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Elevation of fetal dopamine following exposure to methamphetamine in utero.

The effect of methamphetamine on fetal dopaminergic function was examined following treatment of pregnant mice twice daily with 40 mg/kg methamphetamine from either gestational day (GD) 7-13 or from GD 7-15. Dopamine levels were elevated in fetal GD 16 corpus striatum and rostral mesencephalon following both treatment regimens. This increase in fetal dopamine is consistent with our findings that exposure to methamphetamine in utero results in adult dopaminergic neurons which are more responsive in terms of methamphetamine induced release of the neurotransmitter and more sensitive to the neurotoxic effects of the drug.

Animals↗

Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine.

Gene targeting experiments, in which both alleles of the Nurr1 gene were deleted, have shown that this molecule plays an essential role in the development of midbrain dopaminergic neurons, as shown by the loss of dopaminergic markers and the neurotransmitter dopamine (DA) in the ventral mesencephalon of Nurr1 null mutant mice. Nurr1-deficient mice die within a few hours of birth. Herein, we investigated whether adult mice (12-15-month-old), heterozygous for the Nurr1 mutation (Nurr1(+/-)), show alterations in locomotor function and in the nigrostriatal dopaminergic system after acute exposure to methamphetamine. We first evaluated spontaneous and amphetamine-induced (5mg/kg) locomotor response of >12-month-old wildtype (Nurr1(+/+)) and Nurr1(+/-) mice. Both, spontaneous and methamphetamine-induced locomotor behavior was significantly increased in the Nurr1(+/-) animals as compared to Nurr1(+/+) mice. Striatal DA and DA metabolite levels were measured in untreated animals and methamphetamine-treated animals. No significant differences in striatal dopamine levels or its metabolites DOPAC and HVA were found in the Nurr1(+/-) as compared to Nurr1(+/+) mice in untreated or methamphetamine-treated animals. These data show that deletion of a single allele of the Nurr1 gene alters the locomotor activity of 12-15-month-old Nurr1(+/-) animals. While total dopamine levels were not altered in the striatum of Nurr1(+/-) mice, future studies will be necessary to determine if processes involved with the dynamics of DA release/clearance within the nigrostriatal system may be altered in Nurr1(+/-) mutant mice.

Animals↗

Methamphetamine toxicity prevented by activated charcoal in a mouse model.

STUDY OBJECTIVE: To determine the effectiveness of activated charcoal in preventing toxicity from oral methamphetamine HCI. DESIGN: Randomized, prospective, nonblinded, controlled animal study. SETTING: Animal care facility. PARTICIPANTS: CD-1 male mice. INTERVENTIONS: Mice were given 100 mg/kg methamphetamine HCI (lethal dose 60) in water by oral gavage. Within 1 minute of methamphetamine administration, mice received either 1 g/kg activated charcoal or an equivalent volume of water as control. MEASUREMENTS AND MAIN RESULTS: Mice were observed for time to onset of symptoms (piloerection, agitation, and tremor) and mortality at 1, 24, and 48 hours. Activated charcoal delayed onset of symptoms (5.53 +/- 1.25 minutes versus 4.27 +/- 1.22 minutes, P < .002) and decreased mortality compared to controls at 1 hour (1 of 20 versus 10 of 20, P < .003) and 24 hours (five of 20 versus 12 of 20, P < .05). There was no difference between groups in mortality at 48 hours. CONCLUSION: A single dose of activated charcoal given after oral methamphetamine delayed onset of toxicity and decreased early mortality in mice. There was no effect on overall mortality.

Animals↗

Inhibition by ginsenosides Rb1 and Rg1 of methamphetamine-induced hyperactivity, conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice.

The ginsenosides Rb1 and Rg1, the major components of ginseng saponin, inhibited not only methamphetamine-induced hyperactivity but also conditioned place preference (CPP) in mice following a single or repeated administration. Dopamine (DA) receptor supersensitivity, which developed in methamphetamine-induced CPP mice, was also inhibited by both Rb1 and Rg1. Therefore, the present results suggest that Rb1 and Rg1 may be the active components of ginseng saponin in the modulation of methamphetamine-induced dopaminergic behaviors such as hyperactivity and CPP, supporting our previous conclusion that ginseng saponin might modulate methamphetamine-induced dysfunction at both the pre- and postsynaptic DA receptors.

