Search

Trace amine-associated receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.

We provide an overview of the recent achievements in psychiatric genetics research in the Russian Federation and present genotype-phenotype, population, epigenetic, cytogenetic, functional, ENIGMA, and pharmacogenetic studies, with an emphasis on genome-wide association studies. The genetic backgrounds of mental illnesses in the polyethnic and multicultural population of the Russian Federation are still understudied. Furthermore, genetic, genomic, and pharmacogenetic data from the Russian Federation are not adequately represented in the international scientific literature, are currently not available for meta-analyses and have never been compared with data from other populations. Most of these problems cannot be solved by individual centers working in isolation but warrant a truly collaborative effort that brings together all the major psychiatric genetic research centers in the Russian Federation in a national consortium. For this reason, we have established the Russian National Consortium for Psychiatric Genetics (RNCPG) with the aim to strengthen the power and rigor of psychiatric genetics research in the Russian Federation and enhance the international compatibility of this research.The consortium is set up as an open organization that will facilitate collaborations on complex biomedical research projects in human mental health in the Russian Federation and abroad. These projects will include genotyping, sequencing, transcriptome and epigenome analysis, metabolomics, and a wide array of other state-of-the-art analyses. Here, we discuss the challenges we face and the approaches we will take to unlock the huge potential that the Russian Federation holds for the worldwide psychiatric genetics community.

Relapse rates among treatment-seeking opioid-addicted individuals are extremely high but can be markedly reduced by agonist-based maintenance therapies such as methadone or buprenorphine. However, these therapies are not always available due to a limited number of providers, waiting lists to access treatment, or laws that prevent their use. In addition, some persons do not want agonist-based therapy because they do not like its subjective effects, tried it with less than optimal results, and had trouble stopping it when they felt ready or because family or other external pressures oppose it. For these individuals, antagonist-based therapy can fill an important niche, particularly when administered as an extended-release formulation that blocks opioid effects for several weeks or months, thus offering protection from the adverse effects of opioid use including overdose and giving the patient a chance to begin working on lifestyle changes that are necessary to work toward sustained remission. This paper will review existing findings on naltrexone for opioid addiction treatment. Antagonist treatment, particularly when delivered as an extended-release formulation, is a meaningful addition to current treatment options for opioid-dependent patients who do not want or do not have easy access to agonist or long-term residential treatment. Genetic analysis might be useful for determining potential responders to naltrexone treatment of opioid dependence but additional studies are needed.

Modulation of the mGlu1 receptor was repeatedly shown to inhibit various phenomena associated with exposure to abused drugs. Efficacy in preclinical models was observed with both positive and negative allosteric modulators (PAMs and NAMs, respectively) using essentially non-overlapping sets of experimental methods. Taken together, these data indicate that the mGlu1 receptor certainly plays a significant role in the plasticity triggered by the exposure to abused drugs and is involved in the maintenance of drug-seeking and drug-taking behaviors. Understanding whether modulation of the mGlu1 receptor activity can also affect drug-seeking and drug-taking in humans could have a significant impact on the future development of medications in this field. We argue that the mGlu1 receptor NAMs have a significant value as potential tools for human experimental pharmacology that could help to validate methods used in preclinical research. Compared with the PAMs, the mGlu1 receptor NAMs appear to be better candidates for this role due to the following: (1) a number of highly potent, selective, and chemically diverse mGlu1 receptor NAMs to choose from; (2) availability of high-quality PET ligands to monitor target exposure; and (3) a rich pharmacological profile with a number of effects that can complement anti-addictive action (e.g., anxiolytic/antidepressant) and may also serve as additional pharmacodynamic readouts during the preclinical-to-clinical translation. We believe that the mGlu1 receptor NAMs have a significant value as potential tools for human experimental pharmacology that could help to validate methods used in preclinical research.

