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Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia.
Matsumoto RR, Seminerio MJ, Turner RC, Robson MJ, Nguyen L, Miller DB, O'Callaghan JP
(2014) Pharmacol Ther 144: 28-40
MeSH Terms: Animals, Body Temperature, Body Temperature Regulation, Central Nervous System Stimulants, Dopamine, Drug Overdose, Fever, Humans, Methamphetamine
Show Abstract · Added August 26, 2015
Reports of methamphetamine-related emergency room visits suggest that elevated body temperature is a universal presenting symptom, with lethal overdoses generally associated with extreme hyperthermia. This review summarizes the available information on methamphetamine toxicity as it pertains to elevations in body temperature. First, a brief overview of thermoregulatory mechanisms is presented. Next, central and peripheral targets that have been considered for potential involvement in methamphetamine hyperthermia are discussed. Finally, future areas of investigation are proposed, as further studies are needed to provide greater insight into the mechanisms that mediate the alterations in body temperature elicited by methamphetamine.
Copyright © 2014 Elsevier Inc. All rights reserved.
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9 MeSH Terms
SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation.
Robson MJ, Turner RC, Naser ZJ, McCurdy CR, O'Callaghan JP, Huber JD, Matsumoto RR
(2014) Exp Neurol 254: 180-9
MeSH Terms: Animals, Astrocytes, Benzoxazoles, Central Nervous System Stimulants, Corpus Striatum, Cytokine Receptor gp130, Dopaminergic Neurons, Drug Interactions, Fever, Glial Fibrillary Acidic Protein, Gliosis, Male, Methamphetamine, Mice, Oncostatin M Receptor beta Subunit, Phosphorylation, Piperazines, Receptors, sigma, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added August 26, 2015
Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.
Copyright © 2014 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Sigma (σ) receptors as potential therapeutic targets to mitigate psychostimulant effects.
Matsumoto RR, Nguyen L, Kaushal N, Robson MJ
(2014) Adv Pharmacol 69: 323-86
MeSH Terms: Animals, Central Nervous System Stimulants, Clinical Trials as Topic, Cocaine, Drug Delivery Systems, Humans, Methamphetamine, Opipramol, Protein Binding, Receptors, sigma, Substance-Related Disorders
Show Abstract · Added August 26, 2015
Many psychostimulants, including cocaine and methamphetamine, interact with sigma (σ) receptors at physiologically relevant concentrations. The potential therapeutic relevance of this interaction is underscored by the ability to selectively target σ receptors to mitigate many behavioral and physiological effects of psychostimulants in animal and cell-based model systems. This chapter begins with an overview of these enigmatic proteins. Provocative preclinical data showing that σ ligands modulate an array of cocaine and methamphetamine effects are summarized, along with emerging areas of research. Together, the literature suggests targeting of σ receptors as an innovative option for combating undesired actions of psychostimulants through both neuronal and glial mechanisms.
© 2014 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro.
Kaushal N, Robson MJ, Rosen A, McCurdy CR, Matsumoto RR
(2014) Eur J Pharmacol 724: 193-203
MeSH Terms: Animals, Apoptosis, Benzoxazoles, Caspases, Cell Line, Tumor, Fever, Ligands, Methamphetamine, Mice, Necrosis, Neuroprotective Agents, Piperazines, Reactive Nitrogen Species, Reactive Oxygen Species, Receptors, sigma, eIF-2 Kinase
Show Abstract · Added August 26, 2015
Exposure to high or repeated doses of methamphetamine can cause hyperthermia and neurotoxicity, which are thought to increase the risk of developing a variety of neurological conditions. Sigma receptor antagonism can prevent methamphetamine-induced hyperthermia and neurotoxicity, but the underlying cellular targets through which the neuroprotection is conveyed remain unknown. Differentiated NG108-15 cells were thus used as a model system to begin elucidating the neuroprotective mechanisms targeted by sigma receptor antagonists to mitigate the effects of methamphetamine. In differentiated NG108-15 cells, methamphetamine caused the generation of reactive oxygen/nitrogen species, an increase in PERK-mediated endoplasmic reticulum stress and the activation of caspase-3, -8 and -9, ultimately resulting in apoptosis at micromolar concentrations, and necrotic cell death at higher concentrations. The sigma receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), attenuated methamphetamine-induced increases in reactive oxygen/nitrogen species, activation of caspase-3, -8 and -9 and accompanying cellular toxicity. In contrast, 1,3-di(2-tolyl)-guanidine (DTG), a sigma receptor agonist, shifted the dose response curve of methamphetamine-induced cell death towards the left. To probe the effect of temperature on neurotoxicity, NG108-15 cells maintained at an elevated temperature (40 °C) exhibited a significant and synergistic increase in cell death in response to methamphetamine, compared to cells maintained at a normal cell culture temperature (37 °C). SN79 attenuated the enhanced cell death observed in the methamphetamine-treated cells at 40 °C. Together, the data demonstrate that SN79 reduces methamphetamine-induced reactive oxygen/nitrogen species generation and caspase activation, thereby conveying neuroprotective effects against methamphetamine under regular and elevated temperature conditions.
