs \\\\\\[ \\\\\\]. This is confirmed by the finding that following chronic METH, there are decreases of 5 -methylcytosine 5mc and 5 -hydroxymethylcytosine 5hmc at the level of the promoter region of these genes \\\\\\[ \\\\\\]. Aspired by the vast body of evidence reporting aberrant promoter DNA methylation in psychotic disorders, a recent study investigated DNA methylation and gene expression pattern in human METH-induced psychosis \\\\\\[ \\\\\\]. Despite carrying the inherent limit of a peripheral analysis, which may not be relevant for brain alterations, these findings demonstrate DNA hypomethylation within promoters of genes related to DA metabolism. Remarkably, alterations of AKT levels and downstream pathways are closely related to the activity of DA receptors \\\\\\[ — \\\\\\]. Once activated, TFs translocate in the nucleus to promote cell proliferation and survival. In line with this, inhibition of mTOR by the gold standard inhibitor rapamycin blocks drug-induced sensitization \\\\\\[ \\\\\\]. In fact, significant hypomethylation of CpG sites in the promoter region of SNCA is reported within leukocytes \\\\\\[ \\\\\\] and postmortem brain samples from patients with sporadic and complicated PD \\\\\\[ , , , \\\\\\]. In recent years, DNA hydroxymethylation, generated by the oxidation of 5-methylcytosine 5mC to 5-hydroxymethylcytosine 5hmC , became increasingly important in epigenetics \\\\\\[ \\\\\\]. The biological functions of 5hmC, which is highly enriched in the adult brain, appear to be crucial to promote gene expression related to quick behavioral adaptation \\\\\\[ \\\\\\]. Two recent studies demonstrated that compulsive METH intake is associated with large-scale changes in DNA hydroxymethylation in the rat NAc, which is consistent with a potential role for DNA hydroxymethylation in addiction \\\\\\[ , \\\\\\]. Remarkably, DNA hydroxymethylation around the transcriptional start site TSS or within intragenic regions of genes coding for neuropeptides was shown to occur following chronic METH administration \\\\\\[ \\\\\\]. Together, these results support the hypothesis that METH produces a variety of epigenetic changes in the neuroendocrine circuitry within the NAc. This same epigenetic mechanism was recently studied within a context of compulsive METH intake \\\\\\[ \\\\\\]. This occurs in different postsynaptic sites within the NAc, dorsal striatum, and prefrontal cortex of METH-addicted animals. The influence of epigenetics in drug abuse provides a novel and deeper insight to understand the molecular mechanisms of addiction. This is key in the case of METH abuse since this drug possesses a variety of effects, which recapitulate the molecular alteration occurring in some neuropsychiatric disorders. As novel epigenetic changes are constantly being identified, it is more and more clear how simple effects induced by transient neurotransmitter alterations may translate into persistent alterations of brain physiology. Moreover, the multiplicity of findings revised here, when joined with a better knowledge of the genetic background, may clarify the interdependence between genetics and epigenetics