The Russian Federation is experiencing a very high rate of HIV infection among people who inject drugs (PWID). However, few studies have explored characteristics of people with co-occurring opioid use disorders and HIV, including psychiatric symptom presentations and how these symptoms might relate to quality of life. The current study therefore explored a.) differences in baseline psychiatric symptoms among HIV+ and HIV- individuals with opioid use disorder seeking naltrexone treatment at two treatment centers in Saint Petersburg, Russia and b.) associations between psychiatric symptom constellations and quality of life.Participants were 328 adults enrolling in a randomized clinical trial evaluating outpatient treatments combining naltrexone with different drug counseling models. Psychiatric symptoms and quality of life were assessed using the Brief Symptom Inventory and The World Health Organization Quality of Life-BREF, respectively.Approximately 60% of participants were HIV+. Those who were HIV+ scored significantly higher on BSI anxiety, depression, psychoticism, somatization, paranoid ideation, phobic anxiety, obsessive-compulsive, and GSI indexes (all p0.05) than those HIV-. A K-means cluster analysis identified three distinct psychiatric symptom profiles; the proportion of HIV+ was significantly greater and quality of life indicators were significantly lower in the cluster with the highest psychiatric symptom levels.Higher levels of psychiatric symptoms and lower quality of life indicators among HIV+ (compared to HIV-) individuals injecting drugs support the potential importance of combining interventions that target improving psychiatric symptoms with drug treatment, particularly for HIV+ patients.

Introduction: The clinical use of kappa-opioid agonists, despite their lack of significant drug potential, is limited by the development of severe sedation, dysphoria, depression, and anhedonia. To this date, there are kappa-opioid receptor agonists lacking these side effects due to the selective activation of intracellular signal transmission pathways without p38-MAPK-kinase activation. Materials and methods: We analyzed assessment of the docking energy of compound RU-1205 to the p38-MAPK active center by the method of similarity to SB203580. The study of possible aversive properties of RU-1205 (0.01–1 mg/kg s.c.) conducted in the tests of the intravenous self-administration and drug differentiation with butorphanol (0.01–0.3 mg/kg). The study of p38 MAPK-inhibitory activity was studied by the ability of RU-1205 to change the aversive properties of U50488 (10 mg/kg i.p.) compared to MAPK-kinase inhibitor SB203580 in the conditioned place avoidance test. Results: The spatial similarity coefficient of the RU-1205 molecule with SB203580 by the molecular conformation method was 1.14 (high similarity), and the docking energy was -8.7 Kcal/mol. RU-1205 did not possess any properties similar to those of butorphanol and did not demonstrate any primary reinforcing aversive properties in the development of intravenous self-administration reaction. Compound RU-1205 did not demonstrate any aversive properties in the conditioned place avoidance test, and reduced the development of aversion caused by U-50488, when they were used together. Discussion: The in silico analysis suggested that, in addition to agonism towards the kappa-opioid receptor, RU-1205 compound exhibits the properties of a p38 MAPK kinase inhibitor, which means it may have a double pharmacological activity. Conclusion: Kappa agonist – compound RU-1205 – is not a trigger of the development of behavioral patterns in animals corresponding to the development of addiction/dysphoria. The mechanism of such an activity may be associated with an inhibitory effect of compound RU-1205 on neuronal p38-MAPK-kinase.

Summary Background Untreated opioid addiction in people with HIV is associated with poor HIV treatment outcomes. Slow-release, long-acting, implantable naltrexone might improve these outcomes. Here, we present results of a study aimed to test this hypothesis. Methods We did a 48 week double-blind, double-dummy, placebo-controlled, phase 3, randomised trial with men and women addicted to opioids who were starting antiretroviral therapy (ART) for HIV and whose viral loads were higher than 1000 copies per mL. Participants were seeking treatment at two HIV and two narcology programme centres in Saint Petersburg, Russia, and the surrounding Leningrad region. The Pavlov statistical department created a table with stratification on gender distribution, viral load, and CD4 cell count. We stratified participants according to gender, viral load, and CD4 cells per μL, and randomly assigned (1:1) them to addiction treatment with a naltrexone implant and oral naltrexone placebo (implant group) or oral naltrexone and placebo implant (oral group). The primary outcome was plasma viral load of less than 400 copies per mL at 24 weeks and 48 weeks. We included all randomly assigned participants in outcome analyses (intention to treat). Treatment staff and patients were masked to group assignment. The study is complete and registered at ClinicalTrials.gov, NCT01101815. Findings Between July 14, 2011, and April 14, 2014, 238 potential participants were recruited and screened, 35 were excluded for not meeting inclusion criteria, three declined to participate, and 200 were randomly assigned to treatment (100 to each group). At week 24, 38 (38) participants in the implant group and 35 (35%) in the oral group had viral loads less than 400 copies per mL (risk ratio 1·1, 95% CI 0·76–1·56; p=0·77). At week 48, 66 participants in the implant group and 50 in the oral group had viral loads less than 400 copies per mL (risk ratio 1·32, 95% CI 1·04–1·68; p=0·045). There were seven serious adverse events: three deaths in the implant group (one due to heart disease, one trauma, and one AIDS), and four in the oral group (two overdoses, one pancreatic cancer, and one AIDS). The overdose deaths occurred 9–10 months after the last naltrexone dose. Interpretation The longer the blockade of opioid effects, the more protection an individual gets from missed ART doses and impulsive behaviours that lead to relapse and poor, even fatal, outcomes. Commercial development of implants could result in a meaningful addition to addiction treatment options. Funding National Institutes of Health, National Institute on Drug Abuse, Penn Centre for AIDS Research, and Penn Mental Health AIDS Research Centre.