Adrenergic Agents↗

Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1 receptor-mediated action in mice: enhancement of the methamphetamine-induced abuse state.

Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been extensively evaluated for toxicity in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. However, little is known about its action on the CNS. In this report, we show that prenatal and neonatal exposure to BPA in mice leads to the enhancement of the dopamine D1 receptor-dependent rewarding effect induced by a psychostimulant methamphetamine. Furthermore, this treatment with BPA markedly enhanced hyperlocomotion and its sensitization induced by methamphetamine, which reflects extensive abuse associated with sociological and psychiatric problems. We also demonstrated that chronic exposure to BPA produced an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain, which is thought to be a critical site for the expression of rewarding effects by abuse drugs. Additionally, chronic BPA exposure produced a significant increase in levels of the dopamine D1 receptor mRNA in the whole brain. In contrast, no change in protein levels of methamphetamine-targeted proteins, dopamine transporter or the type 2 vesicle monoamine transporter in the brain was observed by prenatal and neonatal exposure to BPA. The present data provide the first evidence that prenatal and neonatal exposure to BPA can potentiate the central dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity of methamphetamine-induced pharmacological actions related to psychological dependence on psychostimulants.

Air Pollutants, Occupational↗

Differences between methamphetamine users and cocaine users in treatment.

To better understand the distinguishing characteristics of methamphetamine users versus cocaine users, we conducted a retrospective chart review of the 345 patients admitted to an outpatient stimulant treatment program during 1995--1997. Analyses revealed an increase in methamphetamine patients over the 3-year period, and that these patients were more likely than cocaine patients to be male, Caucasian, and gay or bisexual. Methamphetamine patients were also more likely to be HIV-positive, engage in behaviors such as using and sharing needles that place them at high risk for HIV transmission, have a psychiatric diagnosis, and be on psychiatric medications. The two populations did not differ in treatment adherence, as measured by clinic attendance, drug-free urines, and successful completion of treatment. These findings suggest that highly specialized substance abuse treatments for methamphetamine patients may not be needed. Resources may be directed toward addressing their medical and psychiatric diagnostic issues by providing ancillary services to stimulant treatment programs.

Adult↗

Pharmacological effects of methamphetamine and other stimulants via inhalation exposure.

The effects of methamphetamine-HCl, methcathinone-HCl, cocaine and ephedrine on locomotor stimulation were compared between inhalation exposure and i.v. injection in mice. Methamphetamine-HCl was readily volatilized upon heating at 300 degrees C in a glass pipe with only trace amounts of amphetamine being produced. The ED50 dose (9.4 and 6.5 mumol/kg for inhalation exposure and i.v. injections, respectively) and biodisposition of methamphetamine-HCl were similar for both routes of administration. Methcathinone-HCl and cocaine were readily volatilized. Their dose response profiles also appeared similar for both routes of administration. Ephedrine did not appear to be easily volatilized and was only effective in stimulating locomotor activity after i.v. administration. These findings indicate that inhalation exposure to methamphetamine-HCl, cocaine and methcathinone possess similar pharmacological characteristics as the i.v. route of administration. In particular, this model may have implications in predicting the pharmacological activity of various stimulants via the inhalation route of administration.

Administration, Inhalation↗

Exposure of mice to tobacco smoke attenuates the toxic effect of methamphetamine on dopamine systems.

Methamphetamine treatment of mice rapidly and severely depleted levels of dopamine and its metabolites, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus. Exposure of mice to cigarette smoke by means of nose-only breathing apparatus for 20 min twice daily over 3 days prior to drug treatment significantly attenuated the neurotoxicity of methamphetamine as judged by a lesser depletion of dopamine, DOPAC and HVA. The lesser effect of methamphetamine upon content of serotonin level was unaltered by prior inhalation of smoke. Results suggest a specific protective effect of inhaled tobacco smoke upon the effects of methamphetamine upon dopaminergic circuitry.

3,4-Dihydroxyphenylacetic Acid↗

Simple and sensitive high-performance liquid chromatographic determination of methamphetamines in human urine as derivatives of 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride, a new fluorescence derivatization reagent.

