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Patients and psychotherapists often exhibit behavioral, psychological, and physiological similarity. Here, we test whether oxytocin-a neuropeptide that can enhance expressivity and social perception-influences time-lagged "linkage" of autonomic nervous system responses among participants and facilitators during group therapy. Physiological linkage estimates (n = 949) were created from ten cohorts, each with two facilitators (n = 5) and four to six participants (n = 48), over six weekly sessions of group therapy for methamphetamine use disorder. All participants of a cohort received oxytocin or placebo intranasally in a randomized double-blind procedure before each session. Cardiac interbeat intervals (IBI) were measured continuously during sessions to estimate physiological linkage, operationalized as one cohort-mate's IBI reactivity during one minute predicting another cohort-mate's IBI reactivity during the following minute. In oxytocin cohorts, participants and facilitators experienced significant physiological linkage to their cohort-mates (i.e., their physiological responses were predicted by the prior responses of their cohort-mates) and significantly more linkage than people in placebo cohorts. Both effects occurred during the first and second sessions but not later sessions. Results suggest that oxytocin may enhance psychosocial processes often associated with linkage-such as social engagement-in groups and highlight oxytocin's potential to improve group cohesion during group therapy.Clinical Trials Registration: NCT02881177, First published on 26/08/2016., (© 2021. The Author(s).)

Aim: We investigated DNA methylation of BDNF  in methamphetamine (METH) dependence in humans and an animal model. Materials & methods: BDNF methylation at exon IV was determined by pyrosequencing of blood DNA from METH-dependent and control subjects, and from rat brain following an escalating dose of METH or vehicle. Bdnf expression was determined in rat brain. Results: BDNF methylation was increased in human METH dependence, greatest in subjects with psychosis and in prefrontal cortex of METH-administered rats; rat hippocampus showed reduced Bdnf methylation and increased gene expression. Conclusion: BDNF methylation is abnormal in human METH dependence, especially METH-dependent psychosis, and in METH-administered rats. This may influence BDNF expression and contribute to the neurotoxic effects of METH exposure.

Background: The prefrontal-striatal circuit is a core circuit related to substance dependence. Previous studies have found that repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) (key region of executive network) had limited responses, while inhibiting hyperactivation of ventromedial prefrontal cortex (vmPFC) (key region of limbic network) may be another strategy. However, there is currently no comparison between these two treatment locations., Methods: Seventy-four methamphetamine-dependent patients were randomly assigned to one of treatment groups with two-week treatment: (1) Group A: intermittent theta-burst stimulation (iTBS) targeting the left DLPFC; (2) Group B: continuous theta-burst stimulation (cTBS) targeting the left vmPFC; (3) Group C: a combination of treatment protocol of Group A and Group B; (4) Group D: sham theta-burst stimulation. The primary endpoint was the change of cue-induced craving. The trial was registered at ClinicalTrials.gov (NCT03736317)., Findings: The three real TBS groups had more craving decrease effect than the sham group (p<0.01). The changes of craving were positively correlated with the improvement of anxiety and withdrawal symptom. With the highest respondence rate, group C also had shorter respondence time than Group A (p = 0.03). Group C was effective in improve depression symptoms (p = 0.04) and withdrawal symptom (p = 0.02) compared with Group D. Besides, Group C was significant in improve sleep quality (p = 0.04) compared with Group A. Baseline depression scores and spatial working memory were positively predicting the intervention response., Interpretation: The rTMS paradigms involving vmPFC with cTBS are optimized protocols and well-tolerated for methamphetamine-dependent individuals, and they may have better efficacies compared with DLPFC iTBS. Emotion and cognitive function are rTMS treatment response predictors for methamphetamine-dependent patients., Funding: This work was supported by the National Key R&D Program of China (2017YFC1310400), National Natural Science Foundation of China (81,771,436, 81,801,319, 81,601,164), Shanghai Municipal Health and Family Planning Commission (2017ZZ02021), Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ013), Qihang Project of Shanghai Mental Health Center (2019-QH-05), Shanghai Sailing Program (19YF1442100), Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500), Program of Shanghai Academic Research Leader (17XD1403300), Shanghai Municipal Science and Technology Major Project (2018SHZDZX05), and Shanghai Clinical Research Center for Mental Health (19MC1911100)., Competing Interests: Declaration of Competing interest All authors declared no competing interests for this work., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To determine whether physical dependence developed during lisdexamfetamine dimesylate treatment, as evidenced by presence of withdrawal symptoms after treatment cessation in adults with binge-eating disorder (BED) treated for up to 38 weeks., Methods: Three studies enrolled adults with DSM-IV-TR-defined BED. In two 12-week, randomized, double-blind, placebo-controlled studies conducted from November 2012 to September 2013, participants were treated with placebo or dose-optimized lisdexamfetamine (50 or 70 mg). In a double-blind, placebo-controlled, randomized-withdrawal maintenance-of-efficacy study conducted from January 2014 to April 2015, participants categorized as responders after 12 weeks of open-label lisdexamfetamine (50 or 70 mg) were randomized to continued lisdexamfetamine or placebo for 26 weeks. The Amphetamine Cessation Symptom Assessment (ACSA), a 16-item self-report instrument (total score: 0-64), assessed withdrawal experiences. Mean ± SD ACSA scores and medians are presented for study completers., Results: In the short-term efficacy studies, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine (pooled data) were 7.0 ± 7.60 (n = 275) and 4.9 ± 6.41 (n = 271), respectively, on the day of the last dose at week 12/early termination (ET) and 4.8 ± 6.82 (n = 234) and 5.5 ± 7.50 (n = 221) on day 7 after the last dose. In the maintenance-of-efficacy study, mean ± SD ACSA aggregate scores for placebo and lisdexamfetamine were 4.8 ± 6.67 (n = 44) and 4.7 ± 7.78 (n = 85) on the day of the last dose at week 38/ET and 3.9 ± 5.75 (n = 37) and 5.2 ± 7.93 (n = 71) on day 7 after the last dose., Conclusions: Study results suggest that abrupt lisdexamfetamine termination was not associated with amphetamine withdrawal symptoms at the exposure durations and therapeutic doses analyzed., Trial Registration: Clinicaltrials.gov identifiers: NCT01718483, NCT01718509, and NCT02009163., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

