Toxic Effects Of Methamphetamine Research Articles

Toxic Effects of Methamphetamine on Reproductive Systems, Embryo Development, and Newborns: An Evidence-Based Review.

Methamphetamine (METH), an amphetamine-type stimulant, has been extensively abused globally in the past decades. METH use causes great harm to the major systems of the human body. Specifically, METH has a negative impact on the hypothalamic- pituitary-testicular axis, testicular structure, sperm function, ovarian folliculogenesis, oocyte quality, embryo development, and newborns. However, the mechanisms underlying these toxic effects have not yet been fully described. This study reviews the evidence concerning the impact of METH on male and female reproduction in the context of the testis, sperm, ovaries, oocytes, reproductive hormones, embryo development, and newborns, discussing the potential pathophysiological mechanisms in the reproductive toxicity induced by METH.

Toxic Effects of Methamphetamine on Perivascular Health: Co-morbid Effects of Stress and Alcohol Use Disorders.

Methamphetamine (Meth) abuse presents a global problem and commonly occurs with stress and/or alcohol use disorders. Regardless, the biological causes and consequences of these co-morbidities are unclear. Whereas the mechanisms of Meth, stress, and alcohol abuse have been examined individually and well-characterized, these processes overlap significantly and can impact the neural and peripheral consequences of Meth. This review focuses on the deleterious cardio- and cerebrovascular effects of Meth, stress, alcohol abuse, and their comorbid effects on the brain and periphery. Points of emphasis are on the composition of the blood-brain barrier and their effects on the heart and vasculature. The autonomic nervous system, inflammation, and oxidative stress are specifically highlighted as common mediators of the toxic consequences to vascular and perivascular health. A significant portion of the Meth abusing population also presents with stress and alcohol use disorders, prompting a need to understand the mechanisms underlying their comorbidities. Little is known about their possible convergent effects. Therefore, the purpose of this critical review is to identify shared mechanisms of Meth, chronic stress, and alcohol abuse that contributes to the dysfunction of vascular health and underscores the need for studies that directly address their interactions.

Toxicological Aspect of Fatal Methamphetamine

Drug addiction has become a worldwide problem and the leading cause of death. The global problem of addiction and drug abuse is responsible for hundreds of deaths every year. It affects not only individual users, but also their families and communities. The current study, presents the fatality of some cases caused by the complications brought about the presence of methamphetamine and other abused drugs. It has been a drug of abuse in the past and is still gaining popularity as a recreational drug because of its much longer excitatory duration of more than three hours and its biotransformation to amphetamine, the active metabolite. In present postmortem cases methamphetamine and other combined drugs have issue in cardiac major health problems and poisoning-related deaths. Many postmortem cases found positive to methamphetamine and amphetamine or combined with other drugs include different narcotics/ stimulants drugs such as : benzodiazepines, THC, opium, and lyrica. The toxic effects of methamphetamine can explain increasing reports of heart failure and consequently death in young abusers. As this recognition may prove to be of some forensic value to clarify the death in methamphetamine abusers.

Antibody Gene Therapy Mitigates Adverse Immunological Effects of 3,4‐Methylenedioxymethamphetamine (MDMA) in Male BALB/c Mice

