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PubMed1995

Contrasting effects on methamphetamine sensitization of ceruletide, a cholecystokinin-like decapeptide, and haloperidol.

Ceruletide, a cholecystokinin-like decapeptide, and haloperidol show neuroleptic actions through inhibition of dopamine release and blockade of dopamine receptors, respectively. In this study, the effects of both drugs on methamphetamine sensitization were assessed by means of ambulation in mice. The enhancement in ambulation increase caused by five repeated administrations of methamphetamine (2 mg/kg, SC) at 3- to 4-day intervals was dose-dependently reduced when it was administered simultaneously with ceruletide (0.01-0.1 mg/kg, SC) or haloperidol (0.03-0.3 mg/kg, SC). However, only haloperidol could inhibit the induction of methamphetamine sensitization as assessed by challenge with methamphetamine alone. Post-treatment with ceruletide (0.03 mg/kg) 3 h after each methamphetamine accelerated, whereas such post-treatment with ceruletide (0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) delayed, the induction of methamphetamine sensitization. On the other hand, mice given five pretreatments with ceruletide (0.01-0.1 mg/kg) or haloperidol (0.03-0.3 mg/kg) at 3- to 4-day intervals did not exhibit any significant change in the sensitivity to methamphetamine. The present results suggest that, in contrast to the dose-dependent inhibition of methamphetamine sensitization in the simultaneous administration and post-treatment schedules, although both drugs can antagonize the acute stimulant effect of methamphetamine.

Animals↗

PubMed2002

Effects of the NMDA antagonist memantine on human methamphetamine discrimination.

RATIONALE: The discriminative stimulus effects of N-methyl- D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. OBJECTIVE: This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. METHODS: Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). RESULTS: Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. CONCLUSION: These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects.

Adult↗

PubMed2004

Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls.

RATIONALE: Sigma(1) receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants. We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D(2) autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Involvement of Sig-1R in the self-administration of psychostimulants, however, has never been reported. OBJECTIVES: This study examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine. METHODS: Three groups of rats were tested simultaneously 5 days per week, for 5 weeks (25 daily sessions). Two groups served as yoked controls and passively received an injection of either 0.1 mg/kg methamphetamine or saline (not contingent on responding) each time a response-contingent injection of 0.1 mg/kg methamphetamine was actively self-administered by the first group of rats. Protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively. RESULTS: There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats. CONCLUSIONS: Neuroadaptive increases in Sig-1R seen in this study may contribute to the reinforcing effects of methamphetamine. This upregulation of Sig-1R may be mediated by increased protein kinase A activity due to downregulation of dopamine D(2) autoreceptors.

Animals↗

PubMed2004

Effects of isradipine on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition.

RATIONALE: While the effects of d-amphetamine in increasing performance have been established, there is a paucity of information on the effects of methamphetamine on cognition in drug-naive subjects, and no published information on the effects of intravenous methamphetamine administration in dependent individuals. The dihydropyridine-class calcium channel antagonist, isradipine, has been posited as a putative treatment to prevent methamphetamine-associated hypertensive crisis and its sequelae. Yet, isradipine's effects on cognitive performance in methamphetamine-dependent individuals are not known. OBJECTIVE: Since individuals whose dependence on methamphetamine is attributable to the need to enhance performance may be loath to take a cognition-impairing medication, even for the treatment of life-threatening hypertensive crisis, it would be important to determine isradipine's effects on performance. METHODS: We therefore examined in a blinded, placebo-controlled, crossover design the cognitive effects of low and high doses of intravenous methamphetamine (15 mg and 30 mg, respectively) in both the presence and absence of isradipine. RESULTS: Intravenous d-methamphetamine produced dose-dependent increases in attention, concentration, and psychomotor performance. Isradipine, both with and without methamphetamine, had a modest effect to decrease attention. CONCLUSION: Our results do not support the further testing of isradipine as a medication for improving the cognitive impairments that have been associated with chronic methamphetamine use.