1. Drinks sweetened with both sugar and artificial additives lead to dopamine release at the nucleus accumbens (NAc) in rat models; the basis of experiences of pleasure in humans, resulting in impulsive binging behaviour at times. 2. Evidence from rat models show cross sensitisation between sweetened drinks, alcohol, opiates and stimulants. Therefore, it could be hypothesised that sweetened drinks could be a gateway to multiple substance abuse among humans via 'alcopops'. 3. Identification of an allelic variant of the cyclic adenosine monophosphate responsive element modulator gene (CREM), linking impulsivity and multiple substance abuse, opens up prospects of mass screening to advice on harm reduction. 4. Furthermore, therapies involving cannabinoid receptor antagonists and transcranial brain stimulation are being currently investigated; of benefit to limit binge use of sweetened drinks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Methamphetamine (MA) is an addictive psychostimulant substance that mainly leads to schizophrenia-like psychotic symptoms. The expression of miRNAs in brain plays an important role in neurological disorders and may affect by genetic variant(s) in the target site (MiRSNPs). In this study, we investigated whether polymorphisms in miRNAs are associated with MA disorder with psychosis., Methods: We carried out a case-control association study in 400 MA users with psychotic characters and 448 controls. Six MiRSNPs with predicted functional relevance miRNAs (miR-181b, miR-181a, miR-15b, miR-let-7e and miRlet-7d) were selected for genotyping. Allele and genotype frequencies were compared between MA users and healthy individuals. The expression of five miRNAs were measured by quantitative real-time RT-PCR in 55 cases and 57 controls. We also explored an expression Quantitative Trait Loci (eQTL) analysis based on the miRNAs expression and SNP genotype., Results: The SNP rs10760371 within miR-181a was nominally associated with MA disorder (P = 0.046). For rs1099308, rs10760371 and rs10993081 in strong linkage disequilibrium (LD), no significant association had been detected from haplotype analysis. Discrepancy had been found between MA users and healthy individuals (P < 0.01) in terms of the expression of miR-181a, miR-15b, miR-let-7e and miR-let-7d. and no noticeable difference had been found from the eQTL analysis., Conclusion: Our findings suggest that rs10760371 within miR-181a may relate to the development of MA dependence with psychosis. The miRNAs expression is unlikely to be regulated by the SNPs within it., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Methamphetamine is one of the most abused hard drugs in the Czech Republic. Its popularity is high not only in Eastern Bloc of Europe but is growing in other countries around the world, including the United States. In addition, methamphetamine abuse increases in drug addicts during pregnancy. Although research into the long-term effects of prenatal methamphetamine exposure has been ongoing for many years, the exact mechanism of action and factors that may influence the effect of this drug are still not fully understood. There have been many studies that investigated the effects of addictive substances on the behavior and cognitive function of individuals during adolescence. Some studies have shown prenatal or perinatal influences, e.g. drugs, stress, hypoxia, and malnutrition, can affect drug sensitivity or drug-seeking behavior in adulthood. However, when these factors are most impactful, i.e. prenatal vs. perinatal, and which stages of the prenatal and perinatal periods are the most sensitive to these factors is not yet clear. Our laboratory specializes in research on the effects of drugs (especially methamphetamine) on rat mothers and their offspring during postnatal development, adolescence, and adulthood. This review summarizes our past results on the long-term effects of methamphetamine on the mother and her offspring, its mechanism of action, the role of maternal care, the possible emergence of long-term sensitization, and the critical neurodevelopmental periods for methamphetamine exposure.

Chronic heavy methamphetamine use likely causes dopaminergic neurotoxicity, which is commonly thought to result in cognitive control deficits. Both of these alterations may persist even after the use is discontinued, but tend to (partly) improve with increasing duration of abstinence. While several studies have demonstrated that the reinstatement of comparatively normal dopaminergic signaling may take months, if not years, the amelioration of cognitive deficits has predominantly been investigated in much shorter intervals of several weeks to less than half a year. Against this background, we set out to investigate the effects on prolonged abstinence in n = 27 abstinent former methamphetamine users in a cross-sectional design using behavioral and neurophysiological measures of cognitive control. Our behavioral results suggest that former users struggled to identify and adapt to different degrees of cognitive control requirements, which made their behavioral performance less expedient than that of healthy controls. On the neurophysiological level, this was reflected by reduced modulations of the N2-N450 amplitude in response to high vs. low cognitive control requirements. Yet, those effects could only be observed in methamphetamine users who had been abstinent for a relatively short time (mean 9.9; max. 18 months), but not in former users who had been abstinent two years or longer. While this finding alone does not allow for causal inferences, it suggests that the amelioration of control deficits may take longer than what is commonly investigated (1-6 months). Hence, some of the statements about permanent/irreversible dopamine-dependent executive dysfunctions in former methamphetamine users should be interpreted with caution., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Abuse of psychostimulants, including methamphetamine (MA), has been linked to heightened impulsivity. While previous research has demonstrated differences in impulsivity between MA users and non-substance users, less is known about variability in impulsivity within MA users and whether the severity of MA use related problems predicts impulsivity within individuals who regularly use MA. This study aims to elucidate the relationship between impulsivity and MA use severity., Method: Non-treatment seeking individuals who reported regular MA use (n = 177) completed an impulsivity battery comprising self-report and behavioral measures. A structural equation modeling (SEM) approach was used to test the relationship between the MA use related problem severity and measures of impulsivity., Results: The final SEM model of impulsivity and MA use related problems (CFI = 0.897, RMSEA = 0.059, S-B scaled χ 2 [260,n = 103] = 406.86) revealed that greater MA use severity was associated with greater self-reported impulsiveness, but no relationship was found between MA use severity and behavioral measures of impulsivity., Conclusions: The current findings extend previous research by providing additional evidence that MA use is associated with increased self-reported impulsivity and highlights the importance of evaluating impulsivity as a multidimensional construct., (Copyright © 2018. Published by Elsevier B.V.)