Copyright © 2014 Elsevier B.V. All rights reserved.
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16 MeSH Terms
The complex relationship between the light-entrainable and methamphetamine-sensitive circadian oscillators: evidence from behavioral studies of Period-mutant mice.
Pendergast JS, Niswender KD, Yamazaki S
(2013) Eur J Neurosci 38: 3044-53
MeSH Terms: Animals, Central Nervous System Stimulants, Circadian Rhythm, Female, Light, Male, Methamphetamine, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Period Circadian Proteins, Suprachiasmatic Nucleus
Show Abstract · Added February 19, 2015
The methamphetamine-sensitive circadian oscillator (MASCO) is an enigmatic circadian clock whose output is observed during continuous consumption of low-dose methamphetamine. The MASCO rhythm persists when the light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) is lesioned, but the anatomical location of MASCO is unknown. We recently found that the period of the MASCO rhythm is unusually short (21 h) in mice with disruption of all three paralogs of the canonical clock gene, Period. In this study, we investigated the contribution of each Period paralog to timekeeping in MASCO. We measured wheel-running activity rhythms in intact and SCN-lesioned Per1-, 2- and 3-mutant mice administered methamphetamine, and found that none of the mice displayed a short (21-h) period, demonstrating that no single Period gene is responsible for the short-period MASCO rhythm of Per1(-/-) /Per2(-/-) /Per3(-/-) mice. We also found that the periods of activity rhythms in constant darkness were lengthened by methamphetamine treatment in intact wild-type, Per1(-/-) and Per3(-/-) mice but not Per2(-/-) mice, and Per2(-/-) mice had two distinct activity rhythms upon release to constant light. These data suggest that the SCN and MASCO are not coupled in Per2(-/-) mice. The MASCO rhythm in Per1(-/-) /Per2(-/-) mice in constant darkness alternated between a short (22-h) and a long (27-h) period. This pattern could result from two coupled oscillators that are not synchronised to each other, or from a single oscillator displaying birhythmicity. Finally, we propose a working model of the in vivo relationship between MASCO and the SCN that poses testable hypotheses for future studies.
© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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13 MeSH Terms
σ Receptor antagonist attenuation of methamphetamine-induced neurotoxicity is correlated to body temperature modulation.
Robson MJ, Seminerio MJ, McCurdy CR, Coop A, Matsumoto RR
(2013) Pharmacol Rep 65: 343-9
MeSH Terms: Animals, Benzothiazoles, Body Temperature, Corpus Striatum, Dopamine, Dopamine Agents, Fever, Male, Methamphetamine, Mice, Neurotoxicity Syndromes, Oxalates, Piperazines, Piperidines, Receptors, sigma
Show Abstract · Added July 10, 2013
BACKGROUND - Methamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with σ receptors and σ receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with σ receptor antagonists failed to attenuate METH-induced hyperthermia in mice. This allowed us to determine whether the ability of σ receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia.
METHODS - Mice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment.
RESULTS - The data indicate that the ability of σ receptor antagonists to attenuate METH-induced dopaminergic neurotoxicity is linked to their ability to block METH-induced hyperthermia.
CONCLUSION - The ability of σ receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions.
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15 MeSH Terms
Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence.
Simmler LD, Wandeler R, Liechti ME
(2013) BMC Res Notes 6: 220
MeSH Terms: Amphetamine-Related Disorders, Benzodioxoles, Biological Transport, Bupropion, Dopamine, Humans, Methamphetamine, Methylphenidate, Pyrrolidines
Show Abstract · Added August 3, 2013
BACKGROUND - Methamphetamine-abuse is a worldwide health problem for which no effective therapy is available. Inhibition of methamphetamine-induced transporter-mediated dopamine (DA) release could be a useful approach to treat methamphetamine-addiction. We assessed the potencies of bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone (MDPV) to block DA uptake or to inhibit methamphetamine-induced DA release in HEK-293 cells expressing the human DA transporter.