Adult↗

PubMed2001

Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing.

RATIONALE: At high doses, methamphetamine produces repetitive stereotypic behaviors, and the degree to which this occurs is heritable. OBJECTIVES: Mice of a B6D2F2 genetic background were selectively bred for four generations for high (HMA) and low (LMA) numbers of stereotyped chewing episodes measured for 1 min at 33 min post-injection following 10 mg/kg methamphetamine (changed to 7 mg/kg for the high line and 15 mg/kg for the low line in the third selected generation to avoid ceiling and floor effects, respectively). We sought to determine whether stereotypic behaviors other than number of repetitive chewing episodes were altered by the selective breeding process. METHODS: HMA and LMA mice of the third and fourth selected generations were tested for chewing stereotypy, for a number of other stereotypic behaviors previously observed in rodents, and for several other non-stereotypic responses to methamphetamine. Testing in the third selected generation was conducted by observing behaviors on videotape following 7 mg/kg methamphetamine. In the fourth selected generation, mice were also tested in automated activity monitors following 10 mg/kg methamphetamine and in climbing chimneys following 16 mg/kg methamphetamine. Dose-response curves with doses of 1, 2, 3.5, 7, 10, and 15 mg/kg methamphetamine were constructed for the most commonly observed behaviors. RESULTS: LMA mice, which exhibited low stereotyped chewing, exhibited high stereotyped circling and climbing, and the reverse was true for these behaviors for HMA mice. For most of the other behaviors measured, there were drug effects but no differences between selected lines. CONCLUSIONS: These results suggest that these three stereotyped behaviors, chewing, circling, and climbing, at least partly share the same mechanisms, and therefore are influenced by at least some of the same genes, since animals selectively bred for low methamphetamine-induced stereotyped chewing exhibited high amounts of circling and climbing when given methamphetamine. This also suggests that the other stereotypic behaviors that we measured do not occur by the same genetically determined mechanisms as stereotypic chewing.

Alleles↗

PubMed2006

Methamphetamine and other substance use during pregnancy: preliminary estimates from the Infant Development, Environment, and Lifestyle (IDEAL) study.

OBJECTIVES: Methamphetamine use is a continuing problem in several regions of the United States and yet few studies have focused on prenatal methamphetamine exposure. The purpose of this study was to estimate the prevalence and correlates of alcohol, tobacco, and other substance use-including methamphetamine-during pregnancy. METHODS: The sample consisted of the first 1632 eligible mothers who consented to participate in a large-scale multisite study focused on prenatal methamphetamine exposure. This unselected screening sample included both users and nonusers of alcohol, tobacco, methamphetamine, and other drugs. Substance use was determined by maternal self-report and/or GC/MS confirmation of a positive meconium screen. RESULTS: Overall, 5.2% of women used methamphetamine at some point during their pregnancy. One quarter of the sample smoked tobacco, 22.8% drank alcohol, 6.0% used marijuana, and 1.3% used barbiturates prenatally. Less than 1% of the sample used heroin, benzodiazepines, and hallucinogens. Multivariate modeling results showed that tobacco smokers and illicit drug users were more likely to be single and less educated, have attended less than 11 prenatal visits, and utilize public financial assistance. CONCLUSIONS: This is the first large-scale investigation to report the prevalence of methamphetamine use during pregnancy in areas of the United States where methamphetamine is a notable concern. Follow-up research is ongoing to investigate the outcomes associated with prenatal methamphetamine exposure. Given that this research extends and confirms previous findings showing that high-risk groups of pregnant women can be identified on the basis of basic demographic characteristics, targeted interventions are greatly needed to reduce serious adverse outcomes associated with prenatal alcohol and tobacco use.

Adult↗

PubMed1993

Effects of nimodipine on the amphetamine- and methamphetamine-induced decrease in tryptophan hydroxylase activity.