Introduction and Aims: Smoking methamphetamine is associated with increased risk of HIV among female sex workers (FSW). The structural context of substance use is an important shaper of individual behaviour; however, structural determinants of methamphetamine use among FSWs are largely unknown. We identified individual, structural and neighbourhood factors associated with smoking methamphetamine among FSWs in the border city of Tijuana, Baja California, Mexico., Design and Methods: A prospective cohort of 301 FSWs sampled from indoor and outdoor sex work venues throughout Tijuana participated in quantitative surveys on behaviours and mapping of home and work neighbourhoods across three visits. Multinomial logistic regression using generalised estimating equations identified individual, structural and neighbourhood variables associated with smoking methamphetamine., Results: Methamphetamine use, particularly smoking, was highly prevalent among FSWs. Over half (61%) of FSWs had ever used methamphetamine in their lifetime and at baseline, 38% currently smoked methamphetamine. Smoking methamphetamine daily was associated with living in the red light district [adjusted odds ratio (AOR) = 2.72, 95% confidence interval (CI) = 1.23-6.02] and with perceived homelessness, but only among women in a good financial situation (AOR = 4.08, 95% CI = 1.58-10.50). Smoking methamphetamine less than daily was associated with older age (AOR = 1.06, 95% CI = 1.02-1.10)., Discussion and Conclusions: Our findings point to the important dynamic between the residential environment and more severe methamphetamine use. FSWs may prioritise the purchase of methamphetamine over stable housing if they have the financial means. Given the high prevalence of smoking methamphetamine among FSWs in Tijuana, drug treatment options, especially for women living in the red light district, are needed., (© 2017 Australasian Professional Society on Alcohol and other Drugs.)

Background: Methamphetamine cannot be detected through conventional urine screening tests or other analytical methods in methamphetamine abusers who have not used the drug for some time. In some instances, detection of methamphetamine in fingernails can be a good alternative. We aimed to determine the sensitivity and specificity of the one-step methamphetamine test strip used in the detection of methamphetamine in urine in the detection of methamphetamine in fingernails., Methods: We took 72 fingernail samples, including 60 samples from methamphetamine abusers and 12 samples as controls from their relatives who had no history of methamphetamine use. The liquid-liquid extraction method was used on fingernail samples, and the resultant solution was tested with one-step methamphetamine test strip. We analysed participants' demographics including age, gender, duration of methamphetamine abuse and strip test results., Results: The mean (SD) age of the participants was 25 (4.33) years. The mean (SD) duration of methamphetamine abuse was 10 (4.5) months. Of the 72 participants, 61 (84.7%) had positive and 11 (15.3%) had negative strip test results. All 60 methamphetamine abusers had positive test results. A positive or negative history of methamphetamine abuse was taken as the gold standard. The sensitivity and specificity of the test was 100% and 91.6%, respectively., Conclusion: Performing liquid-liquid extraction on fingernails and using the strip test for detection of methamphetamine is a simple, inexpensive, rapid and accessible method, and its high sensitivity and specificity make it appropriate for screening. This method may be preferred over other urine and blood methamphetamine detection methods when the patient has not used the drug for a few days., Competing Interests: None

Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3-30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.

An alcohol use disorder is a major predisposing factor for methamphetamine (MA) abuse. Further, MA-alcohol co-abuse is a risk factor for treatment discontinuation and non-compliance in MA-dependent individuals. No effective treatment exists for MA addiction, let alone treatments directed at those suffering from MA-alcohol addiction co-morbidity. Thus, it is imperative that we develop high-throughput animal models to study the biobehavioral interactions between MA and alcohol of relevance to the etiology and treatment of co-abuse. To this end, we reported that a history of binge alcohol-drinking [5,10, 20 and 40% (v/v); 2 h/day for 10-14 days] reduces MA reinforcement and intake, but it augments MA-preference and intake when drug availability is behaviorally non-contingent. To reconcile this apparent discrepancy in findings, we employed a comparable 2-week binge-drinking paradigm as that employed in our previous studies followed by place-conditioning procedures (4 pairings of 0.25, 0.5, 1, 2 or 4 mg/kg MA, i.p.). This was meant to determine how a prior binge-drinking history impacts the affective valence of MA and sensitivity to MA-induced psychomotor-activation/sensitization. Prior binge-drinking history blunted spontaneous locomotor activity and shifted the MA dose-place-preference function upwards of water drinking controls. The potentiation of MA-conditioned reward by prior binge-drinking history was independent of any alcohol effects upon the locomotor-activating or -sensitizing effects of MA. Based on these results we propose that the reduced MA reinforcement reported previously by our group likely reflects a compensatory response to an increased sensitivity to MA's positive subjective effects rather than increased sensitivity to the drug's psychomotor-activating effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Methamphetamine abuse has been linked to an increased risk of Parkinson's disease., Objective: The objective of this study was to investigate structural abnormality of the substantia nigra in past methamphetamine users using transcranial sonography., Methods: In a cross-sectional, observational study, echogenicity of the substantia nigra was assessed in 59 past methamphetamine users and 59 matched controls. The frequencies of an abnormal spatial extension of the substantia nigra as well as the average sizes of left and right substantia nigra were evaluated., Results: The average echogenic size of the substantia nigra was larger in methamphetamine users (0.22 ± 0.06 cm 2 ) when compared with controls (0.17 ± 0.05 cm 2 , P < .001). Furthermore, the frequency of enlarged, echogenic substantia nigra was increased in methamphetamine users (42% vs 12% in controls, P < .001). Partial correlation analysis revealed an association of echogenic substantia nigra size with estimated total lifetime intake of methamphetamine (r 55  = 0.395, P = .002)., Conclusions: Current data link methamphetamine abuse in humans to injury of substantia nigra neurons and an increased risk of Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Amphetamine-type stimulants (ATS) use is increasingly prevalent in Malaysia, including among individuals who also use opioids. We evaluated cognitive functioning profiles among individuals with co-occurring opioid and ATS dependence and their lifetime patterns of drug use. Participants (N = 50) enrolling in a clinical trial of buprenorphine/naloxone treatment with or without atomoxetine completed the Raven's Standard Progressive Matrices, Rey-Osterrieth Complex Figure Test, Digit Span, Trail Making and Symbol Digit Substitution tasks. Multidimensional scaling and a K-means cluster analyses were conducted to classify participants into lower versus higher cognitive performance groups. Subsequently, analyses of variance procedures were conducted to evaluate between group differences on drug use history and demographics. Two clusters of individuals with distinct profiles of cognitive performance were identified. The age of ATS use initiation, controlling for the overall duration of drug use, was significantly earlier in the lower than in the higher cognitive performance cluster: 20.9 (95% CI: 18.0-23.8) versus 25.2 (95% CI: 22.4-28.0, p = 0.038). While adverse effects of ATS use on cognitive functioning can be particularly pronounced with younger age, potentially related to greater vulnerability of the developing brain to stimulant and/or neurotoxic effects of these drugs, the current study findings cannot preclude lowered cognitive performance before initiation of ATS use.

