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PubMed2006

An association study between catechol-O-methyl transferase gene polymorphism and methamphetamine psychotic disorder.

OBJECTIVE: A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. BASIC METHODS: We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. MAIN RESULTS: We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. CONCLUSIONS: Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Adult↗

PubMed2006

The prevalence of psychotic symptoms among methamphetamine users.

AIMS: To examine the prevalence of psychotic symptoms among regular methamphetamine users. DESIGN: Cross-sectional survey. SETTING: Participants were recruited from Sydney, Australia, through advertisements in free-press magazines, flyers and through word-of-mouth. PARTICIPANTS: Methamphetamine users (n = 309) who were aged 16 years or over and took the drug at least monthly during the past year. MEASUREMENTS: A structured face-to-face interview was used to assess drug use, demographics and symptoms of psychosis in the past year. Measures of psychosis included: (a) a psychosis screening instrument derived from the Composite International Diagnostic Interview; and (b) the Brief Psychiatric Rating Scale subscales of suspiciousness, unusual thought content, and hallucinations. Dependence on methamphetamine was measured using the Severity of Dependence Scale. FINDINGS: Thirteen per cent of participants screened positive for psychosis, and 23% had experienced a clinically significant symptom of suspiciousness, unusual thought content or hallucinations in the past year. Dependent methamphetamine users were three times more likely to have experienced psychotic symptoms than their non-dependent counterparts, even after adjusting for history of schizophrenia and other psychotic disorders. CONCLUSION: The prevalence of psychosis among the current sample of methamphetamine users was 11 times higher than among the general population in Australia. Dependent methamphetamine users are a particularly high-risk group for psychosis.

Adolescent↗

PubMed1993

Differing neurotoxic potencies of methamphetamine, mazindol, and cocaine in mesencephalic cultures.

The potent reinforcing effects of methamphetamine and cocaine are thought to be mediated by their interactions with CNS dopamine neurons. Both stimulants share the ability to block dopamine uptake potently, and methamphetamine can release cytoplasmic dopamine as well. There is also abundant evidence demonstrating the neurotoxic effects of methamphetamine. There are, however, limited studies that attempt to discern the neurotoxic mechanisms of these agents. The purpose of the present study was to characterize and compare the chronic in vitro effects of methamphetamine, cocaine, and the dopamine uptake blocker, mazindol, on cultured fetal mesencephalic dopamine neurons. Our studies examined biochemical mechanisms to evaluate the contribution of reuptake blockade versus release of dopamine. Using a dispersed cell preparation of fetal mesencephalon, cultures were treated for 5 days with the three uptake blockers. Dopamine function was assessed by measuring high-affinity [3H]dopamine uptake and by examining cultures for the presence of tyrosine hydroxylase-immunopositive neurons. Nonspecific neurotoxicity was assessed by staining for neuron-specific enolase and measuring lactate dehydrogenase activity. The results indicate that repeated administration of high concentrations of methamphetamine (10(-4) and 10(-3) M) caused a generalized neurotoxicity whereas the effects of 10(-5) M methamphetamine appeared to be specific to dopamine cells. Likewise, treatment of the cultures with mazindol (10(-6) M) resulted in reduced dopamine uptake while not significantly affecting neuron-specific enolase or tyrosine hydroxylase immunostaining. On the other hand, repeated exposure to cocaine (10(-5) and 10(-4) M) did not alter dopaminergic function in these cultures. The different mechanisms of action of these stimulants may explain the differences in neurotoxic potency of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Dual alteration of limbic dopamine D1 receptor-mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization.

The central dopamine system plays significant roles in motor activity and drug-induced behavioural sensitization. Our goal was to determine the significance of dopamine D(3) receptors in the development of behavioural sensitization to methamphetamine, assessed with D(3) receptor mutant mice. The absence of D(3) receptors significantly increased the behavioural responses to acute methamphetamine and evoked a faster rate of behavioural sensitization to chronic methamphetamine. In addition, both D(3) receptor protein and mRNA levels in the limbic forebrain decreased in sensitized wild-type mice. Further analyses indicated that D(1)-dependent behavioural sensitization and the number of limbic D(1) receptors increased in sensitized D(3) mutants as compared with sensitized wild-type mice. Consistent with this finding, we observed higher levels of D(1) receptor-evoked cAMP accumulation and basal phosphoDARPP-32/Thr34 in the limbic forebrain of D(3) mutants than wild-type mice and the difference was more pronounced after chronic methamphetamine treatment. We also observed an increase in phospho-extracellular signal-regulated kinase 2 but a decrease in phosphoAkt/Ser473 and phosphoglycogen synthase kinase 3 (GSK3)-alpha/beta in the limbic forebrain of D(3) mutants compared with wild-type mice after methamphetamine treatment. The convergent results implicate D(3) receptors as a negative regulator of the development of methamphetamine sensitization. A compensatory up-regulation of D(1) receptor-mediated signals, in addition to an altered Akt/GSK3 pathway, could contribute to the accelerated development of behavioural sensitization.