A simple, rapid and highly sensitive high-performance liquid chromatographic method for the determination of methamphetamine and its metabolites in human urine was developed. Without tedious pretreatment procedures, aliquots of methamphetamine spiked or abusers' urine samples were simply acidified, dried under a stream of N2 gas, and then derivatized with 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride in acetonitrile in the presence of traces of triethylamine. Five derivatives were isocratically separated within 33 min by an ODS column, and the effluent was monitored at 440 nm (lambda(ex), 330 nm). Using 1-phenylethylamine as an internal standard calibration curves were confirmed to be linear up to at least 2x10(-5) M in urine with correlation coefficients of 0.998-1.000, while the detection limits at S/N=3 were 0.6-5.2 fmol per 5-microl injection. The relative standard deviations (n=5) of inter- and intra-day variations were less than 8.9%. The correlation between the concentrations of methamphetamine and amphetamine in urine determined by the proposed method and another currently accepted one was satisfactory. The method was successfully applied to urine samples collected from methamphetamine addicts.

Adult↗

Direct determination of methamphetamine enantiomers in urine by liquid chromatography with a strong cation-exchange precolumn and phenyl-beta-cyclodextrin-bonded semi-microcolumn.

Methamphetamine enantiomers in drug abusers' urine were clearly separated by semi-microcolumn liquid chromatography using a column-switching system. The system consists of two separation processes: firstly, a strong cation-exchange precolumn removes neutral and anionic substances in urine, and then methamphetamine enantiomers trapped in the column are transferred to and separated in a phenyl-beta-cyclodextrin-bonded semi-microcolumn (Chiral Drug, 150 mm x 1.5 mm I.D.). (S)-(+)-Methamphetamine was baseline separated from (R)-(-)-methamphetamine within 25 min, directly from urine samples. The detection limit for both enantiomers was 0.1 microg/ml.

Cation Exchange Resins↗

Determination of chronic methamphetamine abuse by hair analysis.

A 30-year-old male truck driver, known to be asthmatic, was found dead at the roadside lying near his car. A nebulizer bottle of Berotec (fenoterol hydrobromide) was found near his hand. The anatomic cause of death was suspected to be asthma. Toxicological screening of urine using Triage demonstrated the presence of methamphetamine. The blood concentration of methamphetamine was 0.4 microg/ml, and fenoterol was not detected. Hair analysis clearly indicated chronic methamphetamine abuse and medium dependency during the 2 months before death. We conclude that death might have been induced by the interaction of fenoterol and methamphetamine.

Adult↗

Identification of impurities and statistical classification of methamphetamine tablets (Ya-Ba) seized in Thailand.

Impurity profiles of methamphetamine tablets seized in Thailand have been investigated. The samples are extracted with small amounts of ethyl acetate under alkaline condition and the extracts are analyzed by capillary gas chromatography. Nine compounds (1,2-dimethyl-3-phenylaziridine, ephedrine, methylephedrine, N-formylmethamphetamine, N-acetylmethamphetamine, N-formylephedrine, N-acetylephedrine, N,O-diacetylephedrie, methamphetamine dimer) are identified as impurities in methamphetamine tablet. Caffeine and ethyl vanillin are also detected as diluents and/or adulterants, and acetylcodeine monoacetylmorphine and diacetylmorphine are contained in many samples. In addition, trans-3,4-dimethyl-5-phenyl-2-oxazolidone is newly found as an impurity. For characterization and comparison of methamphetamine tablet exhibits, intensely and commonly detectable nine peaks are selected as the factor for multivariate analysis. The procedures reported here permit classification of 250 analyzed exhibits into five groups and characterization of classified groups.

Central Nervous System Stimulants↗

Methamphetamine-related stroke: four cases.

Amphetamine use in certain parts of the United States has risen dramatically. Methamphetamine, the most-common illicitly abused type of amphetamine, can be inhaled, injected intravenously, or smoked. It is a potent sympathomimetic that may lead to vascular events including myocardial infarction and stroke. Because of the demographics of drug use, these potentially devastating events usually occur in relatively young patients. The pathophysiology of stroke related to amphetamine use is multifactorial. Elevation in blood pressure, vasculitis, or other vascular toxicity are postulated as major mechanisms. Four cases of stroke associated with the use of methamphetamine, all occurring in patients ranging in age from 29-45 years, are described. Methamphetamine use appears to be a risk factor for the development of stroke. The rise in methamphetamine use will undoubtedly result in increased Emergency Department admissions with clinical presentations very similar to those of cocaine intoxication.

Adult↗

Sexual HIV risk among gay and bisexual male methamphetamine abusers.