Crystal methamphetamine (MA) is a potent psycho-stimulant that is increasingly used worldwide. It is highly addictive, is often made in clandestine laboratories, and can cause serious health issues in adults. Health professionals caring for women in the perinatal period must counsel women about the health risks to infants if they are exposed to MA in breast milk. Most guidelines recommend that women who have current or recent MA use do not breastfeed. This article explores approaches to breastfeeding advice in the context of MA use. Women who have made lifestyle changes, engaged well with services in the antenatal period, and are committed to drug counseling services after discharge from hospital may be supported to breastfeed if they are assessed as safe to do so. The importance of assessing each woman individually when developing infant feeding plans throughout the perinatal period is advocated.

Global motion perception is often used as an index of dorsal visual stream function in neurodevelopmental studies. However, the relationship between global motion perception and visuomotor control, a primary function of the dorsal stream, is unclear. We measured global motion perception (motion coherence threshold; MCT) and performance on standardized measures of motor function in 606 4.5-year-old children born at risk of abnormal neurodevelopment. Visual acuity, stereoacuity and verbal IQ were also assessed. After adjustment for verbal IQ or both visual acuity and stereoacuity, MCT was modestly, but significantly, associated with all components of motor function with the exception of fine motor scores. In a separate analysis, stereoacuity, but not visual acuity, was significantly associated with both gross and fine motor scores. These results indicate that the development of motion perception and stereoacuity are associated with motor function in pre-school children., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D 2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D 3 receptor levels in stimulant users prompting the view that D 3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D 3 -rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D 3 -preferring probe [ 11 C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [ 11 C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D 3 -rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D 2 -rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [ 11 C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D 3 -areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D 3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D 3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D 3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.

Rationale and Objectives: Addiction to psychostimulant methamphetamine (METH) remains a major public health problem in the world. Animal models that use METH self-administration incorporate many features of human drug-taking behavior and are very helpful in elucidating mechanisms underlying METH addiction. These models are also helping to decipher the neurobiological substrates of associated neuropsychiatric complications. This review summarizes our work on the influence of METH self-administration on dopamine systems, transcription and immune responses in the brain., Methods: We used the rat model of METH self-administration with extended access (15 h/day for eight consecutive days) to investigate the effects of voluntary METH intake on the markers of dopamine system integrity and changes in gene expression observed in the brain at 2 h-1 month after cessation of drug exposure., Results: Extended access to METH self-administration caused changes in the rat brain that are consistent with clinical findings reported in neuroimaging and postmortem studies of human METH addicts. In addition, gene expression studies using striatal tissues from METH self-administering rats revealed increased expression of genes involved in cAMP response element binding protein (CREB) signaling pathway and in the activation of neuroinflammatory response in the brain., Conclusion: These data show an association of METH exposure with activation of neuroplastic and neuroinflammatory cascades in the brain. The neuroplastic changes may be involved in promoting METH addiction. Neuroinflammatory processes in the striatum may underlie cognitive deficits, depression, and parkinsonism reported in METH addicts. Therapeutic approaches that include suppression of neuroinflammation may be beneficial to addicted patients.

Objective: To assess the relationship between prenatal methamphetamine exposure (PME) and behavior problems at age 7.5 years and the extent to which early adversity mediated this relationship., Study Design: The multicenter, longitudinal Infant Development, Environment, and Lifestyle study enrolled 412 mother-infant pairs at 4 sites. Methamphetamine-exposed participants (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched participants (n = 208) denied methamphetamine use and had a negative meconium screen. At the 7.5-year follow-up, 290 children with complete Child Behavior Checklist data and an early adversity index score were available for analysis (n = 146 exposed)., Results: PME was significantly associated with an increased early adversity index score (P < .001) and with increased externalizing, rule-breaking behavior, and aggressive behavior (P < .05). Early adversity was also associated with higher externalizing behavior scores. Early adversity significantly mediated the relationship between PME and behavioral problems. After adjusting the mediation model for sex, prenatal tobacco, alcohol, and marijuana exposures, and study site, the association of PME with early adversity remained significant., Conclusions: Though PME is associated with behavioral problems, early adversity may be a strong determinant of behavioral outcome for children exposed to methamphetamine in utero. Early adversity significantly mediated the relationship between PME and behavioral problems., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Data from a cross-sectional study of gay, bisexual, and other men who have sex with men who were active methamphetamine users were analyzed to assess temporal relations between HIV seroconversion and initiation of methamphetamine use. Of the 100 men, 58 reported being HIV-positive. Most HIV-positive participants (65%) initiated methamphetamine use after seroconverting. Among those who initiated use before seroconversion, 8 years elapsed between onset of use and time of infection. Findings suggest the need to develop nuanced and targeted interventions aimed at disentangling the "meth-sex" link in this population. Findings also suggest use of the drug as a coping mechanism for those living with HIV., (© The Author(s) 2014.)

