Chronic Methamphetamine Use Research Articles

Microglial and astrocytic changes in the striatum of methamphetamine abusers

Little is known about the role of glial cells in the striatum of chronic methamphetamine (METH) users. In this study, we immunohistochemically examined glial reactions in the striatum of chronic METH users who did not abstain from METH use and died of drug intoxication. Human glucose transporter 5 (hGLUT), a useful marker of microglia, and CR3.43, a major histocompatibility complex class II antigen specific for reactive microglia, were immunostained. Glial fibrillary acidic protein (GFAP) and S100Β were used for astrocyte immunohistochemistry. We analyzed 12 chronic METH users and 13 control subjects, and detected a 200–240% increase in the number of hGLUT5-positive cells in chronic METH users ( p < 0.01). However, we did not detect any proliferation of CR3.43-positive cells. The number of GFAP-positive astrocytes increased, but this increase was not significant ( p > 0.05). Moreover, S100B-positive cell density between the two groups was not significant ( p > 0.05). This study demonstrates the absence of reactive gliosis in the striatum of chronic METH users who did not abstain for prolonged periods from METH use. The results suggest that chronic METH use by itself did not activate glial cells in humans and reactive gliosis may not be involved in the mechanism underlying the loss of control in drug intake, which is a characteristic feature of drug addiction.

Metabolic Abnormalities in Abstinent Methamphetamine Dependent subjects

INTRODUCTION: Chronic methamphetamine use results in persistent neuropsychological deficits in abstinent methamphetamine dependent (AMD) subjects. We examined the hypothesis that elevated concentration of cerebral glutamate (Glu), an excitatory neurotransmitter and neurotoxin, occurs in human AMD. MATERIALS AND METHODS: We examined 40 subjects, 18 of whom were AMD, abstinent more than 3 weeks and 22 were age matched controls. A Structured Clinical Interview was applied to exclude AMD with comorbid depression. We used TE-Averaged technique of MRS to uniquely identify and quantify the glutamate resonance at 2.35 ppm on a 3T clinical MR scanner. Statistics, including Bonferroni correction for multiple MRS variables were applied. RESULTS: Glu was significantly higher in frontal white matter of AMD (+19%, P = 0.01) and N-acetylaspartate (NAA), an axonal marker, was lower (-14%, P = 0.004). No significant MRS abnormalities were detected in posterior gray matter. Significant correlations were observed between NAA and Glu (P = 0.002 for AMD and P = 0.06 for controls in the posterior gray matter and P = 0.01 for controls and not significant for AMD in the frontal white matter). CONCLUSION: Our results demonstrate a significant excess of glutamate in frontal white matter of AMD subjects and offer support for the hypothesis that methamphetamine abuse may exert its long-term neuro-toxicity via glutamate.

Serotonin 2 receptor modulation of hyperthermia, corticosterone, and hippocampal serotonin depletions following serial exposure to chronic stress and methamphetamine

Chronic stress precipitates drug seeking behavior and alters the effects of drugs of abuse. Although it is known that chronic stress potentiates acute neurochemical and hyperthermic responses to the drug of abuse methamphetamine, no studies have investigated if and how chronic stress alters other physiological responses to methamphetamine. Therefore the objective of these studies was to determine if 10 days of chronic unpredictable stress modulates corticosterone (CORT) responses to methamphetamine and furthermore how chronic stress may modulate methamphetamine-induced increases in hyperthermia and CORT. As chronic stress potentiates hyperthermic responses to serotonin 2 (5-HT2) stimulation and 5-HT2 receptors are important in mediating both hyperthermic and CORT responses, we also investigated if 5-HT2 antagonism would block hyperthermia and CORT secretion by the serial exposure to stress and methamphetamine (stress/methamphetamine). The results of these studies illustrate that stress potentiates methamphetamine-induced increases in body temperature and CORT secretion and that these increases are blocked by the 5-HT2 antagonist ketanserin. Furthermore, the combination of stress and methamphetamine depletes 5-HT content in the hippocampus 7 days after methamphetamine administration which is blocked by the 5-HT2 antagonist ketanserin. Overall, these results indicate a pharmacological mechanism for the depletion of hippocampal 5-HT by the serial exposure to stress and methamphetamine and further illustrate the deleterious interactions between chronic stress and methamphetamine use.

