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PubMed2004

Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats.

Chlormethiazole is a positive modulator of gamma-aminobutyric acid (GABA)(A) receptors used in the treatment of alcohol withdrawal seizures. It recently has been reported to attenuate seizures engendered by acute and repeated exposure to cocaine in mice and neurotoxic effects of methamphetamine in rats. The aim of the present study was to determine whether chlormethiazole could also attenuate the discriminative stimulus effects of methamphetamine, a behavior predictive of the subjective effects of methamphetamine in humans. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine [intraperitoneally (i.p.)] from saline under a fixed-ratio schedule of food delivery, the ability of chlormethiazole (i.p.) to (1) substitute for methamphetamine, (2) antagonize effects of methamphetamine and to (3) shift the methamphetamine dose-effect function was investigated. Chlormethiazole (18 and 30 mg/kg, i.p.) partially substituted for the discriminative stimulus effects of methamphetamine when administered alone (maximum group average, 60% responses on the methamphetamine-appropriate lever). Chlormethiazole did not attenuate effects of methamphetamine when coadministered with the training dose of methamphetamine. Instead, chlormethiazole potentiated the discriminative stimulus effects of methamphetamine as demonstrated by a significant (about 2.5-fold) leftward and upward shift in the methamphetamine dose-effect function in the presence of chlormethiazole (10 mg/kg). In conclusion, the present findings suggest that there is a behavioral interaction between methamphetamine and chlormethiazole. The profile of this interaction is qualitatively different from that of methamphetamine and classical GABAergic drugs (i.e., benzodiazepines and barbiturates), suggesting the involvement of non-GABAergic mechanisms in the effects produced by chlormethiazole.

Animals↗

PubMed2004

Chronic stress augments the long-term and acute effects of methamphetamine.

There is growing evidence that exposure to stress alters the acute effects of abused drugs on the CNS. However, it is not known whether stress augments the longer-term neurotoxic effects of psychostimulant drugs, such as methamphetamine. Methamphetamine at high doses decreases forebrain dopamine concentrations. The current study tested the hypothesis that 10 days of unpredictable stress augmented striatal dopamine depletions 7 days following four injections of either 7.5 or 10 mg/kg methamphetamine (1 injection every 2 h). Furthermore, to assess the effects of chronic stress on immediate responses to methamphetamine, extracellular striatal dopamine and methamphetamine concentrations, and rectal temperature were monitored during the methamphetamine injection regimen. Seven days following either a 7.5 mg/kg or 10 mg/kg methamphetamine injection regimen, male rats exposed to unpredictable stress showed greater depletions in striatal dopamine tissue content compared with non-stressed controls injected with methamphetamine. Stressed rats had increased hyperthermic responses and dopamine efflux in the striatum during the methamphetamine injections when compared with non-stressed control rats. Moreover, stressed rats had an increased mortality rate (33%) compared with non-stressed controls (16.7%) following four injections of 10 mg/kg methamphetamine. The enhanced acute and longer-term effects of methamphetamine in stressed rats was not due to a greater concentrations of methamphetamine in the striatum, as extracellular levels of methamphetamine during the injection regimen did not differ between the two groups. In summary, exposure to 10 days of chronic unpredictable stress augments longer-term depletions of dopamine in the striatum, as well as acute methamphetamine-induced hyperthermia and extracellular dopamine levels. These findings suggest that chronic stress increases the responsiveness of the brain to the acute pharmacological effects of methamphetamine and enhances the vulnerability of the brain to the neurotoxic effects of psychostimulants.

Amphetamine-Related Disorders↗

PubMed2000

Modulation of the neurotoxic effects of methamphetamine by the selective kappa-opioid receptor agonist U69593.