The effects of nimodipine on the amphetamine- and methamphetamine-induced decrease in central tryptophan hydroxylase activity was examined. Rats were administered 4 or 5 injections of amphetamine or methamphetamine at 6-h intervals with or without nimodipine (1 mg/kg), and killed 1 or 18 h after the last drug administration. The decrease in hippocampal tryptophan hydroxylase activity induced by amphetamine and methamphetamine was potentiated by the administration of nimodipine. Moreover, while hippocampal tryptophan hydroxylase activity was not altered by 2.5 mg/kg methamphetamine alone, the coadministration of 1 mg/kg nimodipine decreased the enzymatic activity to 68% of control. The decrease in striatal tryptophan hydroxylase activity caused by these amphetamine analogues was not significantly altered by the coadministration of nimodipine. Interestingly, nimodipine increased hippocampal and striatal amphetamine concentrations to 187 and 162%, respectively, of the concentrations measured in animals treated with amphetamine alone. Nimodipine also increased by 2-fold the plasma concentration of methamphetamine and amphetamine measured 3 h after a single administration of methamphetamine, whereas the hippocampal concentrations of these compounds were raised to 354 and 516%, respectively, of that in animals treated with methamphetamine alone. These results suggest that nimodipine altered drug distribution and potentiated the methamphetamine-induced decrease in hippocampal tryptophan hydroxylase activity by increasing the cerebral methamphetamine concentration.

Amphetamine↗

PubMed1992

Competitive and non-competitive N-methyl-D-aspartate antagonists fail to prevent the induction of methamphetamine-induced sensitization.

In order to elucidate the possible roles of the glutamate system in the mechanisms underlying behavioral sensitization, which is used as an animal model for human psychosis, we investigated the effects of 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and MK-801 ((+)-dizocilpine), a competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, respectively, on methamphetamine-induced behavioral sensitization in rats. Administration of 0.5 mg/kg MK-801 enhanced 2 mg/kg methamphetamine-induced hyperactivity, whereas it reduced 6 mg/kg methamphetamine-induced stereotyped behavior markedly. CPP (10 mg/kg) reduced 2 mg/kg methamphetamine-induced stereotypy slightly. Repeated treatment with 2 and 6 mg/kg methamphetamine alone induced progressive augmentation of stereotypy, whereas combining either MK-801 or CPP with methamphetamine treatment abolished or attenuated this augmentation. However, when rats were challenged with methamphetamine after a 7-day period of abstinence, the intensity of stereotypy among the rats pretreated with repeated doses of methamphetamine alone or in combination with MK-801 or CPP did not differ significantly. These results indicate that competitive and non-competitive NMDA receptor antagonists modulate acute methamphetamine-induced abnormal behavior and sensitization expression, but they failed to prevent the induction of the neural mechanisms underlying behavioral sensitization.

Animals↗

PubMed1991

Selective effects of behaviorally active doses of methamphetamine on mRNA expression in the gerbil brain.

Administration of methamphetamine results in neuronal damage that may be mediated through the production of oxygen-free radicals and modulations in levels of calcium and glutamate in the brain. These changes have been associated with alterations in gene expression, which may play a role in cell damage. To assess the differences in gene expression related to treatment with methamphetamine, levels of mRNA were evaluated for the proto-oncogene c-fos, heat-shock protein (HSP 70) and actin. It was found that c-fos mRNA expression increased in a dose-dependent manner after administration of methamphetamine. Whereas, levels of HSP mRNA dropped at small doses of methamphetamine and increased dramatically at large doses. In addition, both c-fos and HSP mRNA showed increased levels throughout the brain. Actin mRNA expression was unaffected by any dose of the drug. At the doses that altered gene expression, methamphetamine produced dose-related behavioral changes. Spontaneous locomotor activity was increased at 1.0 mg/kg of methamphetamine, while, larger doses did not alter activity. The data demonstrated that effects of methamphetamine on gene expression occurred within the behaviorally-active dose range and might correlate with the degree of neuronal damage. Selective modulation of gene expression may have a role in determining the acute quantitative and qualitative effects of methamphetamine and the long-term changes that occur after administration of methamphetamine.

