Long-Term Protective Effects of Methamphetamine Preconditioning Against Single-Day Methamphetamine Toxic Challenges
Amber B. HodgesBruce LadenheimMichael T. McCoyGeneviève BeauvaisNing-Sheng CaiIrina N. KrasnovaJean Lud Cadet
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Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH – induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems. Keywords: Methamphetamine, striatum, dopamine, preconditioning, METH-induced neurodegenerative, Monoamine Depletion, Tympanic Temperature, 3,4-dihyroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), DA, DOPAC, HVA, 5-HTKeywords:
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A bstract : Methamphetamine (METH) is a drug of abuse, causing neurotoxic effects in mammals. Many hypotheses have been proposed to explain the underlying mechanisms of METH‐induced toxicity, based on neurochemical/neuroanatomical changes. However, the pharmacokinetic properties of METH in the METH‐induced neurotoxic model have not yet been evaluated. Thus, we investigated plasma and tissue levels of METH in the METH‐induced neurotoxic model. As a result, when METH is administered multiply (5 mg/kg 4 times at 2‐h intervals) in male Wistar rats, plasma METH levels at the third and forth injections were significantly higher than those at the first. The tissue distributions of METH in the brain as well as in the kidney were significantly decreased in the third injections, suggesting the importance of decreased transport of METH into tissues. Alternatively, one week after the establishment of METH‐induced neurotoxicity, plasma levels of METH were back to normal, although METH levels in brain microdialysates were significantly higher than those in normal animals. These results suggest that the altered pharmacokinetic properties of METH, due to the abnormal membrane transport/disposition of METH into both central and peripheral tissues, might partially affect the emergence of METH‐induced neurotoxicity.
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Understanding the relationship between the molecular mechanisms underlying neurotoxicity of high-dose methamphetamine (METH) and related clinical manifestations is imperative for providing more effective treatments for human METH users. This article provides an overview of clinical manifestations of METH neurotoxicity to the central nervous system and neurobiology underlying the consequences of administration of neurotoxic METH doses, and discusses implications of METH neurotoxicity for treatment of human abusers of the drug.
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Abstract The abuse of methamphetamine (METH) continues to increase throughout all age groups in different regions of the United States. "Ice," the popularized jargon for (+) methamphetamine hydrochloride, is the predominant drug form that is now consumed. "Ice" is effectively absorbed after either smoking or snorting and it is this rapid influx of drug that produces effects similar to those after intravenous administration. The intensity of METH actions in the central and peripheral nervous system shows tolerance after chronic administration, indicating that neuro-adaptations have occurred. Thus, the physiological processes and corresponding biochemical mechanisms that regulate neuronal function have been changed by METH exposure. These biological alterations contribute to the craving and dependence associated with METH abuse and the withdrawal syndrome upon abstinence. However, these changes in behavior may also result from METH-induced neurotoxicity. This article reviews aspects of METH pharmacokinetics and related molecular pharmacodynamics that represent METH pharmacology and then relates those actions to their potential to produce neurotoxicity in humans.
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Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH – induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems. Keywords: Methamphetamine, striatum, dopamine, preconditioning, METH-induced neurodegenerative, Monoamine Depletion, Tympanic Temperature, 3,4-dihyroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), DA, DOPAC, HVA, 5-HT
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Matrix metalloproteinase (MMP) 9 is up regulated following various types of insults to the brain. Recent studies have also implicated MMP9 in neural remodeling after stimulant doses of methamphetamine (METH). The involvement of MMP9 in METH‐induced neurotoxicity, however, remains unclear and was thus evaluated in the present study. Male, Swiss Webster mice were injected with stimulant or toxic doses of METH. MMP9 gene expression was up regulated in the brain within 5 min. By 24 h, MMP9 gene expression returned to control levels in the stimulant treated mice, but remained elevated in animals exposed to toxic doses of METH. The development of neurotoxicity was evidenced between 17 days following METH exposure as depletions in striatal dopamine levels. However, this marker of METH neurotoxicity was not accompanied by concomitant changes in striatal MMP9 gene expression. In MMP9 knock out mice, neurotoxic dosing with METH produced depletions in striatal dopamine levels that were comparable to wild type mice. Although the absence of MMP9 did not affect METH neurotoxicity, the knock out mice exhibited the expected decrease in behavioral sensitization following repeated administration of stimulant doses of METH. Together, the data suggest that changes in MMP9 expression do not affect METH‐induced neurotoxicity, and may instead be contributing to remodeling of the nervous system.
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The anxiety profile in the stimulant-sensitized animals is not clear. Thus, this study was conducted to elucidate the effects of acute and chronic administration of methamphetamine (METH) on the anxiety profile. The aim of this study was to examine whether METH-sensitized rats would show an increase in the expression of anxiogenic-like behaviors and to determine whether a low dose of METH elicits behavioral sensitization.Rats were repeatedly given METH (2 mg/kg, s.c., once a day for 14 days), and the immediate and delayed effects of METH on the anxiety profile was compared considering 30 minutes (min) and 120 min after injections in METH-sensitized, withdrawn and intact rats using the elevated plus-maze (EPM), also, to re-challenge with a low dose of METH (0.5 mg/kg) in withdrawn groups.RESULTS have shown that METH-sensitized rats exhibited an increase in the open arm time and entries 120 min after injection compared to the control group. We found a reduction in the time spent in open arms for the immediate effects of METH (30 min after injection) in METH-sensitized rats as compared to the control group. In withdrawn rats, METH/METH groups exhibited an increase in the open arm time and entries than METH/Sal and Sal/METH groups.It was found that unlike delayed effects, an immediate effect of METH exhibited anxiogenic-like behaviors in METH-sensitized rats using the EPM. Also, results indicated that a low dose of METH is a potent stimulus for reinstatement of methamphetamine behavioral sensitization in a long withdrawn period.
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Monoamine neurotransmitters are released by specialized neurons that regulate behavioral and cognitive functions. Although localization of monoaminergic neurons in the brain is well known, the distribution, concentration, and kinetics of monoamines remain unclear. We used mass spectrometry imaging (MSI) for simultaneous and quantitative imaging of endogenous monoamines to generate a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. We observed several nuclei rich in both 5-HT and a catecholamine (DA or NE). Additionally, we analyzed de novo monoamine synthesis or fluctuations in those nuclei. We propose that MSI is a useful tool to gain deeper understanding of associations among the localization, levels, and turnover of monoamines in different brain areas and their role in inducing behavioral changes.
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Monoaminergic systems are important modulators of the responses to stress and stress may influence feeding behavior, and the involvement of monoamines in the control of food intake is well to recognize and other functions.
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