Naltrexone is a μ-opioid receptor antagonist that blocks opioid effects. Craving, depression, anxiety, and anhedonia are common among opioid dependent individuals and concerns have been raised that naltrexone increases them due to blocking endogenous opioids. Here, we present data that address these concerns.Assess the relationship between affective responses and naltrexone treatment.Opioid dependent patients (N = 306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Test, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the Tukey test for those who remained and treatment and did not relapse, and between the last measure before dropout with the same measure for those remaining in treatment.Depression, anxiety, and anhedonia were elevated at baseline but reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. Other than a slight increase in two anxiety measures at week two, there were no significant between-group differences prior to treatment dropout.These data do not support concerns that naltrexone treatment of opioid dependence increases craving, depression, anxiety or anhedonia.

To assess the relationship between long-term naltrexone treatment and anxiety, depression and craving in opioid dependent individuals.Opioid dependent patients (n=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Inventory, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the post hoc Tukey test.Anhedonia, depression, anxiety, and craving for opiates were elevated at baseline but gradually reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. There were no significant between-group differences prior to treatment dropout as well as between those who relapsed and who continued on naltrexone.These data do not support concerns that naltrexone treatment of opioid dependence precipitates anhedonia, depression, anxiety or craving for opiates.Цель исследования. Изучение влияния длительной терапии налтрексоном больных с синдромом зависимости от опиоидов на ангедонию, депрессию, тревогу и влечение к опиатам. Материал и методы. Пациенты (n=306) с синдромом зависимости от опиоидов были включены в рандомизированное двойное слепое плацебо-контролируемое 6-месячное исследование, сравнивающее эффективность в трех группах больных, в лечении которых использовались имплантируемая лекарственная форма налтрексона, пероральная его форма или плацебо. Для ежемесячной психометрической оценки были использованы визуальная аналоговая шкала влечения к употреблению опиоидов, шкала депрессии Бека, шкала тревоги Спилбергера, шкалы ангедонии Чапмена и Фергюсона. Для оценки межгрупповых различий проводился дисперсионный анализ (Mixed ANOVA) с апостериорным тестом Тьюки. Результаты и обсуждение. Показатели ангедонии, депрессии, тревоги и влечения к опиоидам были повышены в периоде включения больных в исследование и постепенно снижались до нормальных значений в течение первых 1-2 мес среди больных, удерживающихся в программе терапии. Значимых различий между тремя группами больных, а также между пациентами, прекратившими лечение и приверженными терапии, не обнаружено. Полученные данные не подтвердили предположение о том, что длительное лечение налтрексоном может способствовать развитию ангедонии, депрессии, тревоги и влечения к опиатам у больных с синдромом зависимости от опиоидов.