3,4‐Methylenedioxymethamphetamine (MDMA) is a popular recreational psychostimulant and hallucinogen typically used in “rave” settings. Despite the “positive” feelings sometimes associated with its use, there are toxicities that accompany its use. In the periphery, MDMA causes immunosuppression that can make users more susceptible to infection. Conversely, in the CNS MDMA initiates a proinflammatory response that is linked to glial activation and the subsequent overproduction of cytokines, chemokines, and even cellular adhesion molecules. A treatment that could potentially mitigate these effects would be beneficial.In our laboratory, we are developing an anti‐MDMA/methamphetamine (METH) dual‐acting antibody gene therapy as a treatment for substance use disorders (SUD). Utilizing the adeno‐associated virus AAV8 as our gene therapy vector, we packaged the single chain‐Fc fusion fragment 7F9‐Fc to create AAV‐7F9‐Fc. AAV‐7F9‐Fc expresses anti‐MDMA/METH antibodies systemically that work as pharmacokinetic antagonists to slow and possibly reduce entry of drug into the brain and other organs. AAV‐7F9‐Fc produces effective long‐term serum concentrations of antibodies in mice (>7 months from a single dose) and has been shown to alter METH‐induced locomotor effects in mice. Because of the chemical backbone similarity between METH and MDMA, we hypothesized that AAV‐7F9‐Fc would also be able to bind to MDMA in serum and reduce the immunomodulatory effects induced by MDMA. If proven effective, this treatment could provide some protection against the toxic effects of METH and MDMA during recovery.We hypothesized that an AAV delivered antibody fusion fragment (AAV‐7F9‐Fc) will provide extended protection from MDMA‐induced neuroinflammation and systemic immune suppression. To begin to test this hypothesis, we are evaluating an acute mouse model of MDMA use. Drug administration followed a binge dosing regimen of an ip injection every 2 hr for 4 consecutive doses. After the MDMA dosing regimen, we measured serum cytokine levels by multiplex analysis, and CNS proinflammatory cytokine and glial cell activation markers by qRT‐PCR. BALB/c mice were divided into nine groups (n=5/group); 1) Saline + Saline, 2) Saline + MDMA (10 mg/kg 2hr × 4), 3) Saline + MDMA (3 mg/kg 2hr × 4), 4) Saline + MDMA (1 mg/kg 2hr × 4) 5) LPS, 6) AAV‐7F9‐Fc + Saline, 7) AAV‐7F9‐Fc + MDMA (10 mg/kg 2hr × 4), 8) Empty Vector + saline & 9) Empty Vector + MDMA (10 mg/kg 2hr × 4). Our results indicate significant decreases (p< 0.05) in the serum concentration of proinflammatory cytokine IL‐1β & IFN‐γ and increases in the anti‐inflammatory cytokine IL‐10 (p< 0.05) in response to the 10 mg/kg MDMA dose. In the striatum, 10 mg/kg MDMA elicited a significant increase in expression of IL‐1β and astrocyte activation marker GFAP. AAV‐7F9‐Fc treatment mitigated the increase of IL‐10 in the serum and IL‐1β in the striatum. These results indicate that in addition to its previously reported protection against METH, AAV‐7F9‐Fc can mitigate an immunomodulatory cascade in the periphery and CNS resulting from MDMA exposure.Support or Funding InformationThis research was funded by NIH/NIDA:R01‐DA036600 & R01 DA036600‐03S1, NIH/NIGMS:T32‐GM106999, and R25GM083297.

Effects of methamphetamine acute exposure on neural damage

Objective To explore the neural damage induced by acute exposure to methamphetamine (METH). Methods The mice were administrated with METH, then the stereotyped behavior of mice was evaluated, and spatial recognition memory was analyzed by Y-maze test. In addition, nitric oxide synthase (NOS) activity was detected by kit, and the apoptotic proteins including Bax, Bcl-2, Caspase-3 were assayed by using Western blot. The DNA injury induced by METH was observed by using the comet assay. Moreover, mitochondrial membrane potential was detected to assess the toxic effects of METH on mitochondria by JC-1. With the Western blot assay, the phosphorylation of MAPK signaling pathways were also investigated. Results Acute METH exposure significantly increased the stereotyped behavior in mice, and spatial recognition ability of mice was obviously decreased. On the molecular level, total nitric oxide synthase (TNOS) and induced nitric oxide synthase (iNOS) were increased, and the apoptotic proteins, such as Bax and cleaved caspase-3 were markedly enhanced. With the comet assay, it showed that METH exposure resulted in DNA damage. In parallel, mitochondrial membrane was damaged which manifested as mitochondrial membrane potential decreased. With the western blot, It was further found that METH enhanced the activation of MAPKs. However, p38 MAPK signaling pathway was demonstrated to be the only one factor involved in METH-induced neural damage. Conclusion METH induced neural damage, and MAPK signaling pathways might be involved in this process, since inhibition of p38 MAPK signaling pathway significantly ameliorated METH-induced neural damage. Key words: Methamphetamine; Neural damage; MAPK signaling pathway

Abstract 17289: A Baffling Heart: a 30 Year-old Man with Biventricular Heart Failure and Severe Pulmonary Hypertension