Background: Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents., Objectives: Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross-sensitization with cocaine (COC) were also investigated., Methods: Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross-sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days., Results: Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross-sensitization with COC., Conclusions: Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

Chronic consumption of processed food causes structural changes in membrane phospholipids, affecting brain neurotransmission. Here we evaluated noxious influences of dietary fats over two generations of rats on amphetamine (AMPH)-conditioned place preference (CPP). Female rats received soybean oil (SO, rich in n-6 fatty acids (FA)), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans fatty acids (TFA)) for two successive generations. Male pups from the 2nd generation were maintained on the same supplementation until 41 days of age, when they were conditioned with AMPH in CPP. While the FO group showed higher incorporation of n-3 polyunsaturated-FA (PUFA) in cortex/hippocampus, the HVF group showed TFA incorporation in these same brain areas. The SO and HVF groups showed AMPH-preference and anxiety-like symptoms during abstinence. Higher levels of protein carbonyl (PC) and lower levels of non-protein thiols (NPSH) were observed in cortex/hippocampus of the HVF group, indicating antioxidant defense system impairment. In contrast, the FO group showed no drug-preference and lower PC levels in cortex. Cortical PC was positively correlated with n-6/n-3 PUFA ratio, locomotion and anxiety-like behavior, and hippocampal PC was positively correlated with AMPH-preference, reinforcing connections between oxidative damage and AMPH-induced preference/abstinence behaviors. As brain incorporation of trans and n-6 PUFA modifies its physiological functions, it may facilitate drug addiction., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Studies show that illicit cannabis (marijuana) use is related to use of other illicit drugs and that reasons for use are related to frequency of marijuana use. However, research is needed to examine whether specific reasons for marijuana use are associated with use of other illicit drugs., Methods: Data from recent marijuana-using high school seniors were examined from 12 cohorts of Monitoring the Future (Weighted n = 6481) to examine whether reasons for recent marijuana use are associated with use of eight other illicit drugs., Results: Using "to experiment" decreased odds of reporting use of each drug and using to decrease effects of other drugs increased odds of reporting use of each drug. In multivariable models, using marijuana "to experiment" decreased the odds for reporting use of hallucinogens other than LSD and narcotics other than heroin. Using marijuana for "insight" increased the odds for use of hallucinogens other than LSD, and use due to "boredom" increased the odds for reporting use of powder cocaine and hallucinogens other than LSD. Using marijuana to increase effects of other drugs increased odds of reporting use of each of the eight drugs, and using it to decrease other drug effects increased odds of reporting use of crack, hallucinogens other than LSD, and amphetamine/stimulants., Conclusions: This study helped identify illicit marijuana users who are more likely to report use of other illicit drugs. Prevention efforts need to focus on students who report certain reasons for marijuana use as they may be at risk for use of other illicit drugs.

Background: Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile., Methods: In this double-blind, placebo-controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways., Results: At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function., Conclusion: Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions.

4-Methylamphetamine (4-MA) was originally developed as an appetite suppressant, but development was halted due to side effects. It has recently resurfaced as a new psychoactive substance in Europe, and is mostly found together with amphetamine. Around 11.5% of tested Dutch speed samples were positive for 4-MA. In Belgium, 4-MA was also found in speed samples. In 2011 and 2012, several fatal incidents after amphetamine use were observed in Belgium, the United Kingdom and The Netherlands. In all victims, toxicological analysis confirmed the presence of 4-MA, in addition to amphetamine. The observed blood amphetamine levels were too low to be fatal. Contrary to amphetamine, which displays noradrenergic and dopaminergic activity, 4-MA also shows serotonergic activity, which may contribute to the observed toxicity. Other mechanisms of toxicity are put forward in this paper as well. To conclude, the observed toxicity is most likely the result of the combined dopaminergic activity of amphetamine and the serotonergic activity of 4-MA. In addition, the presence of 4-MA may have dampened the psychoactive effects of amphetamine by attenuation of the amphetamine-induced dopamine release, potentially inclining users to ingest higher doses of contaminated speed. Also, slower metabolism of 4-MA and its MAO-inhibiting properties can also contribute to the unusual high toxicity of 4-MA.

Repeated administration of psychostimulant drugs, such as amphetamine, induces an enhanced behavioral response to subsequent drug challenge. This behavioral sensitization is proposed to model the increased drug craving observed in human psychostimulant abusers. Current thinking is that the ventral tegmental area, but not the nucleus accumbens, plays a critical role in the development of behavioral sensitization. Here, we report that the concomitant blockade of glutamatergic and nicotinic ionotropic receptors in the core of the nucleus accumbens blocks the development of behavioral sensitization to amphetamine and further abolishes the increase in extracellular dopamine release induced by amphetamine in the nucleus accumbens. These findings demonstrate that the development of behavioral sensitization to amphetamine depends, in addition to the well-known role of the ventral tegmental area, on glutamatergic and nicotinic-dependent mechanisms in the core of the nucleus accumbens and further indicate that the dopaminergic mesolimbic pathway must be viewed as a single coordinated system of critical importance in the development of behavioral sensitization to psychostimulant drugs., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Background: Although ecstasy is often consumed in the electronic music scene, not everyone with the opportunity to use it chooses to do so. The objective of this study was to understand the reasons for non-use or the cessation of use, which could provide information for public health interventions., Methods: A qualitative reference method was used. Our "snowball" sample group consisted of 53 people who were split into three subgroups: non-users (NU, n = 23), ex-light users (EX-L, n = 12) and ex-moderate users (EX-M, n = 18). Individual, semi-structured interviews were conducted, transcribed and subjected to content analysis with the aid of NVivo8., Results: Adverse health effects and personal values were given as reasons for non-use in the three groups. Non-users (NU) and ex-light users (EX-L) provided reasons that included fear of possible effects as well as moral, family and religious objections. Ex-moderate users (EX-M) cited reasons related to health complications and concomitant withdrawal from the electronic music scene. However, most of the ex-moderate users did not rule out the possibility of future use., Conclusions: Potential effects and undesirable consequences appear to guide the decisions within the different groups. Prevention might target these motivations. Individuals who have used ecstasy indicate that social and environmental factors are the most important factors.