The current report examined HIV-related high risk sexual behaviors among a small sample of gay and bisexual male methamphetamine abusers in Los Angeles. Participants were 16 methamphetamine-abusing or -dependent gay or bisexual males who participated in a treatment demonstration project between 1989 and 1993. All participants completed the NIDA/WAVE survey, a detailed inventory of HIV-related risk behaviors. Findings indicate a strong connection between methamphetamine abuse and high-risk sexual behavior. For the 12 months prior to treatment 62.5% of participants reported having anal insertive sex without a condom, and 56.3% reported having sex with someone who had HIV. Drug use before or during sex, measured on a 5-point Likert scale, was frequent (M = 4.27, SD = 0.7). Implications for treatment of gay and bisexual male methamphetamine abusers and prevention of HIV among this population are discussed.

Behavior Therapy↗

A controlled trial of imipramine for the treatment of methamphetamine dependence.

At the Drug Detoxification Program of the Haight Ashbury Free Clinics, we conducted a randomized clinical trial of imipramine in the treatment of methamphetamine dependence. The purposes of the trial were to test the efficacy of imipramine as a treatment for methamphetamine dependence and to establish the feasibility of conducting a controlled clinical trial at the Clinic. Thirty-two subjects were randomly assigned to receive either 10 or 150 mg/day of imiprine for 180 days. Imipramine 10 mg/day was the control. Subjects received intensive counseling. Retention in treatment was significantly longer for subjects who were treated with 150 mg of imipramine compared to control (median days: 33.0 vs. 10.5). There were no consistent differences in percent of urine samples positive for methamphetamine, Beck Depression Inventory scores, or craving. Determination of the full extent of imipramine's utility in the treatment of methamphetamine dependence awaits a larger trial.

Adult↗

Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects.

Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions. Studies of drug craving, reward association, and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence. Here, a functional magnetic resonance imaging (fMRI) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas. This investigation tested the behavioral hypothesis that methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection. It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex. Ten methamphetamine-dependent subjects were compared with ten age- and education-matched controls performing a two-choice prediction task and a two-choice response task during a fMRI session. Response bias, latency, and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained. First, methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects. Second, methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex (BA 9) and failed to activate ventromedial cortex (BA 10,11) during the two-choice prediction task compared with the two-choice response task. These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction.

Adult↗

Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons.

Both HIV infection and methamphetamine dependence can be associated with brain dysfunction. Little is known, however, about the cognitive effects of concurrent HIV infection and methamphetamine dependence. The present study included 200 participants in 4 groups: HIV infected/methamphetamine dependent (HIV+/METH+), HIV negative/methamphetamine dependent (HIV-/METH+), HIV infected/methamphetamine nondependent (HIV+/METH-), and HIV negative/methamphetamine nondependent (HIV-/METH-). Study groups were comparable for age, education, and ethnicity, although the HIV-/METH- group had significantly more females. A comprehensive, demographically corrected neuropsychological battery was administered yielding a global performance score and scores for seven neurobehavioral domains. Rates of neuropsychological impairment were determined by cutoff scores derived from performances of a separate control group and validated with larger samples of HIV+ and HIV- participants from an independent cohort. Rates of global neuropsychological impairment were higher in the HIV+/METH+ (58%), HIV-/METH+ (40%) and HIV+/METH- (38%) groups compared to the HIV-/METH- (18%) group. Nonparametric analyses revealed a significant monotonic trend for global cognitive status across groups, with least impairment in the control group and highest prevalence of impairment in the group with concurrent HIV infection and methamphetamine dependence. The results indicate that HIV infection and methamphetamine dependence are each associated with neuropsychological deficits, and suggest that these factors in combination are associated with additive deleterious cognitive effects. This additivity may reflect common pathways to neural injury involving both cytotoxic and apoptotic mechanisms.

Adult↗

Immunological consequences of methamphetamine protein glycation.

The drug of abuse methamphetamine has been found to participate in the aberrant glycation of proteins. The importance of this chemical process has been shown wherein mouse albumin was readily modified with methamphetamine, and injection of this protein into mice yields a significant immune response, even in the absence of adjuvants. Competition experiments revealed that although methamphetamine binds weakly to the elicited antibodies, the primary epitope is composed of both the methamphetamine moiety and glucose-derived cross-linking region. Implications of this phenonomenon in the context of drug addiction are discussed.

Central Nervous System Stimulants↗