A thirty year-old man with an unknown surgery for congenital heart disease presented with intermittent chest pain and progressive decline in his exercise tolerance. Cardiovascular examination revealed a soft S1, loud S2 without splitting, right ventricular heave, a sustained and laterally displaced apical impulse and clubbing of his fingers. An echocardiogram showed d-transposition of the great arteries (d-TGA), a dilated, sub-pulmonic left ventricle (LV) with reduced function, smaller than expected sub-aortic right ventricle with reduced function, and elevated sub-pulmonic left ventricular systolic pressure without LV outflow tract obstruction. Cardiac MRI revealed d-TGA status post Senning repair, biventricular dysfunction without baffle obstruction, no evidence of repaired atrial or ventricular septal defect or delayed gadolinium enhancement. Cardiac catheterization showed a suprasystemic pulmonary artery pressure, a pulmonary vascular resistance of 18.4 Wood units and a small right to left shunt due to a baffle leak. No coronary disease was found on angiography. The patient was diagnosed with severe pulmonary arterial hypertension and biventricular dysfunction. This pattern of heart failure was discordant from the expected sequelae of palliated congenital heart defects as pulmonary arterial hypertension and LV dysfunction are both uncommon long-term complications after atrial switch. Systematic evaluation for a unifying cause of the patient’s pattern of heart failure was unrevealing until the patient presented with decompensated heart failure and evidence of stimulant withdrawal. Urine toxicology was positive for methamphetamine and the patient was diagnosed with methamphetamine induced pulmonary arterial hypertension and subpulmonic LV dysfunction. This case demonstrates the importance of understanding the common, long-term patterns of heart failure in repaired congenital heart disease and the need to search for alternative etiologies when the pattern is inconsistent. This case further shows the toxic effects of methamphetamine on the pulmonary vasculature and myocardium, which in our patient resulted in a highly unique pattern of sub-pulmonic LV dysfunction and pulmonary arterial hypertension.

Methamphetamine and lentivirus interactions: Reciprocal enhancement of central nervous system disease

Use of methamphetamine is increasingly a significant factor for the spread of human immunodeficiency virus type 1, for in certain populations, there is a convergence of methamphetamine abuse with human immunodeficiency virus type 1 infection. Methamphetamine and human immunodeficiency virus type 1 are both individually neuropathogenic, and the neuropathology caused by these two agents occurs in overlapping brain regions. However, the biological interaction of methamphetamine with lentiviruses remains unknown. Here, we investigate the effects of simultaneous exposure of these two agents on disease progression using the feline immunodeficiency virus model. The study models the bingeing methamphetamine user with sequential and repeated episodes of use, which were interrupted by periods of abstinence. Methamphetamine exposure significantly accelerated and enhanced the severity of the feline immunodeficiency virus model-induced central nervous system functional pathology, as measured in delays in brainstem auditory evoked potentials. Reciprocally, feline immunodeficiency virus enhanced the severity of the methamphetamine-induced effects on brain monoamine neurotransmitter and dopamine transporter levels. The results of this study indicate that a dual potentiation occurred. That is, methamphetamine enhanced feline immunodeficiency virus model-induced central nervous system disease and feline immunodeficiency virus model enhanced the toxic effects of methamphetamine, heralding a significant concern for those individuals that are exposed to both agents.

Toxic Effect of Methamphetamine on the Retina of CD1 Mice

Purpose: To investigate whether systemic administration of methamphetamine (METH) induces retinal damage in CD1 mice. Materials and Methods: Eighteen male CD1 mice were randomly assigned to three groups, six mice per group: Group 1 receiving a single dose of 40 mg/kg METH, Group 2 receiving four doses of 10 mg/kg METH, and Group 3 (control) receiving 40 mg/kg 0.9% NaCl solution. METH and NaCl were administered by intraperitoneal injection. Immunostaining of glial fibrillary acidic protein (GFAP), S-100 for astrocytes and Muller cells, CD11b for microglia, and tyrosine hydroxylase (TH) and TUNEL labeling for apoptotic cell death were performed on the retinal sections on day 1 and day 7 post-exposure. Results: GFAP and S-100 immunoreactivity was observed in Group 1 mice. CD11b+ cells in Group 1 mice showed more intensely stained shorter and thicker cellular processes than Groups 2 and 3, indicating activated microglia in the mice exposed to large-dose METH. No significant difference in TH level was seen among the three groups. TUNEL labeling did not reveal positive cells in the retinas of any of the 18 CD1 mice. Conclusions: A single large dose of METH induces an increase in short-term protein expression of GFAP and S-100 and in microglial activation. The results suggest that METH has a neurotoxic effect on CD1 mouse retina.

Melatonin reduces induction of Bax, caspase and cell death in methamphetamine-treated human neuroblastoma SH-SY5Y cultured cells

Several studies demonstrated that methamphetamine (MA)-treated human neuroblastoma cells exhibit increased oxidative stress, which regulates intracellular signaling cascades leading to cell death. Melatonin has a potential as a direct free radical scavenger and protects against cell death caused by MA. The objective of this study was to investigate the neuroprotective properties of melatonin on MA-induced induction of death signaling cascade and neuronal cell degeneration in human neuroblastoma SH-SY5Y cultured cells. The results of the present study demonstrate that MA significantly reduced cell viability in SH-SY5Y cultured cells. Desipramine, a monoamine uptake blocker, and melatonin reversed the toxic effect of MA in reducing cell viability. Induction of Bax, Bcl-2 and cleaved caspase-3 protein levels were observed in SH-SY5Y cultured cells treated with MA, whereas the induction of Bax and cleaved caspase-3 was diminished by melatonin. Visualization of the induction of Bax using immunofluorescence but a reduction in mitochondrial sites using red-fluorescent mitochondria-staining dye was more obviously apparent in MA-treated cells than in untreated control cells and, again, this effect was abolished by melatonin. These findings demonstrate important roles of Bax and caspase in death signaling cascade, and the protective effects of melatonin in MA-treated SH-SY5Y cells.