Objective: We examined the association between methamphetamine (meth) use and dental problems in a large sample of HIV-positive adults., Methods: We gathered data from 2,178 interviews across 14 sites of the U.S. Health Resources and Services Administration HIV/AIDS Bureau's Special Projects of National Significance Innovations in Oral Health Care Initiative from May 2007 to August 2010. We used multivariate generalized estimating equations to test the association between meth use and dental problems, adjusting for potential confounders., Results: Past and current meth use was significantly associated with more dental problems. The study also found that poor self-reported mental health status, fewer years since testing positive for HIV, a history of forgoing dental care, less frequent teeth brushing, poor self-reported oral health status, oral pain, grinding or clenching teeth, some alcohol use, more years of education, and self-reported men-who-have-sex-with-men HIV risk exposure (compared with other exposure routes) were significantly associated with dental problems., Conclusion: Individuals who are HIV-positive with a history of meth use experience access barriers to oral health care and more dental problems. Our study demonstrated that it is possible to recruit this population into dental care. Findings suggest that predisposing, enabling, and need factors can serve as demographic, clinical, and behavioral markers for recruiting people living with HIV/AIDS into oral health programs that can mitigate dental problems.

Methamphetamine is the leading illicit substance used by adolescents in Taiwan and the rise of its production and use is a major public health concern in Southeast and East Asia. The purpose of this study was to develop and test a new instrument to identify high-risk situations related to methamphetamine relapse among incarcerated Taiwanese adolescents. Participants in this study were arrested for methamphetamine use and mandatorily held at an abstinence center. In the instrument development phase, an item pool was generated from a qualitative study and further revised based on content evaluations by 6 clinical content experts. In the instrument analysis phase, the new tool was psychometrically tested. The intra-class correlation coefficient showed high stability of the instrument (r = .92). Factor analysis resulted in a 6-factor solution accounting for 66.68% of the variance in the 16-item model. Although this instrument was developed for use with Taiwanese adolescents, it needs further testing to confirm its usefulness in other cultural groups. The identified risky situations provide a beginning assessment tool that is easy to administer and can be used to identify teens at particular risk for relapse before being released from incarceration or other mandatory treatment programs. More research is needed to target specific and culturally determined triggers that can improve the validity of this tool for non Asian adolescents at risk for methamphetamine relapse.

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Maternal smoking during pregnancy is associated with enduring psychopathology, such as increased likelihood of substance use, in offspring. Various animal models demonstrate that continuous nicotine exposure produces teratogenic effects in offspring, as well. In this experiment, a novel intravenous (IV) exposure model was used to determine if gestational nicotine (GN) treatment produced alterations in methamphetamine-induced sensitization and the expression of brain-derived neurotrophic factor (BDNF) in the mesocorticolimbic dopamine (DA) system of adolescent offspring. Dams were injected with IV saline or nicotine (0.05 mg/kg/injection) three times per day on gestational days 8-21. Habituation was measured on postnatal day (PND) 25-27 and baseline activity on PND 28. On PND 29-35, offspring were injected with saline or methamphetamine (0.3 mg/kg) and locomotor activity was measured after the first and seventh injections. On PND 36, brains were removed, flash frozen, and BDNF protein levels in the nucleus accumbens (NAcc), dorsal striatum (Str), frontal cortex (FC), and hippocampus (Hipp) were analyzed. GN did not affect habituation or the induction of methamphetamine-induced sensitization. Interestingly, GN, but not adolescent methamphetamine treatment, elevated levels of BDNF in the NAcc and Str; however, the GN-induced increase in BDNF in the FC was attenuated by adolescent methamphetamine treatment. Both GN and adolescent methamphetamine treatment increased BDNF in the Hipp. These findings indicate that GN exposure will result in increased levels of BDNF protein throughout the mesocorticolimbic DA system during adolescent development and suggests that methamphetamine abuse will modulate the expression of BDNF in motivational circuitries of adolescent offspring exposed to GN., (Copyright © 2011 Wiley-Liss, Inc.)