Kappa-opioid receptor agonists prevent alterations in dopamine neurotransmission that occur in response to repeated cocaine administration. The present microdialysis study examined whether administration of the selective kappa-opioid receptor agonist U69593 with methamphetamine prevents alterations in dopamine levels produced by neurotoxic doses of methamphetamine. Swiss Webster mice were injected intraperitoneally with methamphetamine (10.0 mg/kg) or saline, four times in 1 day, at 2-h intervals. Prior to the first and third injection, they received U69593 (0.32 mg/kg s.c.) or vehicle. Microdialysis was conducted 3, 7, or 21 days later. Basal and K+-evoked (60 and 100 mM) dopamine overflow were reduced 3 days after methamphetamine administration. These effects were long-lasting in that they were still apparent 7 and 21 days after methamphetamine treatment. Intrastriatal (5.0 and 50 microM) or systemic (1.0-10.0 mg/kg) administration of methamphetamine increased dopamine concentrations in control animals. In mice preexposed to methamphetamine, methamphetamine-evoked dopamine overflow was reduced. In animals that had received methamphetamine with U69593, basal dopamine levels did not differ from those of vehicle-treated controls. U69593 treatment attenuated the decrease in K+-evoked dopamine produced by prior methamphetamine exposure. The reduction in methamphetamine-evoked dopamine levels was also attenuated. The administration of U69593 alone did not modify basal or stimulus-evoked dopamine levels. These data demonstrate that repeated methamphetamine administration reduces presynaptic dopamine neuronal function in mouse striatum and that co-administration of a selective kappa-opioid receptor agonist with methamphetamine attenuates these effects. U69593 treatment did not modify the hyperthermic effects of methamphetamine, indicating that this kappa-opioid receptor agonist selectively attenuates methamphetamine-induced alterations in dopamine neurotransmission.

Analgesics↗

PubMed2005

Safety of intravenous methamphetamine administration during treatment with bupropion.

RATIONALE: Methamphetamine dependence is a growing problem for which no medication treatments have proven effective. OBJECTIVES: We evaluated bupropion, an antidepressant with beneficial effects for the treatment of nicotine dependence, in patients with methamphetamine dependence, to assess the safety and tolerability of methamphetamine administration during bupropion treatment. METHODS: Twenty-six participants entered the study and 20 completed the protocol. Participants received intravenous methamphetamine (0, 15, and 30 mg) before and after randomization to twice-daily bupropion (150 mg SR) or matched placebo. Dependent measures included cardiovascular effects of methamphetamine, methamphetamine and amphetamine pharmacokinetics, and peak and trough plasma concentrations of bupropion and its metabolites. RESULTS: Bupropion treatment was well tolerated, with bupropion- and placebo-treated groups reporting similar rates of adverse events. Methamphetamine administration was associated with expected stimulant cardiovascular effects, and these were not accentuated by bupropion treatment. Instead, there was a trend for bupropion to reduce methamphetamine-associated increases in blood pressure and a statistically significant reduction in methamphetamine-associated increases in heart rate. Pharmacokinetic analysis revealed that bupropion treatment reduced the plasma clearance of methamphetamine and also reduced the appearance of amphetamine in the plasma. Methamphetamine administration did not alter the peak and trough plasma concentrations of bupropion or its metabolites. CONCLUSIONS: Methamphetamine administration was well tolerated during bupropion treatment. There was no evidence of additive cardiovascular effects when the drugs were coadministered. This study provides initial evidence for the safety of prescribing bupropion for the treatment of methamphetamine abuse and dependence. The impact of bupropion treatment in patients who abuse larger doses of methamphetamine remains undetermined.

Adolescent↗

PubMed2006

Methamphetamine detection in maternal and neonatal hair: implications for fetal safety.