Animals↗

PubMed1992

Pharmacological mechanisms in the cardiovascular effects of methamphetamine in conscious squirrel monkeys.

The effects of methamphetamine were studied on cardiovascular function in conscious squirrel monkeys. Methamphetamine (0.1-3.0 mg/kg, IV) produced a dose-dependent increase in blood pressure. Its effects on heart rate were more complex, with lower doses (0.1-0.3 mg/kg) producing increases in heart rate and higher doses (1.0-3.0 mg/kg) producing decreases. To determine the pharmacological mechanisms involved in methamphetamine's effects, a number of drugs were tested as pretreatments to an injection of 0.2 mg/kg methamphetamine. This dose produced the maximal heart rate increase. The alpha 1-antagonist prazosin completely antagonized the effects of methamphetamine on blood pressure, while the nonselective beta-antagonist propranolol and beta 1-selective antagonist atenolol completely antagonized the tachycardiac effect of methamphetamine. The dopaminergic antagonists SCH 23390 and haloperidol antagonized some of the cardiovascular effects of methamphetamine. These results indicate that the pressor and tachycardiac effects of methamphetamine are mediated via alpha 1- and beta 1-adrenoceptor mechanisms, respectively. Dopaminergic mechanisms are also involved in methamphetamine's cardiovascular effects.

Animals↗

PubMed1996

Effects of chronic methamphetamine on SCH23390- or haloperidol-induced catalepsy, and effects of coadministration of SCH23390 or haloperidol in mice.

The influence of chronic treatment of mice with methamphetamine, an indirect dopamine agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7ol hydrochloride (SCH23390), a D1 receptor agonist, or haloperidol, a mainly D2 antagonist, was investigated. Once every other day treatment with 3 mg/kg SC methamphetamine for 15 days resulted in an increase in the catalepsy produced by haloperidol (0.3 mg/kg IP) (haloperidol catalepsy), but in a decrease in the catalepsy produced by SCH23390 (0.3 mg/kg IP) (SCH23390 catalepsy), 24 h and 7 days after withdrawal of methamphetamine. These effects of chronic methamphetamine were antagonized by coadministration of either SCH23390 (0.5 mg/kg SC) or haloperidol (1.0 mg/kg SC). These results suggest that the decreased responsiveness to SCH23390 in chronic methamphetamine-pretreated mice results from a supersensitivity of D1 receptors, and that the increased responsiveness to haloperidol catalepsy results from a subsensitivity of D2 receptors. The attenuated response to SCH23390 may be interpreted as an example of sensitization to methamphetamine, and the enhanced haloperidol response as an example of tolerance to methamphetamine, based on the development of supersensitivity and subsensitivity of D1 and D2 receptors, respectively, after chronic methamphetamine administration. Furthermore, it is suggested that coadministration of either SCH23390 or haloperidol could prevent the development of D1 receptor supersensitivity and D2 receptor subsensitivity induced by chronic methamphetamine.

Animals↗

PubMed1996

Methamphetamine modifies the photic entraining responses in the rodent suprachiasmatic nucleus via serotonin release.