We have shown that a single "binge" dose of methamphetamine (Meth) in mice has long-lasting effects on open-field behavior dependent on mouse strain and age. Here we further investigated the impact of genotype and age on tyrosine hydroxylase (TH) loss and dopamine (DA) metabolism due to a high binge dose of Meth (4 × 5 mg/kg × 2 h × 2 days). Administration of high dose Meth or saline (Sal) to adolescent (PND 40) and adult (PND 80) C57BL/6 (B6), DBA/2 (DBA), and 129S6SvEv/Tac (129) mice was followed by a 1mg/kg Meth or Sal (control) challenge 40 days later. Striatal and prefrontal cortex tissues were collected 1h following the challenge. Meth-pretreated adolescent B6 and DBA mice exhibited losses in striatal DA concentrations; DBA adolescents also showed losses in striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and increased DA turnover. Pre-exposed B6 and 129 adults demonstrated significant decreases in striatal DA, DOPAC, and increased DA turnover; DBA adults showed significant losses in striatal DA and increased DA turnover. 129 and DBA adults exhibited increases and decreases, respectively, in prefrontal cortex DA. Adult pretreated B6 mice produced significant losses in striatal TH. The results again show age and genotype dependent differences in Meth-induced DA alterations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Studies of the chronic effects of MDMA, or 'ecstasy', in humans have been largely inconsistent. We explored whether study-level characteristics are associated with the effect size estimate reported. We based our analyses on the recent systematic review by Rogers and colleagues, focusing on those meta-analyses within this report where there was a relatively large number of studies contributing to each individual meta-analysis. Linear regression was used to investigate the association between study level variables and effect size estimate, weighted by the inverse of the SE of the effect size estimate, with cluster correction for studies which contributed multiple estimates. This indicated an association between effect size estimate and both user group, with smaller estimates among studies recruiting former users compared with those recruiting current users, and control group, with smaller estimates among studies recruiting polydrug user controls compared with those recruiting drug-naïve controls. In addition, increasing year of publication was associated with reduced effect size estimate, and there was a trend level association with prevalence of ecstasy use, reflecting smaller estimates among studies conducted in countries with higher prevalence of ecstasy use. Our data suggest a number of study-level characteristics which appear to influence individual study effect size estimates. These should be considered when designing future studies, and also when interpreting the ecstasy literature as a whole.

We investigated the differential influence of family dysfunction on alcohol and methamphetamine dependence in Japan using the Addiction Severity Index (ASI), a useful instrument that multilaterally measures the severity of substance dependence. The participants in this study were 321 male patients with alcohol dependence and 68 male patients with methamphetamine dependence. We conducted semi-structured interviews with each patient using the ASI, which is designed to assess problem severity in seven functional domains: Medical, Employment/Support, Alcohol use, Drug use, Legal, Family/Social relationships, and Psychiatric. In patients with alcohol dependence, bad relationships with parents, brothers and sisters, and friends in their lives were related to current severe psychiatric problems. Bad relationships with brothers and sisters and partners in their lives were related to current severe employment/support problems, and bad relationships with partners in their lives were related to current severe family/social problems. The current severity of psychiatric problems was related to the current severity of drug use and family/social problems in patients with alcohol dependence. Patients with methamphetamine dependence had difficulty developing good relationships with their father. Furthermore, the current severity of psychiatric problems was related to the current severity of medical, employment/support, and family/social problems in patients with methamphetamine dependence. The results of this study suggest that family dysfunction differentially affects alcohol and methamphetamine dependence. Additionally, family relationships may be particularly related to psychiatric problems in these patients, although the ASI was developed to independently evaluate each of seven problem areas.

Methamphetamine abuse has reached epidemic proportions in the United States. The repetitive use of methamphetamine causes massive and sustained elevations in central monoamines. These elevations, particularly in dopamine, can cause changes in the function of the central nervous system that can manifest as a variety of neurologic disorders. This article focuses on these disorders, such as neurocognitive disorders and mental illness, including drug-induced psychosis; motor disorders, including the possible risk of Parkinson's disease, the development of choreoathetoid movements, and punding; and changes in the physical appearance of the methamphetamine users, including dental caries., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Based on the findings of postnatal tactile stimulation (TS), a favorable experience in rats, the present study examined the influence of prenatal TS on juvenile behavior, adult amphetamine (AMPH) sensitization, and structural alteration in the prefrontal cortex (PFC) and the striatum. Female rats received TS through a baby hair brush throughout pregnancy, and the pups born were tested for open field locomotion, elevated plus maze (EPM), novel object recognition (NOR), and play fighting behaviors. Development and persistence of drug-induced behavioral sensitization in adults were tested by repeated AMPH administration and a challenge, respectively. Structural plasticity in the brain was assessed from the prefrontal cortical thickness and striatum size from serial coronal sections. The results indicate that TS females showed enhanced exploration in the open field. TS decreased the frequency of playful attacks whereas the response to face or evade an attack was not affected. Anxiety-like behavior and cognitive performance were not influenced by TS. AMPH administration resulted in gradual increase in locomotor activity (i.e., behavioral sensitization) that persisted at least for 2 weeks. However, both male and female TS rats exhibited attenuated AMPH sensitization compared to sex-matched controls. Furthermore, the drug-associated alteration in the prefrontal cortical thickness and striatum size observed in controls were prevented by TS experience. In summary, TS during prenatal development modified juvenile behavior, attenuated drug-induced behavioral sensitization in adulthood, and reorganized brain regions implicated in drug addiction., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Macrophages are one of HIV-1's principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3's binding to DA, would be more likely to develop CI. Cochran-Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.

Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To estimate prevalence and incidence of HIV and sexually transmitted infections (STI) and associated risk factors among young women working as sex workers (SWs) in Phnom Penh, Cambodia., Methods: A prospective study of young (<29 years) women working as SWs in brothels, entertainment establishments, and freelance. Sociodemographics, sexual risk, and use of amphetamine-type stimulants (ATS) ("yama" and "crystal") were assessed by self-report. HIV and STI (Chlamydia trachomatis and Neisseria gonorrhoeae) testing were conducted on blood and urine specimens, respectively., Results: Baseline prevalences of HIV, C. trachomatis, and N. gonorrhoeae were 23%, 11.5%, and 7.8%, respectively. HIV incidence was 3.6 per 100 person-years (95% confidence interval [CI], 1.2%-11.1%); STI incidence was 21.2 per 100 person-years (95% CI, 12.6%-35.8%). At baseline, 26.5% reported recent ATS use. HIV infection was associated with freelance SW (adjusted odds ratio, 5.85; 95% CI, 1.59-21.58) and younger age of first sex (≤15 years; adjusted odds ratio, 3.06; 95% CI, 1.01-8.46). Incident STI was associated with duration (per year) of SW (adjusted hazard ratio, 1.1; 95% CI, 1.1-1.2) and recent yama use (adjusted hazard ratio, 3.9; 95% CI, 1.5-10.3)., Conclusions: HIV and STI infection rates were high among SWs working in various settings; freelancers had highest risk. ATS use was associated with incident STI. Venue of sex work and drug prevention should be considered in prevention programs.