BACKGROUND: Methamphetamine misuse is a serious health problem of epidemic proportions. Use of this drug, particularly during pregnancy, is difficult to ascertain. Sparse information is available on gestational exposure. OBJECTIVES: To quantify methamphetamine accumulation in hair, identify the use of methamphetamine with other drugs of abuse and characterise correlations between concentrations of methamphetamine in maternal and neonatal hair. SUBJECTS AND METHODS: Motherisk laboratory at the Hospital for Sick Children routinely carries out analysis of methamphetamine in hair. Mothers and infants with positive results for methamphetamine in hair were identified. Drugs present in hair were analysed by ELISA and positive results were confirmed by gas chromatgraphy/mass spectrometry. RESULTS: 396 people positive for methamphetamine in their hair were identified from our database. Almost 85% of them were positive for at least one other drug of abuse, mostly cocaine. Eleven mother-baby pairs with hair positive for methamphetamine were identified. Methamphetamine levels in hair ranged between 0.13 and 51.97 ng/mg in the mothers and between 0 and 22.73 ng/mg in the neonates. Methamphetamine levels in mothers and neonates correlated significantly. One (9%) neonate was negative for methamphetamine even though the mother was positive. CONCLUSION: To our knowledge, this is the first report on fetal exposure to methamphetamine during pregnancy, showing transplacental transfer of the drug, with accumulation in fetal hair. Hair measurement for methamphetamine in neonates is a useful screening method to detect intra-uterine exposure to the drug. The data also indicate that positive exposure to methamphetamine strongly suggests that the person is a polydrug user, which may have important implications for fetal safety.

Adolescent↗

PubMed1999

Does nicotine modify the psychotoxic effect of methamphetamine? Assessment in terms of locomotor sensitization in mice.

In this study, effects of nicotine on locomotor sensitization to methamphetamine in mice were investigated to assess whether nicotine modified induction and expression of psychotoxic action of methamphetamine. Although nicotine (0.03-1 mg/kg s.c.) had no effect at first administration, 5-time nicotine administrations at 3-day intervals progressively developed a significant locomotor stimulant effect, and caused an enhanced sensitivity (cross-sensitization) to methamphetamine (2 mg/kg s.c.). Five-time administrations of methamphetamine (2 mg/kg) at 3-day intervals produced not only a locomotor sensitization to methamphetamine itself, but also a cross-sensitization to nicotine (0.1-1 mg/kg). Nicotine (0.03-1 mg/kg) did not affect the locomotor stimulant effect of methamphetamine (2 mg/kg) in the drug-naive mice. However, nicotine acted dose-dependently to reduce the progressive enhancement of the locomotor stimulant effect of methamphetamine during 5-time repeated administrations. Mice treated with coadministration of methamphetamine with nicotine (1 mg/kg) showed less sensitization to methamphetamine than mice treated with methamphetamine alone. In addition, nicotine (1 mg/kg) inhibited the locomotor stimulant effect of methamphetamine in mice sensitized to methamphetamine. These results suggest that methamphetamine and nicotine produce a symmetrical cross-sensitization, although nicotine may act to inhibit the induction and expression of locomotor sensitization to methamphetamine in mice.

Animals↗

PubMed1999

Effects of dopamine and serotonin-releasing agents on methamphetamine discrimination and self-administration in rats.

To analyze the involvement of dopamine (DA) and serotonin (5-HT) release in the stimulus properties of methamphetamine, two amphetamine analogs that selectively release either brain DA (phentermine) or 5-HT (fenfluramine) were tested for their ability to substitute for methamphetamine in rats discriminating methamphetamine (1.0 mg/kg) from saline. They were subsequently tested for their ability to alter IV methamphetamine (0.06 mg/kg per injection) self-administration in the same species when given as a pretreatment. The DA releaser phentermine, like methamphetamine itself, decreased methamphetamine self-administration (to 70% of baseline responding), but only at a dose of 3.0 mg/kg that fully generalized to the methamphetamine stimulus in the discrimination study. The 5-HT releaser fenfluramine attenuated methamphetamine self-administration to a much larger extent than phentermine (to 37% of baseline responding) at a dose of 1.8 mg/kg that did not generalize to methamphetamine and did not decrease rate of responding in the discrimination study. Tolerance developed to the inhibitory effect of 1.8 mg/kg fenfluramine on methamphetamine self-administration when it was given repeatedly over four consecutive daily sessions. The fenfluramine-induced decrease in methamphetamine self-administration was also attenuated when it was given together with the small 1.0 mg/kg dose of phentermine. These results suggest that DA release plays a dominant role in the discriminative stimulus effects of methamphetamine. However, stimulation of 5-HT release can strongly modify methamphetamine self-administration.