Animals↗

PubMed2005

Cyclooxygenase-2 is an obligatory factor in methamphetamine-induced neurotoxicity.

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. The mechanisms underlying its neurotoxicity are not fully understood, but considerable evidence points to oxidative stress as a probable mechanism. A recent microarray analysis of gene expression changes caused by methamphetamine revealed that cyclooxygenase-2 (COX-2) was induced along with its transcription factor CCAAT/enhancer-binding protein (Thomas DM, Francescutti-Verbeem DM, Liu X, and Kuhn DM, 2004). We report presently that methamphetamine increases striatal expression of COX-2 protein. Cyclooxygenase-1 (COX-1) expression was not changed. Mice bearing a null mutation of the gene for COX-2 were resistant to methamphetamine-induced neurotoxicity. COX-1 knockouts, like wild-type mice, showed extensive dopamine nerve terminal damage. Selective inhibitors of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole (SC-560)], COX-2 [N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398), rofecoxib], or COX-3 (antipyrine) or a nonselective inhibitor of the COX-1/2 isoforms (ketoprofen) did not protect mice from neurotoxicity. Finally, methamphetamine did not change striatal prostaglandin E(2) content. Taken together, these data suggest that COX-2 is an obligatory factor in methamphetamine-induced neurotoxicity. The functional aspect of COX-2 that contributes to drug-induced neurotoxicity does not appear to be its prostaglandin synthetic capacity. Instead, the peroxidase activity associated with COX-2, which can lead to the formation of reactive oxygen species and dopamine quinones, can account for its role.

Animals↗

PubMed2003

Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms.

OBJECTIVE: The authors examined dopamine transporter density in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in methamphetamine users and assessed the relationship of these measures to the subjects' clinical characteristics. METHOD: Positron emission tomography with [(11)C]WIN 35,428 was used to examine the regions of interest in 11 methamphetamine users and nine healthy comparison subjects. Psychiatric symptoms were evaluated with the Brief Psychiatric Rating Scale. RESULTS: Dopamine transporter density in the three regions studied was significantly lower in the methamphetamine users than in the comparison subjects. The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms. CONCLUSIONS: Chronic methamphetamine use may cause dopamine transporter reduction in the orbitofrontal cortex, dorsolateral prefrontal cortex, and amygdala in the brain. Psychiatric symptoms in methamphetamine users may be attributable to the decrease in dopamine transporter density in the orbitofrontal cortex and the dorsolateral prefrontal cortex.

Adult↗

PubMed2004

Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment.

Amphetamine abuse may be associated with adaptive changes in gene expression in the brain. In the present study, a newly developed cDNA array system comprising mouse KIAA (mKIAA) cDNA clones was used to examine the gene expression affected by chronic methamphetamine treatment. Approximately 800 mKIAA clones were blotted onto a nylon membrane and hybridized with 33P-labeled cDNA derived from mRNAs isolated from the whole brains of mice that had been treated daily with saline or methamphetamine (2 mg/kg, i.p.) for 2 weeks. The arrays displayed robust hybridization for almost all transcripts. The results obtained from five experiments were averaged, each performed with triplicate samples. Several clones were chosen as positive candidates for methamphetamine-induced changes; however, only Per2 and mKIAA0099 genes showed a significantly increased expression (P < .05). Subsequently, with the focus on the period-related proteins, the expression of these proteins in various parts of the rat brain were assessed by immunoblot analysis. Chronic administration of methamphetamine (8 mg/kg, i.p., for 10 days) caused increased Per2 protein expression in the hippocampus. Interestingly, chronic methamphetamine treatment at a lower dose (4 mg/kg, i.p., for 10 days) induced an increase in SCN circadian oscillatory protein (SCOP) expression, also in the hippocampus. These data suggest that long-lasting alterations of the period-related gene expressions in the hippocampus might play an important role in methamphetamine addiction.