Stimulant drugs are often associated with increased seizure susceptibility. Inhibitory gamma-aminobutyric acid (GABA) and excitatory N-methyl-D-aspartate (NMDA) systems play a role in the effect of stimulants in the genesis of epileptic seizures. Our previous studies showed that prenatal methamphetamine (MA) exposure induced long-term changes in seizure susceptibility. The aim of the present study was to investigate the effect of cross-fostering on the prenatal and postnatal MA-exposed rats, respectively, on their seizures in adulthood. Bicuculline (GABA(A) receptor antagonist), NMDA (NMDA receptor agonist) and flurothyl (a convulsant gas) were used to induce seizures in adult male offsprings. Female dams were injected with MA (5 mg/kg daily) or physiological saline (S) for approx. 9 week [about 3 week prior to impregnation, for the entire gestation period (22 days) and in preweaning period (21 days)]. Absolute controls (C) did not receive any injections. On postnatal day 1, pups were cross-fostered so that each mother received pups from all three treatments. Thus, nine groups (based on the prenatal and postnatal drug exposure) of adult male rats were tested in each seizure test: C/C; C/S; C/MA; S/C; S/S; S/MA; MA/C; MA/S; MA/MA. The present study demonstrates that the effect of prenatal and/or postnatal MA exposure is seizure model specific. In addition, our data show that there is an effect of cross-fostering on seizures; particularly, the effect of prenatal MA exposure shown in animals fostered by control mothers is no longer apparent in animals fostered postnatally by MA-treated mothers. Such effect of postnatal treatment is not manifested in prenatal controls. In summary, it seems that: (1) prenatal MA exposure alters seizure susceptibility more than postnatal MA exposure; (2) especially in seizures induced by chemicals that affect GABAergic system (bicuculline, flurothyl) notable effect of adoption (cross-fostering) is apparent; (3) in seizure models that are associated with NMDA system (NMDA, flurothyl), effect of prenatal stress seems to play a role., (Copyright 2010 ISDN. Published by Elsevier Ltd. All rights reserved.)

3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is a substituted amphetamine with potent central nervous stimulant effects. Increasing evidence suggests that one way of MDMA-induced toxicity involves the production of reactive oxygen and reactive nitrogen species and a subsequent production of oxidative/nitrosative stress. The free radicals can originate from several molecular pathways (oxidative deamination of monoamine, metabolic pathways, cathecolamines autoxidation, and hyperthermia) and their harmful effect causing potential biological damage such as lipoperoxidation and cellular death. The role of oxidative stress in mediating MDMA toxicity is illustrated by decreases in the activity of the endogenous enzymatic and non enzymatic antioxidants observed in cells in vitro and in animals model. This review examines the available evidence for the involvement of oxidative stress in the mechanisms of MDMA-induced cellular damage with the aim to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA toxicity.

Dopamine (DA) has long been implicated in impulsivity, but the precise mechanisms linking human variability in DA signaling to differences in impulsive traits remain largely unknown. By using a dual-scan positron emission tomography approach in healthy human volunteers with amphetamine and the D2/D3 ligand [18F]fallypride, we found that higher levels of trait impulsivity were predicted by diminished midbrain D2/D3 autoreceptor binding and greater amphetamine-induced DA release in the striatum, which was in turn associated with stimulant craving. Path analysis confirmed that the impact of decreased midbrain D2/D3 autoreceptor availability on trait impulsivity is mediated in part through its effect on stimulated striatal DA release.

Objective: Several studies suggest a link between stimulant abuse and attention-deficit hyperactivity disorder (ADHD) symptoms (e.g., inattention and hyperactivity). To further assess the nature of this relationship, the present study examined the association between subclinical symptoms of inattention and hyperactivity and the behavioral effects of d-amphetamine., Methods: Participants were classified into a High- (n = 8) or Low-Score (n = 9) group based on their responses on a rating scale that assessed inattention and hyperactivity symptoms., Results: The participants did not differ across the High-Score and Low-Score groups in their ability to discriminate d-amphetamine. The participants in the High-Score group were significantly more sensitive to the positive participant-rated effects of d-amphetamine (e.g., Good Effects, Like Drug), but less sensitive to drug-induced increases in blood pressure and heart rate., Conclusion: The selective increase in positive subjective effects of d-amphetamine suggests that individuals with subclinical inattention and hyperactivity symptoms may have increased vulnerability to stimulant abuse.

Introduction and Aims: To determine whether recreational methamphetamine use is associated with an increased risk of psychotic symptoms., Design and Method: A cross-sectional survey of 157 people attending dance events in Sydney, Australia. Participants were assessed for psychotic symptoms in the past year using items from the Psychosis Screen. Participants with and without psychotic symptoms were compared on methamphetamine use, polydrug use and other demographic factors. An ordinal logistic regression was used to determine the probability of psychotic symptoms by methamphetamine use and level of polydrug use., Results: Psychotic symptoms in the past year were predicted by methamphetamine use and heavier polydrug use in the past year, and a history of a psychotic disorder (schizophrenia, schizoaffective or bipolar affective disorder). After removing participants with a history of a psychotic disorder (n = 16) and adjusting for polydrug use, methamphetamine use increased the probability of two or more psychotic symptoms (indicative of psychosis risk) from 9% to 21%. There was a non-significant increase in the risk of psychotic symptoms with higher levels of polydrug use. Methamphetamine use was typically monthly or less often (83%), and most users described their use as recreational (85%)., Discussion and Conclusions: Within the context of polydrug use, recreational methamphetamine use is associated with a twofold to threefold increase in the probability of psychotic symptoms.