Methamphetamine‐Induced Early Increase of IL‐6 and TNF‐α mRNA Expression in the Mouse Brain

The mechanisms by which methamphetamine (METH) causes neurotoxicity are not well understood. Recent studies have suggested that METH-induced neuropathology may result from a multicellular response in which glial cells play a prominent role, and so it is plausible to suggest that cytokines may participate in the toxic effects of METH. Therefore, in the present work we evaluated the effect of an acute administration of METH (30 mg/kg in a single intraperitoneal injection) on the interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha mRNA expression levels in the hippocampus, frontal cortex, and striatum of mice. We observed that METH did not induce changes in the IL-1beta mRNA expression levels in both hippocampus and striatum, with immeasurable levels in the frontal cortex. Regarding IL-6, METH induced an increase in the expression levels of this cytokine in the hippocampus and striatum, 1 h and 30 min post injection, respectively. In the frontal cortex, the increase in IL-6 mRNA levels was more significant and remained high even after 2 h. Moreover, the expression levels of TNF-alpha were increased in both hippocampus and frontal cortex 30 min post METH administration, with immeasurable levels in the striatum. We conclude that the pro-inflammatory cytokines IL-6 and TNF-alpha rapidly increase after METH administration, providing a new insight for understanding the effect of this drug of abuse in the brain.

Increased Vesicular Monoamine Transporter Binding during Early Abstinence In Human Methamphetamine Users: Is VMAT2 a Stable Dopamine Neuron Biomarker?

Animal data indicate that methamphetamine can damage striatal dopamine terminals. Efforts to document dopamine neuron damage in living brain of methamphetamine users have focused on the binding of [(11)C]dihydrotetrabenazine (DTBZ), a vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, as a stable dopamine neuron biomarker. Previous PET data report a slight decrease in striatal [(11)C]DTBZ binding in human methamphetamine users after prolonged (mean, 3 years) abstinence, suggesting that the reduction would likely be substantial in early abstinence. We measured striatal VMAT2 binding in 16 recently withdrawn (mean, 19 d; range, 1-90 d) methamphetamine users and in 14 healthy matched-control subjects during a PET scan with (+)[(11)C]DTBZ. Unexpectedly, striatal (+)[(11)C]DTBZ binding was increased in methamphetamine users relative to controls (+22%, caudate; +12%, putamen; +11%, ventral striatum). Increased (+)[(11)C]DTBZ binding in caudate was most marked in methamphetamine users abstinent for 1-3 d (+41%), relative to the 7-21 d (+15%) and >21 d (+9%) groups. Above-normal VMAT2 binding in some drug users suggests that any toxic effect of methamphetamine on dopamine neurons might be masked by an increased (+)[(11)C]DTBZ binding and that VMAT2 radioligand binding might not be, as is generally assumed, a "stable" index of dopamine neuron integrity in vivo. One potential explanation for increased (+)[(11)C]DTBZ binding is that VMAT2 binding is sensitive to changes in vesicular dopamine storage levels, presumably low in drug users. If correct, (+)[(11)C]DTBZ might be a useful imaging probe to correlate changes in brain dopamine stores and behavior in users of methamphetamine.

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function. Two weeks after a methamphetamine binge (4 x 10 mg/kg, i.p., at 2 h intervals), GDNF(+/-) mice had a significantly greater reduction of tyrosine hydroxylase immunoreactivity in the medial striatum, a proportionally greater depletion of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum, and a greater increase in activated microglia in the substantia nigra than wild-type mice. At 12 months of age, methamphetamine-treated GDNF(+/-) mice exhibited less motor activity and lower levels of tyrosine hydroxylase-immunoreactivity, dopamine, DOPAC, and serotonin than wild-type mice. Greater striatal dopamine transporter activity in GDNF(+/-) mice may underlie their differential response to methamphetamine. These data suggest the possibility that methamphetamine use in young adults, when combined with lower levels of GDNF throughout life, may precipitate the appearance of parkinsonian-like behaviors during aging.

Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers

Preclinical investigations have established that methamphetamine (MA) produces long-term changes in dopamine (DA) neurons in the striatum. Human studies have suggested similar effects and correlated motor and cognitive deficits. The present study was designed to further our understanding of changes in brain function in humans that might result from chronic high dose use of MA after at least 3 months of abstinence. Brain function in abstinent users was compared to controls using neuroimaging of monoamine transporters and cognitive assessment. Striatal levels of DA transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined using [11C]methylphenidate and [11C]dihydrotetrabenazine positron emission tomography, respectively. Cognitive function was evaluated using tests of motor function, memory, learning, attention, and executive function. Striatal DAT was approximately 15% lower and VMAT2 was 10% lower in MA abusers across striatal subregions. The MA abusers performed within the normal range but performed more poorly compared to controls on three of the 12 tasks. Failure to find more substantial changes in transporter levels and neurocognitive function may be attributed to the length of time that MA users were abstinent (ranging from 3 months to more than 10 years, mean 3 years), although there were no correlations with length of abstinence. Persistent VMAT2 reductions support the animal literature indicating a toxic effect of MA on nigrostriatal nerve terminals. However, the magnitude of the MA effects on nigrostriatal projection integrity is sufficiently small that it is questionable whether clinical signs of DA deficiency are likely to develop.

Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.

Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1H MRS study.

To determine whether proton MRS (1H MRS) can detect long-term metabolite abnormalities in abstinent methamphetamine users. Methamphetamine is toxic to dopaminergic and serotonergic neurons in rodents; however, little data are available on the toxic effects of methamphetamine on the human brain. 1H MRS was performed in 26 abstinent methamphetamine abusers with a history of methamphetamine dependence (median total cumulative lifetime exposure, 3,640 g; median recency of last methamphetamine use, 4.25 months) and 24 healthy subjects without a history of drug abuse. Cerebral metabolite concentrations on 1H MRS were measured in the frontal cortex, frontal white matter, and basal ganglia. The concentration of N-acetylaspartate ([NA]), a neuronal marker, was reduced significantly (-5 to -6%) in the basal ganglia and frontal white matter of methamphetamine users compared with control subjects. The frontal white matter [NA] correlated inversely with the logarithm of the lifetime methamphetamine use. The methamphetamine users also showed significantly reduced total creatine in the basal ganglia (-8%), and increased choline-containing compounds ([CHO], +13%) and myo-inositol ([MI], +11%) in the frontal grey matter. The reduced [NA] on 1H MRS provides evidence for long-term neuronal damage in abstinent methamphetamine users.

Toxic effects of methamphetamine and dopamine in cell culture

Toxic effects of methamphetamine and dopamine in cell culture

Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice

The toxic effects of methamphetamine (METH) (2.5, 5.0 and 10.0 mg/kg) and methylenedioxymethamphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdr1a wild-type and knockout mice. METH caused significant dose-dependent decreases of dopamine (DA) and DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest doses of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked decreases in the mdr1a knockout mice. The two higher doses (5 mg/kg and 10 mg/kg) caused similar changes in both strains of mice. In contrast to METH, MDMA caused greater percentage decreases in DAT in the wild-type mice. For example, the lowest dose (5 mg/kg) caused significant decreases in DAT in the NAc of wild-type but not of mdr1a knockout mice. The highest dose (20 mg/kg) caused similar changes in both the strains. These results suggest that METH and MDMA interact differentially with P-glycoproteins. These observations document, for the first time, a role for these proteins in the entry of METH and MDMA into the brain via the blood–brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering with that of METH into the brain.

THE ROLE OF GLUTAMATE IN BEHAVIORAL AND NEUROTOXIC EFFECTS OF METHAMPHETAMINE

Studies on the mechanisms of behavioral and neurochemical effects of amphetamine or methamphetamine (MA) have focused on the dopaminergic system. However, recent reports suggest that the glutamatergic system may be involved in the MA effects. Our laboratory has been conducting a series of experiments to further examine the role of glutamate in both behavioral and neurotoxic effects of MA. These studies include (1) behavioral studies on the effect of N-methyl d-aspartate (NMDA) antagonists on the development of MA-induced behavioral sensitization, (2) neurochemical studies on the effects of NMDA antagonists on MA-induced neurotoxicity, and (3) in vivo microdialysis studies on the effects of MA on glutamate release. In the present paper, the authors comment on an important role of glutamatergic systems in the behavioral and toxic effects of MA. Copyright © 1996 Elsevier Science Ltd.