P01-44 In vivo evidence for long-term CNS toxicity associated with chronic binge use of methamphetamine

Purpose:Methamphetamine has strong addictive characteristics and is a potent neurotoxin. We use Single PhotonEmission Computed Tomography (SPECT) to study brain perfusion in persons who were formerly chronic binge users of methamphetamine and who at the time of imaging had abstained from methamphetamine use for anaverage of 2 years.Methods:Members of the methamphetamine group were 20 men who had previously injected methamphetamine intravenously for over 30 months and who were now abstinent for a minimum of 9 months and for an average of 2 years. Controls were 12 healthy men who had never injected methamphetamine. Images were obtained 40 minutes after intravenous injection of 1110 MBq of Tc-99m ECD using a dual-head gamma camera (ECAM plus; Siemens).Results:The mean global count was significantly decreased in methamphetamine group compared with that of control group (p &lt; 0.0001). After global normalization, rCBF in methamphetamine user group compared with the control group was significantly disproportionately reduced in the striatum, thalamus, cingulum, mesiodorsal prefrontal cortex, and pons. Furthermore, normalized rCBF was strongly intercorrelated across all regions where disproportionate hypoperfusion was identified, including striatum and thalamus (r=0.90), thalamus and cingulum (r=0.91), thalamus and pons(r=0.89), and striatum and pons (r=0.94).Conclusions:Binge use of methamphetamine produces long-term changes in global and regional blood flow producing a pattern of hypoperfusion that resembles patterns reported previously for persons with atypical Parkinson disease. These findings suggest that methamphetamine abusers may be at increased risk for neurodegenerative diseases later in life.

Risk factors associated with methamphetamine use and heart failure among Native Hawaiians and other Pacific Island peoples

Heart failure (HF), a long term outcome of chronic methamphetamine use (MU), occurs more frequently in racial and ethnic minority populations at high risk for cardiovascular disparities. This study examined the association of socio-demographic and clinical risk factors with MU among heart failure patients who are Native Hawaiians (NH) or other Pacific Island peoples (PIP). DESIGN/SETTING/PATIENT POPULATION: Cross-sectional study of NHs and PIPs with advanced heart failure enrolled in the Malama Pu'uwai Study, a randomized control trial to test an educational intervention to reduce re-hospitalization and/or death. A total of 82 participants were enrolled between 6/1/06 to 12/31/07 and met the following eligibility criteria: 1) self-identified NH or PIP, 2) Left ventricular systolic ejection fraction <or=45%, 3) Age of 21 years or older. Data were analyzed by odds ratios (OR), 95% confidence intervals (CI), and multiple logistic regression analysis. Methamphetamine use. Twenty-two percent of HF participants were identified as being current or prior methamphetamine users. Younger age and non-married status (combined never married or divorced/separated) were independently associated with MU after adjustment for sex, education, and other co-morbidities associated with HF (ie, age >50 years, OR = 0.16, 95% CI, 0.03-0.84; non-married status combined as never married OR = 8.5, CI, 1.5-47; divorced/separated OR = 11, CI 1.8-75). RISK FACTORS ASSOCIATED WITH MU IN NH AND PIPS WITH HEART FAILURE INCLUDE: younger age and being divorced/separated or never married. Health care providers should be aware of MU as a contributing factor in the approach and treatment of HF in NHs and PIPs.

Methamphetamine Fails to Alter the Noradrenergic Integrity of the Heart

The chronic use of methamphetamine leads to cardiomyopathy and a nigrostriatal dopamine deficiency that partly mimics what occurs in Parkinson's disease. This study examines the cardiac effects occurring after chronic administration of methamphetamine and parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Despite the similarities concerning the nigrostriatal dopamine denervation, methamphetamine failed to produce chronic norepinephrine depletion in the heart, thus contrasting with what occurs in Parkinson's disease or after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These data suggest that the chronic cardiovascular effects induced by methamphetamine rely on biochemical changes which differ from those activated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or during the course of Parkinson's disease.

