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At least 109 records · Page 6Linked to original sources
PubMed2000

Neonatal treatment with L-name (NG-nitro-L-arginine methyl ester) attenuates stereotyped behavior induced by acute methamphetamine but not development of behavioral sensitization to methamphetamine.

1. The neurodevelopmental hypothesis of schizophrenia postulates that disturbed nitric oxide (NO) function during neuronal development is one of premorbid factors for schizophrenia in later life. 2. The aim of present study is to investigate behaviorally whether neonatal inhibition of nitric oxide synthase (NOS) affects dopaminergic function, the abnormality of which may be ascribed to a major pathophysiology of schizophrenia. 3. Male rat pups were injected daily with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), from postnatal day (PD) 1 to 14. 4. When methamphetamine (MAP) was challenged on PD42, MAP-induced stereotypy was significantly attenuated in the L-NAME treated rats. The development of sensitization to the stereotypy-inducing effect of MAP, however, was not prevented with neonatal L-NAME. 5. These results suggest that decreased NO production during neonatal period may disturb normal maturation of dopaminergic system and result in impaired dopaminergic function in adult period.

Animals↗
PubMed2006

Prevalence of use study for amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxy-methamphetamine (MDMA), and 3,4-methylenedioxy-ethylamphetamine (MDEA) in military entrance processing stations (MEPS) specimens.

The Roche Abuscreen Onlinetrade mark Amphetamine immunoassay (IA), modified to include sodium periodate, and the Microgenics DRI Ecstasy IA were used to determine the prevalence of amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA) in urine specimens from applicants seeking to join the United States Armed Forces. Over a 4-month period, a total of 85,658 specimens were IA screened using the Department of Defense 500 ng/mL administrative cutoff level for AMP and MDMA. All presumptively positive specimens were confirmed using a solid-phase extraction procedure coupled with simultaneous analysis of AMP, MAMP, MDA, MDMA, and MDEA by fast gas chromatography-mass spectrometry using the same cutoff levels as the IA. The Roche Online Amphetamine IA identified 216 specimens as presumptively positive; of these, 70 specimens confirmed positive for AMP and 87 specimens confirmed positive for AMP and/or MAMP, resulting in a confirmation rate of 73%. The Microgenics DRI Ecstasy IA identified eight specimens as presumptively positive; of these, five specimens confirmed positive for MDMA and/or MDA, resulting in a confirmation rate of 63%. The total use prevalence for AMP, MAMP, MDA, MDMA, and/or MDEA in military entrance processing stations specimens over the testing period was determined to be 0.19%.

Amphetamines↗
PubMed1996

Positron emission tomography study of the alterations in brain distribution of [11C]methamphetamine in methamphetamine-sensitized dog.

We newly prepared a MAP-sensitized dog by repeated MAP treatment and studied the brain distribution of [11C]MAP in the normal and the MAP-sensitized dog using PET. The maximal level of accumulation of [11C]MAP in the sensitized dog brain was 1.4 times higher than that in the control. No difference was found in the metabolism of MAP between the two conditions. The significant increase of [11C]MAP in the MAP-sensitized brain indicates that subchronic MAP administration causes some functional change in the uptake site of MAP. The pharmacokinetic change may, in part, account for behavioral sensitization.

Animals↗
PubMed2006

Human pharmacology of the methamphetamine stereoisomers.

OBJECTIVE: To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers. METHODS: In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration-time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for "intoxication," "good drug effect," and "drug liking") were obtained. RESULTS: Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3-15.0 hours) than for d-methamphetamine (10.2-10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 +/- 23.4 beats/min, 13.5 +/- 18.5 beats/min, and 10.7 +/- 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 +/- 17.8 beats/min and 34.5 +/- 18.9 beats/min, respectively, versus 19.5 +/- 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 +/- 35.3 versus 30.3 +/- 24.9) and drug liking (47.7 +/- 35.1 versus 28.6 +/- 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures. CONCLUSION: The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities.

Adult↗
PubMed1999

Noradrenergic modulation of the discriminative-stimulus effects of methamphetamine in rats.