We examined whether methamphetamine modifies the photic entraining responses in the rat suprachiasmatic nucleus. Optic nerve stimulation increased vasoactive intestinal polypeptide release from rat suprachiasmatic nucleus slices, and methamphetamine inhibited this increase in a concentration-dependent manner. Optic nerve stimulation has been reported to evoke field potentials in rat suprachiasmatic nucleus slices. Methamphetamine attenuated this field potential, and maximal inhibition (75.5%) was achieved at a concentration of 100 microM. Systemic administration of methamphetamine (1-5 mg/kg) inhibited light (300 lux, 1h)-induced Fos expression in the suprachiasmatic nucleus; methamphetamine at a dose of 5 mg/kg, i.p. caused 40% inhibition of light-induced Fos expression. We examined whether the inhibitory effect of methamphetamine on photic entraining responses mediates serotonin release from the suprachiasmatic nucleus. High-performance liquid chromatographic analysis revealed that methamphetamine application increased serotonin release from rat suprachiasmatic nucleus slices in a concentration-dependent manner, but did not affect noradrenaline release. In addition, reduction of serotonin content attenuated the effect of methamphetamine on field potential induced by optic nerve stimulation in vitro and also light-induced phase advances of wheel running activity rhythm in vivo. The present results support the idea that methamphetamine produces an inhibitory effect on photic entrainment in the suprachiasmatic nucleus via serotonin release.

Animals↗

PubMed1996

Acute methamphetamine-induced zif/268, preprodynorphin, and preproenkephalin mRNA expression in rat striatum depends on activation of NMDA and kainate/AMPA receptors.

This study tested the role of N-methyl-D-aspartate and kainate/AMPA receptors in mediating mRNA expression of the immediate early gene zif/268 and the opioid peptide genes preprodynorphin and preproenkephalin in rat forebrain following a single injection of methamphetamine. At 3 h after acute methamphetamine [4 mg/kg, intraperitoneally (IP)], quantitative in situ hybridization histochemistry revealed that zif/268 mRNA expression was increased in the dorsal striatum (caudoputamen) and in the sensory cortex. Preprodynorphin was increased in both dorsal and ventral striatum (nucleus accumbens) and preproenkephalin was increased in the dorsal striatum. Pretreatment with (+ or -)-3-(2-carboxypiperazin-4-yl)-propyl-1 -phosphonic acid (CPP) (10 mg/kg, IP), an N-methyl-D-aspartate receptor antagonist, blocked the methamphetamine-induced zif/268 mRNA expression in the striatum and in the region of sensory cortex representing the upper limb and nose. 6,7-Dinitro-quinoxaline-2,3-dione (DNQX) (100 mg/kg, IP), a kainate/AMPA receptor antagonist, did not reduce the ability of methamphetamine to induce zif/268 mRNA in striatal and cortical neurons. Furthermore, both antagonists caused a parallel blockade of methamphetamine-stimulated preprodynorphin mRNA expression in the dorsal and ventral striatum but did not significantly affect methamphetamine-stimulated preproenkephalin mRNA expression. CPP and DNQX reduced basal levels of zif/268 mRNA in cortical and striatal neurons but did not affect the constitutive expression of the two opioid mRNAs in the striatum. Neither antagonist had a significant effect on methamphetamine-induced hyperlocomotion and stereotypies. These results demonstrate that both N-methyl-D-aspartate and kainate/AMPA receptor-mediated glutamatergic transmission is linked to modulation of the methamphetamine-stimulated oploid peptide gene expression in rat forebrain. Furthermore, N-methyl-D-aspartate receptors participate in methamphetamine-stimulated zif/268 expression.

Animals↗

PubMed2004

Short-term effects of the nociceptin receptor antagonist Compound B on the development of methamphetamine sensitization in mice: a behavioral and c-fos expression mapping study.