Animals↗

PubMed2001

Brain proton magnetic resonance spectroscopy in children exposed to methamphetamine in utero.

OBJECTIVE: To examine the possible neurotoxic effects of prenatal methamphetamine exposure on the developing brain using 1H-MRS. METHODS: Methamphetamine-exposed children (n = 12) and age-matched unexposed control subjects (n = 14) were evaluated with MRI, localized 1H-MRS, and a Child Behavior Checklist. Metabolite concentrations of N-acetyl-containing compounds (NA), total creatine (Cr), choline-containing compounds, myoinositol, and glutamate + glutamine were measured in the frontal white matter and striatum. RESULTS: Despite an absence of visible structural abnormalities in either group, children exposed to methamphetamine in utero had higher [Cr] (+10%, p = 0.02) in the striatum. [NA], primarily a measure of N-acetylaspartate, was normal in both regions, which suggests no significant neuronal loss or damage in the two brain regions examined. There were no differences in reported behavior problems among the methamphetamine-exposed children relative to the unexposed group. CONCLUSIONS: The authors found increased [Cr] in the striatum with relatively normal [NA] in children exposed to methamphetamine. These findings suggest an abnormality in energy metabolism in the brains of children exposed to methamphetamine in utero.

Brain↗

PubMed1996

Opioid receptor agonists selective for mu and kappa receptors attenuate methamphetamine-induced behavioral sensitization in the mouse.

The effects of intracerebroventricular (i.c.v.) injection of the mu-selective opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) and the kappa-selective opioid receptor agonist dynorphin A-(1-13) on the development of methamphetamine-induced behavioral sensitization in the mouse were determined using multidimensional behavioral analyses based upon a capacitance system. Methamphetamine (2 mg/kg, s.c.) was administered to mice on 6 occasions at 3- or 4-d intervals. The methamphetamine-induced increase in linear locomotion and circling was markedly augmented by repeated administrations (3 or more times) of the drug, showing behavioral sensitization. Although repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior, repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) attenuated the behavioral sensitization induced by methamphetamine (2 mg/kg, s.c.). The attenuating effects of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) were fully reversed by withdrawal of these drugs for 3 weeks. Additionally, a single administration of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior; DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) only attenuated the behavioral sensitization which had previously been developed by methamphetamine (2 mg/kg,s.c.). These results suggest that opioid receptor agonists selective for mu and kappa receptors play an inhibitory role in the development of methamphetamine-induced behavioral sensitization.

Analgesics↗

PubMed1989

Reverse tolerance to ambulation-increasing effects of methamphetamine and morphine in 6 mouse strains.

Effects of single administration of methamphetamine (1, 2 and 4 mg/kg, s.c.) and morphine (5, 10 and 20 mg/kg, s.c.) and repeated administration of methamphetamine (2 mg/kg, s.c.) and morphine (10 mg/kg, s.c.) on ambulatory activity were investigated in 6 mouse strains: dd, ICR, BALB/c, C57BL/6, C3H/He and DBA/2. Although there were differences in the drug sensitivities among mouse strains, methamphetamine and morphine increased the ambulatory activity in all the strains except for the DBA/2 strain that showed an increase only after morphine. Repeated 5 times administration of methamphetamine at intervals of 3-4 days induced a reverse tolerance (an enhancement in the sensitivity) to the ambulation-increasing effect in all the strains with a marked degree in dd, ICR, C3H/He and DBA/2 strains and a slight degree in BALB/c and C57BL/6 strains. The same treatment with morphine induced reverse tolerance to the effect of morphine markedly in C57BL/6 and C3H/He strains and moderately in dd, ICR and BALB/c strains, but the DBA/2 strain showed no significant change in the ambulatory activity throughout the repeated 5 times administration of morphine. There was positive correlation between the initial drug sensitivities of animals and the degrees of the reverse tolerance in either methamphetamine or morphine. Furthermore, the reverse tolerance to methamphetamine and morphine was sometimes transferable, although such cross interaction varied among mouse strains.