Animals↗

PubMed1995

Mechanistic studies on the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine.

Recent studies have shown that methamphetamine is capable of potentiating the hepatotoxicity of carbon tetrachloride in mice. In the present study, it was found that this potentiation is sensitive to changes in the timing of the methamphetamine dose relative to the administration of carbon tetrachloride. Potentiation of hepatotoxicity, measured using serum alanine aminotransferase (ALT) activity, was observed only if the dose of methamphetamine (15 mg/kg, i.p.) was given with, or 3 h after, the carbon tetrachloride dose (0.005 ml/kg, i.p.). No increase in carbon tetrachloride hepatotoxicity was evident when methamphetamine was administered 3 h before the carbon tetrachloride dose, or when given 6 or more hours after carbon tetrachloride. Increased covalent binding of carbon tetrachloride to proteins and lipids, shown previously to occur when methamphetamine and carbon tetrachloride are administered together, was not observed when methamphetamine was administered 3 h after the carbon tetrachloride dose and could not, therefore, account for the increased toxicity resulting from this treatment regimen. Pretreatment with the Kupffer cell inhibitor gadolinium chloride (10 mg/kg, i.v.) significantly diminished the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine, suggesting that potentiation by methamphetamine involves, at least in part, a stimulation of Kupffer cells. Mice administered a methamphetamine pretreatment regimen known to induce behavioral sensitization displayed an enhanced potentiation of carbon tetrachloride hepatotoxicity, i.e. the extent of potentiation by methamphetamine was increased and the methamphetamine dose required for potentiation was diminished. Mice pretreated with a methamphetamine sensitization regimen were also found to be more responsive to the effects of morphine to enhance carbon tetrachloride hepatotoxicity. These observations suggest that there are important CNS, as well as hepatic, components in the potentiation of carbon tetrachloride-induced liver injury by methamphetamine and perhaps other drugs.

Alanine Transaminase↗

PubMed2003

Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats.

Exposure to methamphetamine causes behavioral sensitization in experimental animals. However, the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic properties of methamphetamine in rats behaviorally sensitized to methamphetamine following its repeated administration (6 mg/kg, i.p., once a day for 5 days followed by a 21-day drug abstinence period). In the sensitized rats, methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly enhanced, suggesting the successful establishment of behavioral sensitization to methamphetamine. Significant increases in the concentrations of methamphetamine in plasma and brain dialysate, as well as the delayed disappearance of methamphetamine from plasma, were observed in the sensitized rats after intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma concentration ratio (Kp) of methamphetamine in lung and heart decreased in the sensitized rats. The renal excretion of methamphetamine, which is sensitive to several cations, was also decreased in the sensitized rats. Moreover, in the sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was decreased in kidney, brain and heart as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these results suggest that the behavioral outcome of sensitization to methamphetamine might, in part, be due to the increased levels of methamphetamine in plasma and brain extracellular areas, as well as an altered tissue distribution of methamphetamine associated with changes in the cation transport system.

Animals↗

PubMedDate not supplied

Methamphetamine-associated burn injuries: a retrospective analysis.