The nociceptin antagonist Compound B (CompB) stimulates mesolimbic dopamine release and induces a conditioned place preference but has little effect on locomotion. As behavioral sensitization often occurs as an epiphenomenon to mesolimbic activation and reward, we studied the effect of CompB on behavioral sensitization to methamphetamine. Locomotor responses of C57BL6 mice to repeated methamphetamine (2 mg/kg s.c.) administration alone or immediately following CompB (10 mg/kg s.c.) were recorded for 3 alternating days. Six days later, methamphetamine (1 mg/kg s.c.) was administered and locomotor activity monitored again before determining neural activity by analysis of c-fos expression. Methamphetamine treatment induced a progressive locomotor (behavioral) sensitization, with CompB pretreatment enhancing the locomotor response to methamphetamine during the early stages only. Previous CompB administration little affected methamphetamine-sensitized or acute methamphetamine-induced locomotion on the challenge day. Analysis of c-fos expression supported these results as of the 36 neuroanatomical regions quantified; very few showed CompB-dependent responses. However, numerous regions differentially responsive to either acute (e.g. ventromedial, ventrolateral and central caudate putamen), chronic (e.g. central amygdala, lateral habenula, dorsomedial caudate putamen) or sensitized (e.g. medial nucleus accumbens core, central amygdala, lateral habenula) methamphetamine treatment were identified, thereby providing a comprehensive map of the short and long-term effects of methamphetamine on mouse brain activity per se. Thus, despite its mesolimbic activating and rewarding properties, CompB has little long-term influence on neural activity, suggesting CompB is able to induce short-term increases in hedonic state in the absence of locomotion or major long-term effects.

Analysis of Variance↗

PubMed2006

Nullifying drug-induced sensitization: behavioral and electrophysiological evaluations of dopaminergic and serotonergic ligands in methamphetamine-sensitized rats.

Repeated exposure to methamphetamine produces a persistent enhancement of the acute motor effects of the drug, commonly referred to as behavioral sensitization. Behavioral sensitization involves monoaminergic projections to several forebrain nuclei. We recently revealed that the ventral pallidum (VP) may also be involved. In this study, we sought to establish if treatments with antagonists or partial agonists to monoaminergic receptors could "reverse" methamphetamine-induced behavioral and VP neuronal sensitization. Behavioral sensitization was obtained in rats with five once-daily s.c. injections of 2.5mg/kg methamphetamine, an effect that persisted for at least 60 days. After the development of sensitization, 15 once-daily treatments of mirtazapine (a 5-HT(2/3), alpha(2) and H(1) antagonist), SKF38393 (D(1) partial agonist) or SCH23390 (dopamine D(1) antagonist) nullified indices of motor sensitization as assessed by measuring the motoric response to an acute methamphetamine challenge 30 days after the fifth repeated methamphetamine treatment. VP neurons recorded in vivo from methamphetamine-sensitized rats at the 30-day withdrawal time also showed a robust downward shift in the excitatory responses observed to an acute i.v. methamphetamine challenge in non-sensitized rats. This decreased excitatory effect was reversed by mirtazapine, but not by other antagonists that were tested. These data suggest a potential therapeutic benefit for mirtazapine in the treatment of methamphetamine addiction, and point to a possible role for the VP in the sensitization process to methamphetamine.

Action Potentials↗

PubMed2006

Increasing use and associated harms of crystal methamphetamine injection in a Canadian setting.

BACKGROUND: There is a growing concern surrounding crystal methamphetamine use in Canada despite surprisingly little empirical data to support such claims. We evaluated the trends in crystal methamphetamine injection and factors associated with injection of the drug among a cohort of injection drug users (IDU) in Vancouver. METHODS: We conducted a prospective analysis of factors associated with crystal methamphetamine injection among participants enrolled in the Vancouver Injection Drug Users Study (VIDUS). Since serial measures for each individual were available, variables potentially associated with crystal methamphetamine injection were evaluated using generalized estimating equations (GEE) with logit link for binary outcomes. RESULTS: Overall, 1587 IDU were enrolled into the VIDUS cohort between May 1996 and December 2004. The proportion of IDU who reported injecting crystal methamphetamine during the last 6 months increased during the study period (Cochran-Armitage trend test, p<0.001). In multivariate GEE analyses, crystal methamphetamine injection was independently associated with younger age (adjusted odds ratio [AOR]: 4.77, 95% confidence interval [CI]=3.40-6.70), Caucasian ethnicity (AOR=2.21, 95% CI=1.57-3.12), syringe borrowing (AOR=1.62, 95% CI=1.22-2.13), and syringe lending (AOR=1.40, 95% CI=1.02-1.86). INTERPRETATION: There was a significant trend towards increasing crystal methamphetamine injection in this setting and elevated HIV risk behavior and younger age were independently associated with crystal methamphetamine injection. Given that banning precursor chemicals has had a limited effect on reducing methamphetamine supply in other jurisdictions, pragmatic and effective interventions are needed to address the growing use of this drug.