Animals↗

PubMed1990

Effects of repeated administration of pentazocine on ambulatory activity in mice: comparison with the effects of morphine and methamphetamine.

Effects of single and repeated administration of pentazocine (5 times at intervals of 3-4 days) were compared with those of morphine and methamphetamine by means of ambulatory activity in mice. The interactions among these 3 drugs were also investigated. Pentazocine (25 mg/kg, s.c.), morphine (10 and 20 mg/kg, s.c.) and methamphetamine (2 mg/kg, s.c.) significantly increased the activity, and the effect progressively enhanced (defined here as development of reverse tolerance) during the repeated administration schedule. The induction of reverse tolerance to pentazocine was less dependent on the environmental conditions, and it was abolished within 2 months. A cross reverse tolerance was demonstrated from methamphetamine to pentazocine and to morphine, and from morphine to pentazocine. However, no significant cross reverse tolerance was induced from pentazocine to morphine and to methamphetamine, and from morphine to methamphetamine. The present results suggest that pentazocine possesses an ambulation-increasing effect, although the characteristics are different from that of either morphine or methamphetamine.

Animals↗

PubMed2001

A double epidemic: crystal methamphetamine drug use in relation to HIV transmission among gay men.

Emerging research on methamphetamine use among gay men suggests that growth in the use of this drug could present serious problems for HIV/AIDS prevention within the gay community. This article summarizes current studies on the extent, role, and context of methamphetamine use among gay men and its relationship to high risk sexual behaviors related to HIV transmission. Methamphetamine is often used by gay men to initiate, enhance, and prolong sexual encounters. Use of the drug is, therefore, associated with particular environments where sexual contact among gay men is promoted, such as sex clubs and large "circuit" parties. Research with gay and bisexual men indicates that methamphetamine use is strongly associated with risky sexual behaviors that may transmit HIV. This relationship, coupled with emerging evidence that methamphetamine use is on the rise among gay men, suggests that the drug could exacerbate the HIV/AIDS epidemic among this community. The article offers recommendations for further research and suggestions for prevention programs regarding methamphetamine use by gay men.

Adult↗

PubMed1991

Effects of methamphetamine on copulatory behavior in male rats.

Many papers have reported the effect of amphetamine and its close relative, methamphetamine on sexual activity in humans. The effect of these drugs on animal sexual behavior is unknown. The present study was done to determine whether methamphetamine modifies the copulatory behavior of male rats. Sexually experienced rats of the Wistar-Imamichi strain, 10 weeks of age, were singly injected intraperitoneally with methamphetamine hydrochloride at doses of 0, 1, 2 or 4 mg/kg body weight. Tests were initiated at 19: 30 in the dark period. Observations were conducted for 90 min. At dosages of 1 or 2 mg/kg there were no changes in copulatory behavior ascribed to the administration of methamphetamine. At 4 mg/kg the frequencies of mounting, intromission and ejaculation were greatly decreased but the spontaneous motor activity and stereotypic behavior increased in all males. In a further experiment, males were given methamphetamine by intraperitoneal injection once a week for 8 weeks. The copulatory behavior was tested 5 times at two weeks intervals. In the 4th testing, the percentage showing ejaculation decreased. In the 5th testing, there was no ejaculation and the incidence of intromission decreased. No stereotypic behavior was displayed in any of the males during the testing. From these results, it was concluded that methamphetamine inhibits the intromitting and ejaculating behavior in male rats.

Animals↗

PubMed1993

Evaluation of masked neurological disorders in the chronic stage after middle cerebral artery occlusion in rats--methamphetamine-induced rotation and regional glucose metabolism in basal ganglia.