Methamphetamine production and use has increased dramatically during the past 10 years. Methamphetamine production requires combining hazardous and volatile chemicals that expose the manufacturer to burn injuries from explosions and chemical spills. We sought to review the epidemiology of burn injuries in a rural burn center secondary to the use of amphetamine or methamphetamine and/or the manufacture of methamphetamine. Review of the records of 507 patients who were admitted to our burn unit from December 1, 1998, to December 31, 2001, revealed 34 patients who were involved in the use of amphetamines or methamphetamines and/or the manufacture of methamphetamine. Thirty-one patients tested positive for either amphetamine (n = 2) or methamphetamine (n = 29) on routine admission urine drug screens. Twenty of these patients were involved in the manufacture of methamphetamines. Three additional patients were identified as methamphetamine manufacturers but tested negative for the use of methamphetamines. The mean age of the study population was 31.88 +/- 7.65 years, with a male:female ratio of 10.3:1. The average burn size was 18.86 +/- 20.72, with the majority secondary to flame (n = 26). Patient burn admission histories were vague, and the patient's involvement in the manufacture of methamphetamine was often only later confirmed by media, the fire marshal, family members, or the patient. Fifteen patients showed the usual withdrawal pattern of agitation and hypersomnolence, with seven patients requiring detoxification with benzodiazepines. Two were admitted acutely to the psychiatric ward for uncontrollable agitation. Eighteen patients were offered chemical dependency treatment, and two completed therapy. There was one mortality. The mean cost per person was US 77,580 dollars (range, US 112 dollars - US 426,386 dollars). The increasing use of and manufacture of methamphetamine presents new challenges for the burn team because these patients can become violent and frequently need assistance with detoxification. Routine drug screens are mandatory in identifying methamphetamine use to alert burn unit personnel to particular management problems and target individuals who may be receptive to drug rehabilitation.

Adult↗

PubMed2005

Methamphetamine users in sustained abstinence: a proton magnetic resonance spectroscopy study.

BACKGROUND: Abnormal patterns of metabolite levels have been detected by magnetic resonance spectroscopy in frontostriatal regions of individuals meeting DSM-IV criteria for methamphetamine dependence, but less is known about the effects of drug abstinence on metabolite levels. OBJECTIVE: To assess the effects of long-term methamphetamine use and drug abstinence on brain metabolite levels. DESIGN: To assess regional specific metabolite levels using magnetic resonance spectroscopy imaging techniques in 2 groups of currently abstinent methamphetamine users: methamphetamine users who recently initiated abstinence and methamphetamine users who had initiated abstinence more than 1 year prior to study. SETTING: Participants were recruited from outpatient substance abuse treatment centers. PARTICIPANTS: Eight methamphetamine users with sustained abstinence (1 year to 5 years) and 16 recently abstinent methamphetamine users (1 month to 6 months) were compared with 13 healthy, non-substance-using controls. MAIN OUTCOME MEASURES: Magnetic resonance spectroscopy measures of N-acetylaspartate-creatine and phosphocreatine (NAA/Cr), choline-creatine and phosphocreatine (Cho/Cr), and choline-N-acetylaspartate (Cho/NAA) ratios were obtained in the anterior cingulate cortex as well as in the primary visual cortex, which served as a control region. RESULTS: The absolute values of Cr did not differ between controls and methamphetamine users. Methamphetamine users had abnormally low NAA/Cr levels within the anterior cingulate cortex, regardless of the time spent abstinent (F(2,34) = 12.61; P<.001). No NAA/Cr group differences were observed in the primary visual cortex (F(2,33) = 0.29; P = .75). The Cho/NAA values for the anterior cingulate cortex were abnormally high in the methamphetamine users who recently initiated abstinence but followed a normal pattern in the methamphetamine users who had initiated abstinence more than 1 year prior to study (F(2,34) = 7.31; P = .002). CONCLUSIONS: The relative choline normalization across periods of abstinence suggests that following cessation of methamphetamine use, adaptive changes occur, which might contribute to some degree of normalization of neuronal structure and function in the anterior cingulum. More research is needed to elucidate the mechanisms underlying these adaptive changes.

Adult↗

PubMed2001

Effects of repeated oral methamphetamine administration in humans.