RATIONALE: Neurochemical and clinical studies indicate involvement of noradrenergic (NE) neurotransmitter system in the actions of methamphetamine. OBJECTIVE: The present study investigated NE involvement in the discriminative-stimulus effects of methamphetamine. METHODS: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio schedule of food presentation, effects of various NE agonists, antagonists and uptake inhibitors were tested. RESULTS: Desipramine (3.0-18.0 mg/kg) and nisoxetine (5.6-30.0 mg/kg), two selective NE-uptake inhibitors, did not significantly generalize to methamphetamine when administered alone, but 5.6 mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the methamphetamine dose-response curve to the left. The beta NE agonist, isoproterenol (0.56-3.0 mg/kg), and antagonist, propranolol (1.0-18.0 mg/kg), neither generalized to methamphetamine when given alone nor altered the discriminative-stimulus effects of methamphetamine when administered in combination. The alpha- NE agonist methoxamine (1.0-5.6 mg/kg) failed to generalize to the methamphetamine training stimulus. When given in combination with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted the methamphetamine dose-response curve somewhat to the right and partially blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine, but these changes were not significant or dose-related, with further increases in prazosin dose (1.8-10.0 mg/kg) either producing similar or smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to methamphetamine at doses of 0.1-0.18 mg/kg and increased drug-appropriate responding at lower doses of methamphetamine, but it partially blocked the discriminative-stimulus effects of higher 0.56-1.0 mg/kg doses of methamphetamine over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially generalized to methamphetamine and blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine at doses of 5.6-10.0 mg/kg. A lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate responding when given together with low 0.1-0.3 mg/kg doses of methamphetamine. CONCLUSIONS: The present data suggest that the NE system plays a modulatory role in the discriminative-stimulus effects of methamphetamine. These effects appear to be mediated through NE uptake sites and alpha-2 receptors, with limited involvement of alpha- receptors and beta receptors.

Adrenergic Agents↗
PubMed2006

Methamphetamine modulates gene expression patterns in monocyte derived mature dendritic cells: implications for HIV-1 pathogenesis.

BACKGROUND: The US is currently experiencing a grave epidemic of methamphetamine use as a recreational drug, and the risk for HIV-1 infection attributable to methamphetamine use continues to increase. Recent studies show a high prevalence of HIV infection among methamphetamine users. Dendritic cells (DCs) are potent antigen presenting cells that are the initial line of defense against HIV-1 infection. In addition, DCs also serve as reservoirs for HIV-1 and function at the interface between the adaptive and the innate immune systems, which recognize and internalize pathogens and subsequently activate T cells. Exposure to methamphetamine results in modulation of immune functional parameters that are necessary for host defense. Chronic methamphetamine use can cause psychiatric co-morbidity, neurological complications, and can alter normal biological processes and immune functions. Limited information is available on the mechanisms by which methamphetamine may influence immune function. This study explores the effect of methamphetamine on a specific array of genes that may modulate immune function. We hypothesize that methamphetamine treatment results in the immunomodulation of DC functions, leading to dysregulation of the immune system of the infected host. This suggests that methamphetamine has a role as a cofactor in the pathogenesis of HIV-1. METHODS: We used the high-throughput technology of gene microarray analysis to understand the molecular mechanisms underlying the genomic changes that alter normal biological processes when DCs are treated with methamphetamine. Additionally, we validated the results obtained from microarray experiments using a combination of quantitative real-time PCR and Western blot analysis. RESULTS: These data are the first evidence that methamphetamine modulates DC expression of several genes. Methamphetamine treatment alters categories of genes that are associated with chemokine regulation, cytokinesis, signal transduction mechanisms, apoptosis, and cell cycle regulation. This report focuses on a selected group of genes that are significantly modulated by methamphetamine treatment and that have been associated with HIV-1 pathogenesis. DISCUSSION/CONCLUSION: The purpose of this study was to identify genes that are unique and/or specific to the complex immunomodulatory mechanisms that are altered as a result of methamphetamine abuse in HIV-1-infected patients. These studies will help to identify the molecular mechanisms that underlie methamphetamine toxicity, and several functionally important classes of genes have emerged as targets in methamphetamine-mediated immunopathogenesis of HIV-1. Identification of novel DC-specific and methamphetamine-responsive genes that modulate several biological, molecular, and signal transduction functions may serve as methamphetamine- and/or HIV-1-specific drug targets.

Adult↗
PubMed2004

Alterations in vesicular dopamine uptake contribute to tolerance to the neurotoxic effects of methamphetamine.