Adult↗

PubMed2006

Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum.

The administration of high doses of methamphetamine causes the degeneration of striatal dopaminergic fibers in the brains of rodents, and oxidative stress appears to be one of the main factors of neurotoxicity. This study examined whether edaravone, a radical scavenger, protects against methamphetamine-induced neurotoxicity in mice. Methamphetamine treatment (4 mg/kg, s.c. x 4 with 2 h intervals) showed striatal dopaminergic degeneration as observed by decreases in dopamine levels and tyrosine hydroxylase immunoreactivity in the striatum. The neurotoxicity was reduced by edaravone (3 mg/kg, i.p.), when it was administered four times 30 min before methamphetamine at 2 h intervals and additionally four times after methamphetamine at 12 h intervals. An immunohistochemical study showed that methamphetamine increased 3-nitrotyrosine immunoreactivity, an in vivo marker of peroxynitrite production, and activated microglia and astrocytes in the striatum. Edaravone blocked the increase in 3-nitrotyrosine immunoreactivity and the activation of astrocytes, but it did not affect the activation of microglia. Edaravone did not affect methamphetamine-induced hyperthermia and striatal dopamine release. These results suggest that edaravone protects against methamphetamine-induced neurotoxicity in the striatum by blocking peroxynitrite production. This study also suggests that methamphetamine activates microglia in a radical-independent mechanism.

Animals↗

PubMed2005

Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects.

The stimulant effects of cocaine and methamphetamine are mediated by changes in synaptic concentrations of brain monoamines; however, the drugs alter monoamine levels via different mechanisms. This study examined the subjective and cardiovascular responses produced by investigational administration of cocaine or methamphetamine, in order to examine the onset and patterns of subjective and cardiovascular responses. Subjects included 14 non-treatment seeking cocaine-dependent and 11 non-treatment seeking methamphetamine-dependent volunteers. As part of ongoing research studies, cocaine and methamphetamine subjects received cocaine (40 mg, IV) or methamphetamine (30 mg, IV), respectively. Subjective and cardiovascular responses were assessed for 30 min and 60 min, respectively. The data reveal significant within groups differences for all subjective effects and cardiovascular effects (p<0.05). Significant between group differences in subjective effects were observed for "Any Drug Effect" (p<.008 for group, and p<.029 for group x time), for "High" (p<.002 for group, and p<.0001 for group x time) and for "Stimulated" (p<.001 for group, and p<.006 for group x time). Significant between group differences in cardiovascular effects were observed for Systolic blood pressure (p<.0001 for group, and p<.002 for group x time), Diastolic blood pressure (p<.0001 for group, though p=NS for group x time), and for Heart Rate (p<.0001 for group, and p<.0001 for group x time). The only difference between the groups for placebo was for heart rate, where there was a significant group x time effect (p<.005). Taken together, the data reveal that the subjective effects of cocaine tended to peak and then decline more rapidly than those produced by methamphetamine. The subjective effects of methamphetamine tended to rise more slowly, and remain elevated longer. Cardiovascular effects of cocaine and methamphetamine had similar onset, but effects of cocaine tended to decline more rapidly. Overall, the results reveal differences in the onset, pattern, and duration of subjective and cardiovascular responses following cocaine or methamphetamine administration in stimulant addicted patients. We predict that these differences may impact drug use and relapse patterns, and may have implications in medications development for these addictive disorders.

Cardiovascular System↗