RATIONALE: Although methamphetamine use has increased over the past several years, few studies have evaluated the effects of repeated methamphetamine administration in humans. OBJECTIVES: Because methamphetamine is often taken in a pattern of repeated use followed by a period of abstinence, the present study sought to evaluate the effects of repeated methamphetamine administration in humans. The hypothesis was that tolerance would develop to methamphetamine's effects. METHODS: Seven normal, healthy volunteers participated in a 15-day residential study. Participants completed subjective-effects questionnaires and psychomotor performance tasks repeatedly throughout the experimental day. Oral methamphetamine (5, 10 mg BID) was administered on days 4-6 and 10-12; placebo was administered on all other study days. RESULTS: Relative to placebo baseline, only two "positive" subjective ratings ("I feel a good drug effect" and "I feel high") were significantly elevated, and only on the 1st day of methamphetamine administration. In contrast, numerous "negative" ratings, including "I feel..." "a bad drug effect," "dizzy," and "flu-like symptoms" were elevated on the 3rd day of methamphetamine administration. Total caloric intake decreased and sleep was disrupted after methamphetamine administration, relative to baseline. CONCLUSIONS: The pattern of methamphetamine's positive subjective effects were altered with chronic administration such that tolerance, or a decreased effect, occurred after repeated administration. In contrast, methamphetamine's negative subjective effects increased over days. These results suggest that in this population of normal volunteers, the abuse liability of oral methamphetamine is relatively low.

Adult↗

PubMed2001

Methamphetamine self-administration by humans.

RATIONALE: Methamphetamine abuse has become increasingly problematic. Yet, the reinforcing effects of methamphetamine in humans have not been systematically evaluated. OBJECTIVE: To characterize methamphetamine's reinforcing effects in human research participants under controlled laboratory conditions. METHODS: Eight healthy research volunteers (one female, seven males) completed this 20-day residential study. On days 1, 5, 9, 13 and 17, at 1000 hours, participants received the "sample" oral dose of methamphetamine (0, 5, 10 mg) that was available for the next 3 days and they also received an alternative reinforcer, a $1 voucher (redeemable for cash at study's end). Over a 3-day period, volunteers participated in an eight-trial choice procedure, during which they had the opportunity to self-administer the dose of methamphetamine they most recently sampled or to receive the $1 voucher. RESULTS: Participants' choice to self-administer methamphetamine significantly increased when active methamphetamine (5 mg and 10 mg) was available compared to placebo. No difference of choice was noted between low-dose and high-dose methamphetamine. However, the sampled 10 mg methamphetamine dose significantly increased several "positive" subjective ratings including "High," "Good Drug Effect," and "Stimulated," whereas the sampled 5 mg methamphetamine dose did not. Both active methamphetamine doses caused significant reductions in daily total caloric intake, relative to the respective placebo conditions. CONCLUSION: These data demonstrate that oral methamphetamine is a positive reinforcer in humans.

Adult↗

PubMed1995

Methamphetamine and ethanol interactions in humans.

OBJECTIVE: Methamphetamine and ethanol are commonly used together. We examined the effects of intravenous methamphetamine (30 mg), oral ethanol (1 gm/kg), and the combination of methamphetamine (30 mg) and ethanol (1 gm/kg). METHODS: Eight methamphetamine and ethanol users were studied in a double-blind, double-placebo, within-subject, balanced Latin-square design. Ethanol was administered in six drinks over 30 minutes. Methamphetamine was injected 60 minutes after the first drink was begun. Cardiovascular, subjective, and neuropsychologic effects of the drug combinations were measured for 6 hours. Methamphetamine and amphetamine in plasma and urine were measured by capillary gas chromatography for 48 hours. Data were analyzed by repeated-measures ANOVA. RESULTS: Compared with methamphetamine alone, the combination increased heart rate but decreased systolic blood pressure. The net cardiovascular effect was an increase in rate pressure product, an index of cardiac work and myocardial oxygen consumption. The combination diminished the subjective effects of ethanol while not affecting the subjective effects of methamphetamine. Methamphetamine pharmacokinetics were not altered by the concurrent administration of ethanol, with the exception of lowering the apparent volume of distribution at steady state for methamphetamine. CONCLUSIONS: As a potent sympathomimetic drug with alpha-agonist-like effects, methamphetamine increased systolic blood pressure, with minimal change in heart rate. The concurrent administration of methamphetamine and ethanol increased cardiac work, which could produce more adverse cardiovascular effects than either drug taken alone. The increased perceived global intoxication may explain the popularity of this drug combination.