Preclinical studies suggest that the GABATo test efficacy and adverse effects of baclofen and the novel GABAWe used a well-characterized rat model of long-term alcohol consumption with repeated deprivation phases that result in compulsive alcohol drinking in a relapse situation, and a rat model of long-term intravenous cocaine self-administration resulting in key symptoms of addictive behavior. We tested repeated baclofen (0, 1, and 3 mg/kg; i.p.) and CMPPE doses (0, 10, and 30 mg/kg; i.p.) in relapse-like situations, in either alcohol or cocaine addicted-like rats.Baclofen produced a weak anti-relapse effect at the highest dose in alcohol addicted-like rats, and this effect was mainly due to the treatment-induced sedation. CMPPE had a better profile, with a dose-dependent reduction of relapse-like alcohol drinking and without any signs of sedation. The cue-induced cocaine-seeking response was completely abolished by both compounds.Positive allosteric modulation of the GABA

Background: Untreated opioid addiction in persons with HIV is associated with poor outcome. Agonist maintenance is not always available and some do not want it. Slow release naltrexone may be a useful option. Methods: The study was a 48-week trial in which 200 opioid addicted patients starting antiretroviral treatment (ART) for HIV were stratified according to gender, viral load (VL) and CD4 count, and randomized to addiction treatment using a naltrexone implant and oral naltrexone placebo (NI; n=100), or oral naltrexone 50 mg/day and a placebo implant (ON; n=100). Research staff was blinded to group assignment. Primary outcome was plasma VL

A method for determining buprenorphine and naloxone in human plasma using liquid chromatography and high-resolution time-of-flight mass spectrometry (LC-MS Q-TOF) was developed. The sample preparation technique included liquid extraction with salting out of the analytes in Toxi-Tubes Aintended for the determination of neutral and basic compounds. Quantitative analysis was carried out by the internal standard method. Naltrexone, which was structurally similar to the analytes, was used as the internal standard. The proposed method was developed for clinical trials of the new drug bupraxone, a sublingual dosage form containing buprenorphine and naloxone at doses of 0.2 mg each. The bioavailability of the drug components upon sublingual administration was studied. The buprenorphine concentrations in human plasma after administration at a dose of 0.4 mg via two routes (intravenous and sublingual) were compared.

Opioids have immunosuppressive properties, yet their impact on HIV disease progression remains unclear. Using longitudinal data from HIV-infected antiretroviral therapy-naïve Russian individuals (n = 77), we conducted a pilot study to estimate the effect of heroin use on HIV disease progression. Heroin use was categorized based on past 30 days self-reported use at baseline, 6 and 12 months as none, intermittent or persistent. We estimated the effect of heroin use on HIV disease progression, measured as change in CD4 count from baseline to 12 months, using multivariable linear regression. Those with intermittent (n = 21) and no heroin use (n = 39) experienced mean decreases in CD4 count from baseline to 12 months (-103 and -10 cells/mm(3), respectively; adjusted mean difference (AMD) -93; 95 % CI -245, 58). Those with persistent use (n = 17) showed a mean increase of 53 cells/mm(3) (AMD 63; 95 % CI -95, 220). Future studies exploring the effects of heroin withdrawal on HIV disease progression are warranted.

Aims This study assessed the effectiveness of HERMITAGE (HIV’s Evolution in Russia - Mitigating Infection Transmission and Alcoholism in a Growing Epidemic), an adapted secondary HIV prevention intervention, compared with an attention control condition in decreasing sexually transmitted infections (STIs) and sex and drug risk behaviors among Russian HIV-infected heavy drinkers.

Antiretroviral therapy (ART) became more widely available in the Russian Federation in 2006 when the Global Fund made a contribution to purchase ART with a mandate to increase numbers of patients receiving it. Funds were distributed to AIDS Centers and selected hospitals, and numbers quickly increased. Though ART is highly effective for adherent patients, dropout has been a problem; thus understanding characteristics of patients who remain on ART vs. those who leave treatment may provide information to facilitate engagement. We retrospectively assessed depression, hopelessness, substance use, viral load, and CD4+ counts of 120 patients who dropped out of ART for ≥12 months (Lost-to-Care, LTCs) and 120 who continued for ≥12 months (Engaged-in-Care, EICs). As expected, LTCs had higher viral loads and depression, lower CD4+ counts, more alcohol, heroin, and injection drug use in the past 30 days. A binary logistic regression with Center for Epidemiologic Studies Depression score, Beck Hopelessness score, whether drugs/alcohol had ever prevented them from taking ART, and past 30 days' alcohol use [χ(2)(4) = 64.27, p = .0.000] correctly classified 74.5% of participants as LTC or EIC, suggesting that integrated treatment for substance use, psychiatric, and HIV could reduce dropout and improve outcomes.