underlying diversity in the human genome \\\\\\[ \\\\\\]. This leads to take into account the fact that a molecular cause-effect interplay between genetic and epigenetic factors during METH addiction may exist as well. Despite being yet unexplored in the context of drug abuse, such a close relationship is likely to explain the very peculiar phenotypic alterations observed during METH abuse. Such an intriguing issue surely deserves further attention and may represent a powerful tool for identifying additional genetic and epigenetic biomarkers to develop personalized treatments. The authors declare that there is no conflict of interests regarding the publication of this paper. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We will be providing unlimited waivers of publication charges for accepted articles related to COVID Journal overview. Special Issues. Academic Editor: Margherita Neri. Received 19 Apr Accepted 10 Jun Published 22 Jul Abstract Methamphetamine is a widely abused drug, which possesses neurotoxic activity and powerful addictive effects. Introduction 1. Molecular Mechanisms of Methamphetamine Methamphetamine METH is a widely abused psychostimulant with powerful addictive and neurotoxic properties. Figure 1. These effects disrupt the physiological storage of DA, which diffuses from vesicles to the axoplasm and from the axoplasm to the extracellular space. Figure 2. Such an effect potentiates the accumulation of freely diffusible DA in the extracellular space and prevents the main mechanisms of DA removal reuptake within DA terminals. Figure 3. The effects of METH on mitochondria. Figure 4. Figure 5. The enhanced redox imbalance also disrupts the homeostasis of endoplasmic reticulum ER and mitochondria, which further accelerates the production of ROS. These events converge in producing neurotoxicity within DA terminals, which may either extend to DA cell bodies. Figure 6. Freely diffusible DA-derived free radicals together with GLUT-derived radical species synergize to produce detrimental effects on postsynaptic non-DA neurons. Figure 7. An overview of canonical DA receptor signaling. Figure 8. Such an event also promotes the activation of calmodulin-dependent kinase II CaMKII , which can translocate into the nucleus to regulate gene expression. Figure 9. Figure The latter, together with DA- and GLUT-derived reactive species, is shuttled into the nuclear compartment where they carry posttranslational modifications of histones and TFs. These metabolic events eventually translate into an increase expression of IEGs. Summarizing main epigenetic mechanisms. This cartoon roughly reports the main epigenetic enzymes carrying structural modifications of lysine K residues of histone tails and DNA promoter sequences at the level of CpG islands. METH-induced gene desensitization. Exposure to chronic METH produces epigenetic effects, which repress further gene expression. Me: methyl groups; Ac: acetyl groups. METH-induced gene priming and sensitization. A single dose of METH may be sufficient to induce an epigenetic switch consisting in increased gene expression. Such an effect may also occur