Use of stimulants to treat cocaine and methamphetamine abuse.

The concept of using stimulants to treat cocaine and methamphetamine dependence is largely based on the "replacement" therapy model that has shown efficacy for treating nicotine and opiate dependence. Although results have been mixed, some evidence supports using stimulant medication to reduce cocaine use. There are not enough data to date to determine the efficacy of stimulants for methamphetamine dependence. Drawbacks of stimulants as treatments include the potential for abuse of the treatment, which necessitates careful screening and monitoring of patients. Possible reasons for efficacy of stimulants include enhancement of monoamine function dysregulated by chronic cocaine or methamphetamine use. Newer medications that enhance dopamine function but lack the abuse potential of older stimulants are being studied. It is hoped that these medications will provide safe, effective treatment for cocaine and methamphetamine dependence, but more research on this topic is needed.

MGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats.

Addiction to methamphetamine is a significant public health problem, and there are currently no pharmacological agents that are approved for the treatment of addiction to this powerful psychostimulant. Chronic methamphetamine use leads to cognitive dysfunction as well as numerous psychiatric, neurological, and cardiovascular complications. There is a growing body of literature implicating an important role for glutamate neurotransmission in psychostimulant addiction. In the present study, we examined the effects of the selective type 5 metabotropic glutamate receptor (mGluR5) antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) on intravenous self-administration of methamphetamine and reinstatement of methamphetamine-seeking behavior. Adult male Sprague-Dawley rats were trained to respond for intravenous methamphetamine (0.1 or 0.2 mg/kg per infusion) or food pellets and were subsequently administered vehicle or MTEP (0.3-3 mg/kg) before drug or food self-administration on a fixed-ratio 1 (FR1) schedule of reinforcement or a progressive ratio (PR) schedule of reinforcement. We also examined the effects of vehicle or MTEP (0.3-3 mg/kg) on cue- and drug-induced reinstatement of methamphetamine-seeking behavior as well as cue-induced reinstatement of food-seeking behavior. Our results show that MTEP dose dependently reduced the reinforcing effects of methamphetamine under FR1 and PR schedules of reinforcement without altering overall responding for food. MTEP also dose dependently prevented cue- and drug-induced reinstatement of methamphetamine-seeking behavior, but did not alter cue-induced reinstatement of food-seeking behavior. Together, these results indicate that mGluR5 receptors mediate methamphetamine reinforcement and methamphetamine-seeking behavior, and that pharmacological inhibitors of mGluR5 receptor function may represent a novel class of potential therapeutic agents for the treatment of methamphetamine addiction.

Illicit Stimulant Use in a United States Heart Failure Population Presenting to the Emergency Department (from the Acute Decompensated Heart Failure National Registry Emergency Module)

Illicit stimulant drug use may have a profound clinical impact in acute decompensated heart failure (ADHF). The chronic use of cocaine and methamphetamine may lead to overt cardiomyopathy and ADHF. The Acute Decompensated Heart Failure National Registry Emergency Module (ADHERE-EM) collected data on patients presenting to emergency departments with ADHF at 83 geographically dispersed hospitals in the United States. This registry was queried to determine the rate of self-reported illicit drug use in emergency department patients presenting with ADHF and compare these patients with those without illicit drug use. The registry enrolled 11,258 patients with ADHF with drug use data from January 2004 to March 2006. Of these patients, 594 (5.3%) self-reported current or past stimulant drug use. Compared with nonusers, these patients were more likely to be younger (median age 49.7 vs 76.1 years), to be African American (odds ratio 11.9, 95% confidence interval 9.8 to 14.4), and to have left ventricular ejection fractions <40% (odds ratio 3.4, 95% confidence interval 2.8 to 4.2). Admitted users had no difference in mortality (adjusted odds ratio 0.83, 95% confidence interval 0.25 to 2.72) compared with nonusers. In conclusion, data from ADHERE-EM suggest that a clinically important percentage of patients with ADHF report the use of illicit stimulant drugs. Although these patients are younger with a greater degree of LV dysfunction, they did not have greater risk-adjusted mortality.

