Effects of adenosine A1- and A2A-receptor agonists on enhancement of dopamine release from the striatum in methamphetamine-sensitized rats.
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We report here both adenosine A1- and A2A-receptor agonists inhibit the expression of methamphetamine (MAP)-induced behavioral sensitization in rats. Animals were treated with MAP (1.0 mg/kg, i.p.) every 3 days with a total of 5 administrations. The augmentation of dopamine release from the striatum was demonstrated by MAP re-administration (0.5 mg/kg, i.p.) after 7-day withdrawal by microdialysis. The augmentation of dopamine release was inhibited by pre-treatment not with N6-cyclohexyladenosine (0.01 mg/kg, i.p.) but by with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxy-amide adenosine (0.1 mg/kg, i.p.). These results suggested that adenosine A1 and A2A receptors play an inhibitory role in sensitization via different mechanisms. (+info)
Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex.
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Bcl-2, an inner mitochondrial membrane protein, inhibits apoptotic neuronal cell death. Expression of Bcl-2 inhibits cell death by decreasing the net cellular generation of reactive oxygen species. Studies by different investigators have provided unimpeachable evidence of a role for oxygen-based free radicals in methamphetamine (METH) -induced neurotoxicity. In addition, studies from our laboratory have shown that immortalized rat neuronal cells that overexpress Bcl-2 are protected against METH-induced apoptosis in vitro. Moreover, the amphetamines can cause differential changes in the expression of Bcl-X splice variants in primary cortical cell cultures. These observations suggested that METH might also cause perturbations of Bcl-2-related genes when administered to rodents. Thus, the present study was conducted to determine whether the use of METH might indeed be associated with transcriptional and translational changes in the expression of Bcl-2-related genes in the mouse brain. Here we report that a toxic regimen of METH did cause significant increases in the pro-death Bcl-2 family genes BAD, BAX, and BID. Concomitantly, there were significant decreases in the anti-death genes Bcl-2 and Bcl-XL. These results thus support the notion that injections of toxic doses of METH trigger the activation of the programmed death pathway in the mammalian brain. (+info)
Analysis of pyrolysis products of dimethylamphetamine.
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This study examines the pyrolysis products of dimethylamphetamine (DMAMP) and its pyrolysis mechanism. A sealed glass tube, in which DMAMP-HCI was placed, was wrapped with pyrolysis-foil and heated at the Curie point of the pyrolysis-foil. The pyrolysis products of DMAMP were detected by gas chromatography-mass spectrometry (GC-MS), headspace (HS)-GC-MS and liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). DMAMP-d6-HCl, in which all the hydrogen atoms of the two methyl groups of DMAMP were substituted with deuterium atoms, was pyrolyzed to investigate the elimination and transformation reactions of the methyl group. Methamphetamine (MAMP) and amphetamine (AMP) were produced via demethylation reaction by heating DMAMP, and the maximum amounts of MAMP and AMP were about 31.8% and 13.7% of the starting DMAMP at 358 degrees C and 386 degrees C, respectively. The reactions of a chlorine anion and DMAMP with a methyl group eliminated from the dimethylamino group of DMAMP resulted in the formation of methyl chloride and benzylethyltrimethylammonium, respectively. These results indicate that one of the demethylation and methylation reactions occurs in the form of a methyl cation. (+info)
Amphetamines: an update on forensic issues.
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Methamphetamine is currently enjoying a resurgence of popularity as a recreational drug. It presents a number of challenges to the forensic toxicologist both analytically and interpretively, and these latter interpretive issues are considered here. This review also discusses the current popular syntheses which account for the widespread domestic synthesis of the drug; the demographics of methamphetamine use in the United States as assessed from the Drug Abuse Warning Network (DAWN) data; developments in research of the neurotransporter pharmacology of the drug and its implications for interpretive forensic toxicology; the psychomotor effects of the drug and its potential for cognitive and functional impairment; interpretive issues related to postmortem blood drug concentrations and how these are impacted by evidence for incomplete distribution and the potential for postmortem redistribution; and, finally, concerns caused by designer methamphetamine analogues. All data indicate that methamphetamine and its analogues will present significant interpretive challenges to forensic toxicologists as the popularity of the drug continues to grow. (+info)
Evaluation of Roche Abuscreen ONLINE amphetamine immunoassay for screening of new amphetamine analogues.