during chronic METH resulting in long-term sensitization. This occurs through increased histone acetylation and methylation at specific K residues i. References J. Fowler, N. Volkow, J. Logan et al. Fowler, G. Wang et al. Schepers, J. Oyler, R. Joseph Jr. Cone, E. Moolchan, and M. Meredith, C. Jaffe, K. Ang-Lee, and A. Homer, T. Solomon, R. Moeller, A. Mascia, L. DeRaleau, and P. Marshall and S. Abekawa, T. Ohmori, and T. Stephans and B. Nishijima, A. Kashiwa, A. Hashimoto, H. Iwama, A. Umino, and T. Piccini, N. Pavese, and D. Uehara, T. Sumiyoshi, H. Itoh, and M. Erickson, M. Schafer, T. Bonner, L. Eiden, and E. Suzuki, H. Hattori, M. Asano, M. Oya, and Y. Sulzer and S. Cubells, S. Rayport, G. Rajendran, and D. Ary and H. Brown, G. Hanson, and A. Sandoval, E. Riddle, G. Fleckenstein, T. Volz, E. Riddle, J. Gibb, and G. Volz, A. Fleckenstein, and G. Floor and L. Brown, M. Quinton, and B. Gesi, A. Santinami, R. Ruffoli, G. Conti, and F. Ferrucci, F. Giorgi, A. Bartalucci, C. Busceti, and F. Cadet, S. Ali, and C. Jayanthi, B. Ladenheim, and J. Hattori, Y. Luo, H. Umegaki, J. Munoz, and G. LaVoie and T. Gluck, L. Moy, E. Jayatilleke, K. Hogan, L. Manzino, and P. Sulzer and L. Sulzer, M. Sonders, N. Poulsen, and A. Moratalla, A. Khairnar, N. Simola et al. Wells, Y. Bhuller, C. Chen et al. Iwazaki, I. McGregor, and I. Miyazaki, M. Asanuma, F. Diaz-Corrales et al. Lazzeri, P. Lenzi, C. Busceti et al. Li, H. Wang, P. Qiu, and H. Harold, T. Wallace, R. Friedman, G. Gudelsky, and B. Chen, Y. Lee, C. Huang et al. Krasnova and J. Yamamoto, A. Moszczynska, and G. Schmidt and J. Schneider, D. Rothblat, and L. Fuxe, K. Jacobsen, M. Fuxe, A. Jonsson et al. Northrop and B. Turowski and B. Agid, F. Javoy, and M. Fornai, K. Chen, F. Giorgi, M. Gesi, M. Alessandri, and J. Tipton, S. Boyce, J. Davey, and J. Youdim, D. Edmondson, and K. Wagner, G. Ricaurte, L. Seiden, C. Schuster, R. Miller, and J. Battaglia, C. Busceti, L. Cuomo et al. Battaglia, M. Gesi, P. Lenzi et al. S42—S52, View at: Google Scholar D. Surmeier, W. Shen, M. Day et al. Gerfen and D. Seiden, M. Fischman, and C. Ricaurte, R. Guillery, L. Schuster, and R. Seiden, and C. Sonsalla, N. Jochnowitz, G. Zeevalk, J. Oostveen, and E. Buening and J. Hotchkiss and J. View at: Google Scholar C. Schmidt, J. Ritter, P. Sonsalla, G. Hanson, and J. View at: Google Scholar H. Hirata and J. Granado, S. Ares-Santos, E. Colado, and R. Ares-Santos, I. Oliva et al. Granado, I. Lastres-Becker, S. Ares-Santos et al. Ares-Santos, N. Espadas, R. Martinez-Murillo, and R. Zhu, W. Xu, N. Angulo, and J. Morrow, R. Roth, D. Redmond, and J. Callaghan, J. Cunningham, J. Sykes, and S. Curtin, A. Fleckenstein, R. Robison, M. Crookston, K. Smith, and G. Rumpf, J. Albers, C. Fricke, W. Mueller, and J. Fornai, P. Lenzi, M. Gesi et al. View at: Google Scholar F. Fornai, G. Lazzeri, A. Di Poggio et al. Lenzi, L. Capobianco et al. Castino, G. Ferrucci, L. Ryskalin, F. Biagioni et al. View at: Google Scholar L. Quan, T. Ishikawa, T. Michiue et al. Pasquali, G. Lazzeri, C. Isidoro, S. Ruggieri, A. Paparelli, and F. Weihmuller, and J. Deng and J. Deng, Y. Wang, J. Chou, and