Previous studies demonstrated that tolerance to the long-term neurotoxic effects of methamphetamine on dopamine neurons could be induced by pretreating with multiple injections of escalating doses of methamphetamine. The mechanism(s) underlying this tolerance phenomenon is unknown. Some recent studies suggested that aberrant vesicular monoamine transporter-2 (VMAT-2) and dopamine transporter function contribute to neurotoxic effects of methamphetamine. Hence, the purpose of this study was to explore the role of the VMAT-2 and dopamine transporter in the induction of tolerance to the longterm persistent dopaminergic deficits caused by methamphetamine. A second purpose was to investigate the potential role of hyperthermia and alterations in brain methamphetamine distribution in this tolerance. Results revealed that the methamphetamine pretreatment regimen attenuated both the acute methamphetamine-induced decrease in VMAT-2 function 2 h after the methamphetamine challenge administration and its resulting persistent dopamine deficits without attenuating the acute methamphetamine-induced decreases in dopamine transporter uptake. Furthermore, pretreatment with methamphetamine prior to a high-dose methamphetamine challenge administration also attenuated the acute methamphetamine-induced redistribution of VMAT-2 immunoreactivity within the nerve terminal. This protection was not due to alterations in concentration of methamphetamine in the brain because both the methamphetamine- and saline-pretreated rats had similar amounts of methamphetamine and amphetamine at 30 min to 2 h after the last methamphetamine challenge injection. In summary, these data are the first to demonstrate an association between the prevention of acute alterations in vesicular dopamine uptake and the development of tolerance to the neurotoxic effects of methamphetamine.

Adrenergic Uptake Inhibitors↗
PubMed1993

[Effects of antagonists of NMDA receptor on methamphetamine-induced decrease in the dopamine uptake sites in the rat striatum and on the behavioral sensitization].

In humans, repeated use of methamphetamine produces hypersensitivity to the psychotogenic effects of methamphetamine that persists for months to years after the discontinuation of methamphetamine administration. Methamphetamine-induced psychosis has been thought to be a useful experimental model for schizophrenia. A possible involvement of the glutamate system in the hypersensitivity including behavioral sensitization or reverse tolerance is recognized in an animal model for methamphetamine psychosis. We investigated the effects of antagonists of N-methyl-D-aspartate (NMDA) receptor on methamphetamine-induced decrease in dopamine (DA) uptake sites in the rat striatum and on the behavioral sensitization. Repeated administrations of escalating doses of methamphetamine (2.5, 5, 7.5, 10mg/kg s. c. x 2, every other day for a week) decreased DA uptake sites to about 75% of the control in the striatum assayed by binding with [3H]GBR 12935. Co-administration of MK-801, a non-competitive antagonist of NMDA receptor, and methamphetamine significantly prevented the methamphetamine-induced decrease in striatal [3H]GBR 12935 binding in a dose dependent manner. Administration of MK-801 alone did not affect the [3H]GBR 12935 binding. Furthermore, co-administration of SDZ EAA494, a competitive antagonist of NMDA receptor, and methamphetamine also prevented the methamphetamine-induced decrease in the striatal [3H]GBR 12935 binding in a dose dependent manner. In methamphetamine-pretreated rats, the methamphetamine challenge (2.5mg/kg) after a 7-day-drug-free period produced an initial elevation in locomotion lasting for 10-30 min which was followed by a precipitous drop in the locomotion activity to very low levels for approximately 50-70 min. During the period of reduced locomotor activity, methamphetamine-pretreated rats showed intense focused stereotyped behavior. In contrast, animals treated with both MK-801 and methamphetamine showed neither the progressive enhancement of the locomotor activity nor the stereotyped behavior induced by the drug. Pretreatment with MK-801 blocked the development of the methamphetamine-induced behavioral sensitization. These results suggest an involvement of excitatory amino acids in neurochemical effects of methamphetamine on the dopamine system in the striatum.

Animals↗
PubMed2003

Lack of effect of kappa-opioid receptor agonism on long-term methamphetamine-induced neurotoxicity in rats.

High-dose methamphetamine treatment induces long-term deficits in central monoamine systems. However, the mechanisms underlying these effects are unknown. Previous work has shown that the Kappa-opioid receptor agonist U-69593 [(+)-(5alpha,7alpha,8b)-(+)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl] benzeneacetamide] attenuates the neurotoxic effects of methamphetamine on extracellular dopamine levels in mice, suggesting that endogenous Kappa-opioid receptor ligands, such as dynorphin, may protect against methamphetamine-induced toxicity and play a role in mediating the long-term consequences of methamphetamine. To further examine the role that dynorphin systems play in methamphetamine-induced neurotoxicity, we administered to male rats a total of four injections of methamphetamine (7.5 mg/kg, s.c.), with a 2-h interval between each dose. Rats were pretreated with either the Kappa-agonist U-69593 (0.32 mg/kg, s.c.) or vehicle, 15 min prior to the first and third methamphetamine injection. Furthermore, cages containing the U-69593 + methamphetamine-treated rats were placed on heating pads for 30 min after the first U-69593 injection to prevent the drug from blocking methamphetamine-induced hyperthermia. Rats were sacrificed 7 days after treatment. Striatal dopamine and serotonin contents were decreased approximately 75% and 55%, respectively, in the methamphetamine-treated rats and approximately 88% and 65%, respectively, in rats receiving the U-69593 + methamphetamine combination. There was a approximately 20% mortality rate in the rats treated with methamphetamine compared to approximately 75% mortality rate in rats treated with both U-69593 and methamphetamine. A similar rate of mortality was observed when combining a different Kappa-agonist, U-50488 [trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamine], with methamphetamine. These data suggest that Kappa-agonists do not protect against methamphetamine-induced toxicity to monoamines in rats, and may potentiate mortality when co-administered with methamphetamine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2003

Metabolic profile of amphetamine and methamphetamine following administration of the drug famprofazone.