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Some structural analogues of amphetamine are now important drugs of abuse in Thailand. The utility of the Roche Abuscreen ONLINE reagent amphetamine immunoassay test kit to detect these analogues was studied. The test showed high cross-reactivity to 3,4-methylenedioxyamphetamine (MDA), but low cross-reactivity to its parent drugs, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA), as well as to methamphetamine and ethylamphetamine. Also observed in this study was a methamphetamine detection sensitivity enhancement effect of amphetamine, which is the active metabolite of methamphetamine. Correlation between the measured concentration values and the actual amount of these two drugs in the sample was, however, low. Thus, the test can be used to detect methamphetamine only when amphetamine is also present in the sample resulting from either co-administration or metabolism of methamphetamine. (+info)
Halothane potentiates the effect of methamphetamine and nomifensine on extracellular dopamine levels in rat striatum: a microdialysis study.
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Brain microdialysis was used to study the in vivo release and metabolism of dopamine (DA) in the rat striatum during halothane anaesthesia. Concentrations were measured in microdialysates collected every 20 min and applied directly to an on-line high-performance liquid chromatograph. Halothane was administered at concentrations of 0.5, 1.0, 1.5 and 2.0%. In another series of experiments, rats were treated intraperitoneally or locally with methamphetamine, a drug of abuse, or with nomifensine, a dopamine uptake blocker and antidepressant, in combination with 0.5 or 1.5% halothane. Halothane anaesthesia did not affect the dialysate (extracellular) concentration of DA at 2.0%. By contrast, the concentrations of DA metabolites [3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] increased during inhaled halothane anaesthesia in a dose-dependent manner and recovered after anaesthesia. Halothane potentiated the ability of methamphetamine to increase the extracellular concentration of DA when administered systemically, whereas only a small increase in DA accumulation was seen when methamphetamine was administered locally via the perfusate. Similarly, the increase in extracellular DA was accentuated by systemic nomifensine during halothane anaesthesia, but no obvious enhancement was observed when it was applied locally. It has been shown that the neurotoxic effect of methamphetamine is mediated by the suboxidation of DA released from the cytoplasm into the extracellular space and transformed into highly reactive free radicals. On the basis of our results, it is suggested that care should be exercised when halothane anaesthesia is used in patients abusing phenylethylamines (amphetamines) or being treated with DA uptake blockers (nomifensine). (+info)
Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness.
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BACKGROUND: In rats, amino acid mixtures lacking tyrosine and its precursor phenylalanine decrease the release of dopamine produced by the psychostimulant drug amphetamine. Amphetamine has been proposed as a model for clinical mania. AIMS: To assess whether dietary tyrosine depletion attenuates the psychostimulant effects of methamphetamine in healthy volunteers and diminishes the severity of mania in acutely ill patients. METHOD: Sixteen healthy volunteers received a tyrosine-free amino acid mixture and a control mixture in a double-blind crossover design 4 h before methamphetamine (0.15 mg/kg). Twenty in-patients meeting DSM-IV criteria for mania were allocated blindly and randomly to receive either the tyrosine-free mixture or the control mixture. RESULTS: The tyrosine-free mixture lowered both subjective and objective measures of the psychostimulant effects of methamphetamine. Ratings of mania were lower in the patients who received the tyrosine-free mixture. CONCLUSIONS; Decreased tyrosine availability to the brain attenuates pathological increases in dopamine neurotransmission following methamphetamine administration and putatively in mania. (+info)
Effects of methamphetamine and scopolamine on variability of response location.
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Methamphetamine and scopolamine were studied in monkeys responding under a multiple fixed-ratio fixed-interval schedule of reinforcement. A response on any one of six levers could satisfy the schedule requirements. Variability of response location was evaluated in terms of switches, where a switch was defined as a response on one lever followed by a response on a different lever. Under baseline conditions the fixed-ratio schedule generated a high rate of responding and a low level of variability, while the fixed-interval schedule generated a low rate of responding and a high level of variability. Both methamphetamine (0.1 to 0.5 mg/kg) and scopolamine (2.4 to 240 microgram/kg) decreased overall response rate and increased variability of response location in each component of the multiple schedule with increasing doses of drug. At lower doses both drugs were found to decrease rate without affecting response variability. (+info)