J. Jayanthi, X. Deng, P. Noailles, B. Deng, B. Ladenheim et al. Yu, J. Cadet, and J. Xu, and J. Tulloch, L. Afanador, I. Mexhitaj, N. Ghazaryan, A. GarzaGongora, and J. Jakel and W. Yoshida, M. Ohno, and S. Wersinger, J. Chen, and A. Jayanthi, M. McCoy, G. Beauvais, and N. Nash and B. Marshall, S. Mark, J. Soghomonian, and B. Yamamoto and M. Rodrigues, N. Granado, O. Ortiz, S. Yamamoto, K. Imai, E. Kamegaya et al. Yamamoto and J. Luo, A. Hattori, J. Munoz, Z. Qin, and G. Jeng, A. Wong, R. Ting-A-Kee, and P. Ramkissoon, T. Parman, and P. Frenzilli, M. Giorgi et al. Johnson, J. Venters, F. Guarraci, and M. Potashkin and G. Burnside and G. Grune, T. Jung, K. Merker, and K. Dias, E. Junn, and M. Ujike, T. Onoue, K. Akiyama, T. Hamamura, and S. Kelly, M. Low, M. Rubinstein, and T. Beauvais et al. Beauvais, S. McCoy, B. Friend and K. Granado, and R. Neve, J. Seamans, and H. Stoof and J. Tkatch, E. Perez-Garci et al. Nishi, M. Kuroiwa, and T. Sonsalla, J. Gerfen, T. Engber, L. Mahan et al. Gerfen, S. Miyachi, R. Paletzki, and P. Bejjani, I. Arnulf, S. Demeret et al. Taylor, C. Bishop, and P. Chen, J. Bohanick, M. Nishihara, J. Seamans, and C. Fornai, F. Biagioni, F. Fulceri, L. Murri, S. Ruggieri, and A. Biagioni, A. Pellegrini, S. Ruggieri, L. Murri, A. View at: Google Scholar A. Fasano and I. Gerfen, R. Hamamura, K. Akiyama, K. Akimoto et al. Kuczenski and D. View at: Google Scholar P. Karper, H. De La Rosa, E. Newman et al. Bosse, J. Charlton, L. Susick et al. Moriguchi, S. Watanabe, H. Kita, and H. Miyazaki, Y. Noda, A. Mouri et al. Chen, M. Rusnak, R. Luedtke, and A. Pavon, A. Martin, A. Mendialdua, and R. Westin, L. Vercammen, E. Strome, C. Konradi, and M. Santini, E. Valjent, A. Usiello et al. Girault, E. Valjent, J. Caboche, and D. Pascoli, E. Cahill, F. Bellivier, J. Caboche, and P. Mizoguchi, K. Yamada, M. Mizuno et al. Valjent, V. Pascoli, P. Svenningsson et al. Pascoli, A. Besnard, D. Svenningsson, A. Nishi, G. Fisone, J. Girault, A. Nairn, and P. E—E, Lin, T. Hashimoto, N. Kitamura, N. Murakami, O. Shirakawa, and K. Chen and J. Zachariou, V. Sgambato-Faure, T. Sasaki et al. Greengard, P. Allen, and A. Stipanovich, E. Valjent, M. Matamales et al. Andres, I. Cooke, F. Bellinger et al. Snyder, P. Allen, A. Fienberg et al. Edwards, D. Simmons, D. Galindo et al. Dudman, M. Eaton, A. Rajadhyaksha et al. View at: Google Scholar R. Swayze, M. Lise, J. Levinson, A. Phillips, and A. Gao, X. Sun, and M. Silva, F. Pereira et al. Kerdsan, S. Thanoi, and S. Huang, Y. Shen et al. Mark, M. Quinton, S. Russek, and B. Zhang, T. Lee, X. Xiong et al. Nishi, Y. Higashi, M. Tanaka, A. Chergui, P. Svenningsson, and P. Bibb, G. Snyder, A. Nishi et al. Maccioni, C. Otth, I. Concha, and J. Nishi, J. Snyder, H. Higashi, A. Bibb, J. Taylor et al. Mlewski, F. Krapacher, S. Ferreras, and G. Tang and I. Rashid, C. So, M. Kong et al. Hasbi, T. Fan, M. Alijaniaram et al. Hasbi, B. Moratalla, H. Robertson, and A. Cole, R. Bhat, C. Patt, P. Worley, and J. Konradi, R. Cole, S. Heckers, and S. Simpson and B. Berke, R. Paletzki, G. Aronson, S. Hyman, and C. Fienberg, P. Allen et al. Chen, C. Wersinger, and A. Groth, J. Weick, K. Bradley et