Administration, Oral↗

PubMed1995

Nitric oxide synthase inhibitors block behavioral sensitization to methamphetamine in mice.

Repeated administration of methamphetamine (1.0 mg/kg) once daily for 7 consecutive days resulted in an augmentation of the locomotor-activating effect of methamphetamine (0.5 mg/kg) challenged 72 h after the last injection. Administration of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (10 and 30 mg/kg), before daily methamphetamine injections dose dependently prevented the development of behavioral sensitization to subsequent methamphetamine challenge. The mice given another NO synthase inhibitor, NG-nitro-L-arginine methyl ester (100 mg/kg), before daily methamphetamine injections showed significantly less locomotor activity in response to 0.5 mg/kg methamphetamine challenge than the mice given daily methamphetamine alone. Such effects were not observed when the inactive isomer, NG-nitro-D-arginine methyl ester (100 mg/kg), was administered daily prior to methamphetamine. Both NO synthase inhibitors exerted the acute effect to reduce spontaneous and methamphetamine-stimulated locomotor activity, while neither spontaneous locomotion nor hyperlocomotion in response to 1.0 mg/kg methamphetamine was altered 72 h after repeated administration of NG-nitro-L-arginine (30 mg/kg) or NG-nitro-L-arginine methyl ester (100 mg/kg) alone once daily for 7 days. On the other hand, pretreatment with the NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate), at 0.2 mg/kg also suppressed the development of sensitization to the locomotor-activating effect of methamphetamine. These findings suggest that NO formation possibly mediated by NMDA receptors is involved in mechanisms underlying the development of behavioral sensitization to methamphetamine.

Amino Acid Oxidoreductases↗

PubMed2006

Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals.

Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study, 10 methamphetamine-dependent individuals participated in a double-blind, placebo-controlled, cross-over design, with oral doses of topiramate (0, 100, and 200 mg) administered as a pretreatment before intravenous doses of methamphetamine (0, 15, and 30 mg). The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. Methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.

Adult↗

PubMed2003

Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats.

Our studies examined pharmacokinetic mechanisms involved in high-affinity (K(d) approximately 11 nM) monoclonal antibody-based antagonism of (+)-methamphetamine-induced locomotor effects. Male rats received (+)-methamphetamine (0.3, 1, or 3 mg/kg i.v.) followed 30 min later by saline or anti-(+)-methamphetamine monoclonal antibody. All groups received a constant dose of monoclonal antibody that was equimolar in binding sites to the body burden of a 1 mg/kg i.v. (+)-methamphetamine dose 30 min after administration. The monoclonal antibody antagonized locomotor effects due to 0.3 and 1 mg/kg (+)-methamphetamine. In contrast, monoclonal antibody treatment increased locomotor activity due to 3 mg/kg (+)-methamphetamine. We also investigated the serum and brain pharmacokinetics of (+)-methamphetamine without and with the monoclonal antibody. Rats received (+)-methamphetamine (1 mg/kg i.v.) followed by saline or monoclonal antibody treatment at 30 min. The monoclonal antibody significantly increased serum methamphetamine concentrations and significantly decreased brain methamphetamine concentrations. These data indicate that anti-(+)-methamphetamine monoclonal antibody-induced pharmacodynamics are complex, but are related to time-dependent changes in (+)-methamphetamine brain distribution.

Amphetamine↗

PubMed1999

Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses.

We recently demonstrated that pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.

3,4-Dihydroxyphenylacetic Acid↗