Neurofunctional changes in rats in the chronic stage of focal cerebral ischemia induced by left middle cerebral artery (MCA) occlusion were examined. Neurological disorders and behavioral changes were observed with or without methamphetamine administration. Metabolic changes in the basal ganglia following methamphetamine intraperitoneal injection were evaluated by [14C]deoxyglucose autoradiography 30 days after occlusion. Neurological examination revealed persistent spontaneous rotation to the lesioned side in two of 18 rats, and forelimb flexion to the lesioned side in nine of 18 rats during a 28-day observation period after occlusion. Intraperitoneal administration of methamphetamine (4 mg/kg) induced full 360 degrees rotation toward the lesion side in 14 of 17 rats. The number of rotations was inversely correlated with the size of the intact striatum on the lesion side, especially in rats with cerebral infarct located only in the striatum. Rats with extensive cortical lesion in addition to striatal lesion did not demonstrate this relationship. Deoxyglucose autoradiography in methamphetamine-untreated rats showed symmetrical local cerebral glucose utilization in the basal ganglia except for the subthalamic nucleus, striatum and sensorimotor cortex. Autoradiography in methamphetamine-treated and MCA-occluded rats showed a remarkable increase in glucose utilization in the anterior striatum, entopeduncular nucleus, substantia nigra pars reticulata, and sensorimotor cortex contralateral to the occlusion side, but not on the lesioned side. Rotational movements observed in methamphetamine-treated rats are related to lack of stimulation of the basal ganglia system on the ischemic side.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Distribution and excretion of methamphetamine and its metabolites in rats. II. Time-course of concentration in blood and distribution after multiple oral administration.

The time-course of total blood radioactivity after oral administration of 3H-methamphetamine, following multiple oral administration of non-radioactive methamphetamine for 7 and 14 days to rats, was examined to elucidate the effects of multiple administration on enterohepatic circulation. Whole-body autoradiographs of rats after oral administration of 14C-methamphetamine showed high levels of radioactivity in contents of stomach and small intestine, bladder urine, liver, and various glands. Distribution of methamphetamine and the major metabolite in tissues during multiple dosing was investigated; accumulation occurred in brain, liver, testis and fat. Multiple oral administration of methamphetamine to rats slightly induced enzyme activities of N-demethylation and aromatic hydroxylation of methamphetamine in rat-liver 9000 g supernatant.

Administration, Oral↗

PubMed1984

Metabolism of methamphetamine, amphetamine and p-hydroxymethamphetamine by rat-liver microsomal preparations in vitro.

Methamphetamine N-demethylation and p-hydroxylation activities of rat liver were located mainly in the microsomal fraction. The Km values for methamphetamine and p-hydroxymethamphetamine demethylations were 1.0 and 1.6 mM, respectively. The Km value for amphetamine p-hydroxylation was 10.2 microM; substrate inhibition occurred at high substrate concn. Two Km values were obtained for the aromatic hydroxylation of methamphetamine (10.6 microM and 2.2 mM). N-Demethylation of methamphetamine and p-hydroxymethamphetamine were depressed in rats pretreated with 3-methylcholanthrene, CoCl2 or SKF 525-A. In rats pretreated with phenobarbital, methamphetamine demethylase was induced and p-hydroxymethamphetamine demethylase was depressed. The p-hydroxylation of methamphetamine and amphetamine in rats pretreated with phenobarbital, CoCl2, SKF 525-A or iprindole were depressed.

Amphetamine↗

PubMed1986

Effects of several factors on urinary excretion of methamphetamine and its metabolites in rats.

Effects of dose, route of administration, and sex and strain differences on the metabolism of methamphetamine in vivo were investigated in rats. Excretion of p-hydroxymethamphetamine was decreased with increasing dose of methamphetamine, while that of unchanged methamphetamine and amphetamine increased with dose. Subcutaneous injection instead of oral administration of methamphetamine increased the urinary excretion of unchanged drug and amphetamine, and decreased the excretion of p-hydroxymethamphetamine. No marked sex difference was observed in the urinary excretion of methamphetamine and metabolites. The Donryu strain of rats excreted unchanged methamphetamine and p-hydroxylated metabolites to a lesser extent than did Sprague-Dawley and Wistar strains.

Amphetamine↗

PubMed1988

Illicit methamphetamine: analysis, synthesis, and availability.

Methamphetamine has been marketed illicitly since the 1960s. Much of the street material was illicitly synthesized. Although methamphetamine quality was variable in the past decade, it has emerged since 1978 as the only street stimulant which is likely to contain what it purports to contain. Although there is a small volume of legitimate methamphetamine still made by the pharmaceutical industry, most material analyzed by street-drug laboratories appears to have been illegitimately synthesized and not diverted. For a decade, relatively little methamphetamine was submitted to street-drug analytical labs. In recent years, although the absolute volume of methamphetamine submissions changed little, this drug made up the bulk of alleged stimulant samples submitted to such facilities because of the paucity of amphetamine submissions. Methamphetamine synthesis and use appears to constitute a small but continuing portion of the illicit drug market.

Humans↗