al. Park, X. Shen, L. Tien, R. Roman, and T. Cadet, M. McCoy, and B. Cadet, C. Brannock, S. Jayanthi, and I. Sheng, X. Wang, B. Ladenheim, C. Epstein, and J. Asanuma and J. Asanuma, I. Higashi, T. Tsuji, and N. Barrett, T. Xie, Y. Piao et al. Xie, L. Tong, T. Barrett et al. Lee, B. Hennig, J. Yao, and M. Flora, Y. Lee, A. Nath, W. Maragos, B. Hennig, and M. Thomas, D. Francescutti-Verbeem, X. Liu, and D. Beauvais, K. Atwell, S. Krasnova, M. Chiflikyan, Z. Justinova et al. Krasnova, Z. Justinova, and J. Wang, A. Smith, and J. Moratalla, M. Xu, S. Tonegawa, and A. Shi and J. Uno, T. Miyazaki, K. Sodeyama, Y. Miyamoto, and A. Pregi, L. Belluscio, B. Berardino, D. Castillo, and E. Hebert and J. McDaid, M. Graham, and T. Ryu, M. Yang, M. Jung, J. Jeon, K. Kim, and J. View at: Google Scholar G. Cao, J. Zhu, Q. Zhong et al. Hai and T. Shaulian and M. Bronstein, K. Pennypacker, H. Lee, and J. Pennypacker, X. Gordon, S. Benkovic, D. Saint-Preux, L. Bores, I. Tulloch et al. Torres, M. Renthal, T. Carle, I. Maze et al. Robison and E. Tamminga and E. Cornish, G. Hunt, L. Robins, and I. Palmer, M. Verbitsky, R. Suresh et al. Beckmann and P. Hirata, M. Asanuma, and J. Thiriet, J. Zwiller, and S. McCoy, S. Jayanthi, J. Wulu et al. Asanuma, T. Hayashi, S. Ordonez, N. Ogawa, and J. Frankel, A. Hoonakker, J. Danaceau, and G. McCoy, N. Cai et al. Brannock, B. Youngson and E. Renthal and E. Walker, H. Cates, E. Heller, and E. Aguilar-Valles, T. Griggs et al. Li, F. Rubio, T. Zeric et al. Li, M. Carreria, K. Witonsky et al. Brannock, I. Krasnova et al. Gonzalez, M. Ladenheim, V. Bisagno, and J. Feng, S. Fouse, and G. Seto and M. Vecsey, J. Hawk, K. Lattal et al. Martin, S. Harkness, R. Hitzemann, S. Edmunds, and T. Henry, Y. Kuo, and A. Everitt and T. Omonijo, P. Wongprayoon, B. Feng and E. Lewis, K. Staudinger, L. Scheck, and M. Hyun, J. Park, and J. Suzuki and A. Deaton and A. Kameshita, M. Sekiguchi, D. Hamasaki et al. Scott, J. Song, R. Ewing, and Z. Numachi, S. Yamashita et al. Numachi, H. Shen, S. Yoshida et al. Nohesara, M. Ghadirivasfi, M. Barati et al. Sagud, D. View at: Google Scholar M. Fraga and M. Du and M. Nidai Ozes, L. Mayo, J. Gustin, S. Pfeffer, L. Pfeffer, and D. Chang, M. Samaranayake et al. Brami-Cherrier, E. Garcia, C. Pages, R. Hipskind, and J. Lao, and J. Lebel, C. Patenaude, J. Allyson, G. Massicotte, and M. Beaulieu, T. Sotnikova, M. Lemasson, and R. Yang, H. Wang, L. Liu, and A. Wu, S. McCallum, S. Glick, and Y. Lin, P. Chandramani-Shivalingappa, H. Jin et al. Pitaksalee, Y. Sanvarinda, T. Sinchai et al. Jiang, J. Li, Z. Zhang, H. Wang, and Z. Zhao, B. Zhai, S. Gygi, and A. Lenzi, G. Lazzeri, F. Limanaqi, F. Moszczynska and B. Jowaed, I. Schmitt, O. Kaut, and U. Desplats, B. Spencer, E. Coffee et al. Tan, L. Wu, Z. Zhao et al. Matsumoto, H. Takuma, A. Tamaoka et al. Funahashi, Y. Yoshino, K. Yamazaki et al. Richa and R. Santiago, C. Antunes, M. Guedes, N. Sousa, and C. Hellman and A. View at: Publisher Site Google Scholar. Download other formats More. Dinucleotide composed of cytosine C preceding a guanine G with the interposition of a phosphate group p.

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