There are a several drugs that lead to the production of methamphetamine and/or amphetamine in the body which are subsequently excreted in the urine. These drugs raise obvious concerns when interpreting positive amphetamine drug testing results. Famprofazone is an analgesic found in a multi-ingredient medication (Gewodin) used for pain relief. Two Gewodin tablets (50 mg of famprofazone) were administered orally to healthy volunteers with no history of amphetamine, methamphetamine, or famprofazone use. Following administration, urine samples were collected ad lib for up to six days, and pH, specific gravity, and creatinine values were determined. In order to determine the quantitative excretion profile of amphetamine and methamphetamine, samples were extracted using liquid-liquid extraction, derivatized with heptafluorobutyric anhydride, and analyzed by gas chromatography-mass spectrometry (GC-MS). The ions monitored were 91, 118, 240 for amphetamine and 254, 210, 118 for methamphetamine. Amphetamine-d(6) and methamphetamine-d(11) were used as internal standards. Peak concentrations for amphetamine ranged from 148 to 2271 ng/mL and for methamphetamine 615 to 7361 ng/mL. Concentrations of both compounds peaked between 3 and 7 h post-dose. Amphetamine and methamphetamine could be detected (limit of detection = 5 ng/mL) at 121 and 143 h post-dose, respectively. Using a cutoff of 500 ng/mL, all subjects had individual urine samples that tested positive. One subject had 14 samples above the cutoff with the last positive being detected over 48 h post-dose. The profile of methamphetamine and amphetamine enantiomers was also determined using liquid-liquid extraction, derivatization with N-trifluoroacetyl-l-prolyl chloride and analysis by GC-MS. Data showed the famprofazone metabolites amphetamine and methamphetamine to be both d- and l-enantiomers. The proportion of l-methamphetamine exceeded that of its d-enantiomer from the first sample collected. Initially, the proportion was approximately 70% l-methamphetamine and this proportion increased over time. Amphetamine results showed l- and d-amphetamine were virtually the same in the early samples with the proportion of l-amphetamine increasing as time progressed. Forensic interpretation of drug testing results is a challenging critical part of forensic drug testing area because of the potential repercussions the results found may have on an individual's life. The finding of each enantiomers by itself differentiates famprofazone use from the most commonly abused form of methamphetamine and all medicinal methamphetamine available in the U.S., which is either d-methamphetamine (prescription medication) or l-methamphetamine (Vicks inhaler). Coupling this information with the concentrations of amphetamine and methamphetamine helps to determine the potential for use of this drug.

Administration, Oral↗
PubMed2005

Interactions of dopamine D1 and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions.

The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection. Two ambient temperature conditions were investigated: 24 and 33 degrees C. Methamphetamine administered at 24 degrees C induced hyperthermia and reduced striatal dopamine content by 73%; 0.5 mg/kg eticlopride or SCH-23390 administered in combination with methamphetamine at 24 degrees C attenuated methamphetamine-induced hyperthermia and prevented significant reductions in dopamine content. At 33 degrees C, eticlopride and SCH-23390 were ineffective in blocking methamphetamine-induced hyperthermia and dopamine content was reduced by 65% in the SCH-23390-methamphetamine group. By contrast, dopamine content was reduced by only 31% in the 33 degrees C eticlopride-methamphetamine group. Thus, although the eticlopride-methamphetamine treatment combination at 33 degrees C exhibited a hyperthermic response comparable to that seen with methamphetamine alone at 24 degrees C, reductions in dopamine content were attenuated in the combination group compared with methamphetamine alone at 24 degrees C. Serotonin changes showed similar attenuated reductions after SCH-23390 or eticlopride pretreatment at 24 degrees C in combination with methamphetamine, but this attenuation was absent at 33 degrees C. The dissociation of methamphetamine-induced striatal dopamine reduction and hyperthermia seen after eticlopride pretreatment suggests a dopamine D2 receptor mechanism in mediating methamphetamine-induced dopamine depletion. However this D2 mechanism does not apply to methamphetamine-induced striatal serotonin reductions.

Animals↗