P.6.d.004 In vivo evidence for long-term CNS toxicity associated with chronic binge use of methamphetamine

P.6.d.004 In vivo evidence for long-term CNS toxicity associated with chronic binge use of methamphetamine

Adaptation of Brain Glutamate Plus Glutamine during Abstinence from Chronic Methamphetamine Use

Methamphetamine (METH) is a stimulant drug that is toxic primarily to dopaminergic and serotonergic neurons and may lead to inflammatory changes in the brain. Additionally, the glutamatergic system is altered following METH exposure. Therefore, concentrations of brain glutamate + glutamine (GLX) were assessed during abstinence from chronic METH abuse. Twenty-five subjects with a history of METH dependence (age 31.8 +/- 7.4 years, 14 women and 11 men) and 28 control subjects without a history of drug abuse (age 32.6 +/- 8.8 years, 14 women) were enrolled. Twelve of the METH subjects were followed and rescanned 5 months later. METH users had used the drug 5.9 +/- 1.7 times per week, for 109 +/- 69 months, and had been abstinent for 2.1 +/- 3.0 months. GLX was measured in the basal ganglia and frontal gray and white matter, using proton magnetic resonance spectroscopy. While overall GLX concentrations at baseline were similar between METH and control subjects, METH users with less than or equal to 1 month of abstinence showed reduced frontal gray matter GLX (p = 0.01). Time of abstinence correlated positively with GLX in frontal gray (p < 0.0001) and white matter (p = 0.03). After 5 months, changes in frontal gray matter GLX showed a trend to correlate inversely with the duration of abstinence (p = 0.07). Subjects with craving symptoms had lower frontal gray matter GLX than those without craving (-8%, p = 0.05). These findings suggest dynamic abnormalities in brain GLX in recently abstinent METH users, with a depletion of the glutamatergic system in METH users within the first 2 months of abstinence and some normalization during prolonged abstinence. Since craving may contribute to relapse, medications that normalize GLX may minimize craving in METH users.

A Collaborative Model for Community Action Against Methamphetamine

San Diego County has a long history of chronic use of methamphetamine, and thus also has a track record in organizing an effective community response. This article discusses the formation and structure of the Methamphetamine Strike Force, and discusses its multidisciplinary collaborative problem solving model. Four strategies-prevention, intervention, treatment and interdiction-form a comprehensive set of recommendations that have guided action over the last decade. The Strike Force provides the region with a structure to mobilize its rich in-kind resources towards a shared plan of action. Data, organizing. media, policy and law enforcement are all central to the emerging model.

Neurocognitive Effects of Methamphetamine: A Critical Review and Meta-analysis

This review provides a critical analysis of the central nervous system effects of acute and chronic methamphetamine (MA) use, which is linked to numerous adverse psychosocial, neuropsychiatric, and medical problems. A meta-analysis of the neuropsychological effects of MA abuse/dependence revealed broadly medium effect sizes, showing deficits in episodic memory, executive functions, information processing speed, motor skills, language, and visuoconstructional abilities. The neuropsychological deficits associated with MA abuse/dependence are interpreted with regard to their possible neural mechanisms, most notably MA-associated frontostriatal neurotoxicity. In addition, potential explanatory factors are considered, including demographics (e.g., gender), MA use characteristics (e.g., duration of abstinence), and the influence of common psychiatric (e.g., other substance-related disorders) and neuromedical (e.g., HIV infection) comorbidities. Finally, these findings are discussed with respect to their potential contribution to the clinical management of persons with MA abuse/dependence.

Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol

Although chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans, there are few reports about an animal model that reflects METH-induced impairment of working memory. In this study, we investigated the effect of repeated METH treatment on spatial working memory in rats. Rats were repeatedly administered METH (2 mg/kg) once a day for 7 days, and their memory function was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. METH-treated animals showed an impairment of performance in the test phase when the delay time was increased from 5 to 30 min or longer. The effect of METH persisted for at least 14 days after the drug withdrawal. METH-induced impairment of working memory was reversed by clozapine (3 and 10 mg/kg, for 7 days), but not haloperidol (1 and 2 mg/kg, for 7 days). The improving effect of clozapine diminished 7 days after the withdrawal. Phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) levels were significantly increased in the hippocampus of saline-treated control rats from 5 to 60 min after the training phase. In contrast, hyperphosphorylation of ERK1/2 was abolished in the hippocampus of rats treated with METH. These findings suggest that repeated METH treatment induces impairment of working memory, which is associated with a dysfunctional ERK1/2 pathway in the hippocampus. Furthermore, clozapine may be effective for the treatment of METH-induced cognitive dysfunction.

Preclinical Testing of a High Affinity Single Chain Antibody against (+)‐Methamphetamine (METH)

Chronic METH use and overdose cause severe medical complications. Treatment with an anti-METH antibody antagonist could offer significant advantages by reducing drug concentrations in target organs. A smaller version of the IgG could offer opportunities for customized pharmacokinetics for a variety of treatment options (e.g. chronic vs. overdose). Toward this end, we have developed a novel single chain antibody (scFv) against METH. This scFv was engineered from anti-METH mAb6H4 and was found to have similar immunochemical properties. The anti-METH scFv (scFv6H4) was cloned and expressed in yeast, and purified to homogeneity as a mixture of dimer (25%) and monomer forms (75%). To test the efficacy of the scFv in vivo, we implanted rats with 3-day osmotic pumps delivering METH at 3.2 mg/kg/day. After reaching steady state, a dose of scFv6H4 equimolar to the body burden of METH (32 mg/kg) was delivered in a bolus dose with a 3H-scFv6H4 tracer. Serum pharmacokinetic analysis showed that the introduction of scFv6H4 caused an immediate 65-fold change in the METH concentration, and a 12-fold change in the area under the concentration-time curve. The monomer form was cleared quickly (t½ = 5.5 min), but the dimer form showed a much longer half life (232 min). These data suggest that the dimer was primarily responsible for the in vivo binding of METH in rat serum. Funded by NIH DA11560, DA14361, and DA018039.

Methamphetamine use and violence among young adults

The current research analyzed the relationship between methamphetamine use and violence among young adults eighteen to twenty-five years old. Interviews were conducted with a sample of 106 respondents. The research was based primarily on in-depth, life-history interviews with individuals who used methamphetamine for a minimum of three months and who resided in Los Angeles County. Of the 106 respondents, 37 (34.9 percent) had committed violence while under the influence of methamphetamine. Males comprised two-thirds of the 37 respondents (N = 24). Of the total sample, 38 percent of males and 30 percent of females committed methamphetamine-related violence, respectively. Overall, the 37 respondents reported fifty-four separate violent events while using methamphetamine. Of these fifty-four events, thirty-three (61.1 percent) acts of violence involved domestic relationships, nine (16.7 percent) of the violent events were drug related, seven (13 percent) were gang related, and five (9.3 percent) involved random acts of violence (e.g., road rage, stranger assault). The findings suggest that methamphetamine use is a risk factor for violence. There was, however, no evidence of a single, uniform career path that all chronic methamphetamine users follow. Violence is not an inevitable outcome of even chronic methamphetamine use.

Methamphetamine Modulates Gene Expression Patterns in Monocyte Derived Mature Dendritic Cells