FINDINGS - Bupropion, methylphenidate, and MDPV inhibited methamphetamine-induced DA release with relative potencies corresponding to their potencies to block DA uptake (potency ranks: MDPV > methylphenidate > bupropion).
CONCLUSIONS - Bupropion and methylphenidate antagonize the effects of methamphetamine in vitro and may be potential candidates for the treatment of stimulant addiction. However, drugs that very potently antagonize the effect of methamphetamine are likely to also exhibit considerable abuse liability (MDPV > methylphenidate > bupropion).
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9 MeSH Terms
SN79, a sigma receptor ligand, blocks methamphetamine-induced microglial activation and cytokine upregulation.
Robson MJ, Turner RC, Naser ZJ, McCurdy CR, Huber JD, Matsumoto RR
(2013) Exp Neurol 247: 134-42
MeSH Terms: Analysis of Variance, Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Benzoxazoles, Body Temperature, Brain, Cytokines, Male, Methamphetamine, Mice, Microglia, Piperazines, RNA, Messenger, Receptors, sigma, Time Factors, Up-Regulation
Show Abstract · Added July 10, 2013
Methamphetamine (METH) abuse is associated with several negative side effects including neurotoxicity in specific brain regions such as the striatum. The precise molecular mechanisms by which METH usage results in neurotoxicity remain to be fully elucidated, with recent evidence implicating the importance of microglial activation and neuroinflammation in damaged brain regions. METH interacts with sigma receptors which are found in glial cells in addition to neurons. Moreover, sigma receptor antagonists have been shown to block METH-induced neurotoxicity in rodents although the cellular mechanisms underlying their neuroprotection remain unknown. The purpose of the current study was to determine if the prototypic sigma receptor antagonist, SN79, mitigates METH-induced microglial activation and associated increases in cytokine expression in a rodent model of METH-induced neurotoxicity. METH increased striatal mRNA and protein levels of cluster of differentiation 68 (CD68), indicative of microglial activation. METH also increased ionized calcium binding adapter molecule 1 (IBA-1) protein expression, further confirming the activation of microglia. Along with microglial activation, METH increased striatal mRNA expression levels of IL-6 family pro-inflammatory cytokines, leukemia inhibitory factor (lif), oncostatin m (osm), and interleukin-6 (il-6). Pretreatment with SN79 reduced METH-induced increases in CD68 and IBA-1 expression, demonstrating its ability to prevent microglial activation. SN79 also attenuated METH-induced mRNA increases in IL-6 pro-inflammatory cytokine family members. The ability of a sigma receptor antagonist to block METH-induced microglial activation and cytokine production provides a novel mechanism through which the neurotoxic effects of METH may be mitigated.
Copyright © 2013 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Chronic methamphetamine exposure produces a delayed, long-lasting memory deficit.
North A, Swant J, Salvatore MF, Gamble-George J, Prins P, Butler B, Mittal MK, Heltsley R, Clark JT, Khoshbouei H
(2013) Synapse 67: 245-57
MeSH Terms: Age Factors, Animals, Dopamine Agents, Hippocampus, Long-Term Potentiation, Male, Memory, Short-Term, Methamphetamine, Mice, Mice, Inbred C57BL, Time Factors
Show Abstract · Added July 10, 2015
Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long-term deficits in short-term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short-term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short-term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH-exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short-term as well as long-term consequences of methamphetamine exposure.
Copyright © 2012 Wiley Periodicals, Inc.
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11 MeSH Terms
Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo.
Kaushal N, Seminerio MJ, Robson MJ, McCurdy CR, Matsumoto RR
(2013) Eur Neuropsychopharmacol 23: 960-71
MeSH Terms: Animals, Benzoxazoles, Central Nervous System Stimulants, Corpus Striatum, Dopamine, Dopamine Antagonists, Dopamine Plasma Membrane Transport Proteins, Drug Synergism, Fever, Guanidines, Male, Methamphetamine, Mice, Nerve Tissue Proteins, Neurons, Neuroprotective Agents, Neurotoxicity Syndromes, Piperazines, Random Allocation, Receptors, sigma, Serotonin, Serotonin Antagonists, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added July 10, 2013
Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity.
Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.
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23 MeSH Terms