The US is currently experiencing a grave epidemic of methamphetamine use as a recreational drug, and the risk for HIV-1 infection attributable to methamphetamine use continues to increase. Recent studies show a high prevalence of HIV infection among methamphetamine users. Dendritic cells (DCs) are potent antigen presenting cells that are the initial line of defense against HIV-1 infection. In addition, DCs also serve as reservoirs for HIV-1 and function at the interface between the adaptive and the innate immune systems, which recognize and internalize pathogens and subsequently activate T cells. Exposure to methamphetamine results in modulation of immune functional parameters that are necessary for host defense. Chronic methamphetamine use can cause psychiatric co-morbidity, neurological complications, and can alter normal biological processes and immune functions. Limited information is available on the mechanisms by which methamphetamine may influence immune function. This study explores the effect of methamphetamine on a specific array of genes that may modulate immune function. We hypothesize that methamphetamine treatment results in the immunomodulation of DC functions, leading to dysregulation of the immune system of the infected host. This suggests that methamphetamine has a role as a cofactor in the pathogenesis of HIV-1. We used the high-throughput technology of gene microarray analysis to understand the molecular mechanisms underlying the genomic changes that alter normal biological processes when DCs are treated with methamphetamine. Additionally, we validated the results obtained from microarray experiments using a combination of quantitative real-time PCR and Western blot analysis. These data are the first evidence that methamphetamine modulates DC expression of several genes. Methamphetamine treatment alters categories of genes that are associated with chemokine regulation, cytokinesis, signal transduction mechanisms, apoptosis, and cell cycle regulation. This report focuses on a selected group of genes that are significantly modulated by methamphetamine treatment and that have been associated with HIV-1 pathogenesis. The purpose of this study was to identify genes that are unique and/or specific to the complex immunomodulatory mechanisms that are altered as a result of methamphetamine abuse in HIV-1-infected patients. These studies will help to identify the molecular mechanisms that underlie methamphetamine toxicity, and several functionally important classes of genes have emerged as targets in methamphetamine-mediated immunopathogenesis of HIV-1. Identification of novel DC-specific and methamphetamine-responsive genes that modulate several biological, molecular, and signal transduction functions may serve as methamphetamine- and/or HIV-1-specific drug targets.

Drug-Induced Psychosis Associated with Crystalline Methamphetamine

A case of drug-induced psychosis related to crystalline methamphetamine is described, highlighting the phenomenology and relevant treatment. A 44-year-old woman with borderline personality traits and severe drug dependence developed a protracted drug-induced psychosis related to chronic high-dose crystalline methamphetamine use. Complete resolution of symptoms occurred with antipsychotic medication and abstinence from methamphetamine. Rapid recurrence of symptoms occurred at a time of high stress associated with minimal methamphetamine use and cessation of low-dose quetiapine. Symptoms rapidly resolved with abstinence, quetiapine and reduction of stressors. A drug-induced psychosis resembling paranoid schizophrenia can occur with repeated or high-dose use of methamphetamine. While this generally resolves rapidly with cessation of stimulant use, some cases of protracted drug-induced psychosis in vulnerable individuals have been documented. Behavioural sensitization can also occur, and neuroleptics may prevent the recurrence of further psychosis triggered by ongoing low-dose methamphetamine use.

Methamphetamine use and Violence

The current research analyzed the relationship between methamphetamine use and violence. Interviews were conducted with a sample of 205 respondents. The research was based on life history interviews with individuals who used methamphetamine for a minimum of three months and who resided in Los Angeles County. Of the 205 respondents, 55 (26.8%) had committed violence while under the influence of methamphetamine. Males comprised two thirds of the 55 respondents (N=36). Of the total sample, 30% of males and 23% of females committed methamphetamine-related violence, respectively. Overall, the 55 respondents reported 80 separate violent events while using methamphetamine. Of these 80 events, 41 (51.4%) acts of violence involved domestic relationships, 28.6% (N=23) of the violent events were drug related, 8.6% (N=7) were gang related, and 11.3% (N=9) involved random acts of violence (e.g., road rage, stranger assault). The study findings suggest that methamphetamine use heightens the risk for violence. Everyone interviewed agreed that methamphetamine has clear abuse and violence potential. Having said this, it is crucial to state that there was no evidence of a single, uniform career path that all chronic methamphetamine users follow. Progression from controlled use to addiction is not inexorable. Furthermore, a significant number of sample members experienced limited or no serious social, psychological, or physical dysfunction as a result of their methamphetamine use. Most germane to this study, we found that violence is not an inevitable outcome of even chronic methamphetamine use.

Repeated Methamphetamine Treatment Impairs Recognition Memory Through a Failure of Novelty-Induced ERK1/2 Activation in the Prefrontal Cortex of Mice

Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice. Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2). Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment. These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.