The effects of catechol-O-methyltransferase deficiency on sensitivity to the reinforcing action of cocaine were studied in male C57BL/6J mice with knockout of the COMT gene and wild-type mice of the same generation. Animals were trained to peep into an opening to receive intravenous infusions of cocaine (0.3 mg/kg per infusion; the reinforcement regime had a fixed reward:reinforcement ratio of 3:1 (FR3) and a 30-sec time-out). After the initial response acquisition phase, reinforcement in the FR3 regime and an increasing ratio (IR) regime was used to plot dose-effect curves for cocaine (0.03, 0.1, 0.3, 1, and 3 mg/kg per infusion). Cocaine self-administration reactions showed a relationship between dose and effect, total cocaine consumption in the FR3 and IR regimes being similar in mice of the two types. These results lead to the conclusion that individual differences in COMT activity do not affect the sensitivity of mice to the primary reinforcing action of cocaine.

Stress is a key precipitant to discontinuing naltrexone and relapsing to opiate abuse. Alpha-2 adrenergic agonists like guanfacine may reduce stress induced craving and have reduced opiate relapse in small clinical trials.This randomized, double blind double dummy placebo-controlled 6-month trial tested oral naltrexone with or without guanfacine for reducing stress and preventing opiate relapse. We randomized 301 patients to: naltrexone 50 mg/day+guanfacine 1 mg/day (n=75) (N/G), naltrexone+guanfacine placebo (N/P) (n=76), naltrexone placebo+guanfacine (n=75) (P/G), and double placebo (n=75) (P/P).Among the 75 patients in each group the percentage still retained on naltrexone treatment at six months was: N/G 26.7%, N/P 19.7% (p=0.258 to N/G), P/G 6.7% (p0.05 to both N groups), and P/P 10.7% (p=0.013 to N+G). Guanfacine reduced the severity of stress particularly at weeks 10 and 18. Adverse events (AE) were infrequent (4.7%) without group differences, with most common AEs: headache, poor appetite, insomnia, and dizziness.Adding guanfacine to naltrexone did not improve treatment retention or opiate free urines, but it reduced both stress and craving at later time points in treatment, which may be related to stress-induced craving and the animal model of incubation of reinstatement. During treatment, HIV risk, anxiety, and depression reduced among all patients in treatment, regardless of group.

We analyzed baseline data from an observational cohort of HIV-infected ART-naive patients in St. Petersburg, Russia to explore whether pain was associated with HIV risk behaviors. The primary outcomes were (1) unprotected vaginal or anal sex in the past 90 days and (2) sharing of needles or equipment in the past month. Secondary outcomes included: use of alcohol prior to sex, current injection drug use, number of unprotected sex and sharing episodes, and days injected in the past month. The main independent variable was any past week pain. Multivariable regression models were fit for outcomes. After adjustment, the association with unprotected sex was of borderline significance (AOR = 2.06; 95 % CI 0.98–4.36, p = 0.058); there was no significant association between any past week pain and sharing of needles/equipment (AOR = 1.52; 95 % CI 0.65–3.59, p = 0.33). Participants with pain had higher odds of reporting alcohol use prior to sex (AOR = 2.42; 95 % CI 1.10–5.28, p = 0.03).

Alcohol withdrawal syndrome (AWS) develops after cessation of alcohol intake in alcoholic patients characterizing psychiatric symptoms and changes in autonomous nervous systems. We studied cardiovascular changes during different phases of AWS (1, 2, 3 and 10 days after admission for detoxification; n=34) and compared them with those in early recovery (at least 1 month of abstinence; n=30). The results study showed that cardiovascular system underwent significant changes during AWS characterizing the decrease of heart rate, systolic and diastolic blood pressures, and total peripheral resistance. Stroke index was lower during AWS than in early recovery. As the decreased stroke index was compensated by increased heart rate, cardiac index did not differ during AWS from that in early recovery. Increased functioning of noradrenaline (along with other central and peripheral regulating mechanisms) may be an important factor associated with cardiovascular changes in AWS. Normalization of this function after AWS leads to returning of cardiovascular parameters to baseline levels.

Women initiate cocaine use at a younger age and have more complications (e.g., higher rates of major or minor depression) related to cocaine use than men. It has been proposed that estrogens play an important role in these sex differences. The addictive potential of psychoactive drugs can be measured in rats via a rewarding intracranial self-stimulation (ICSS) procedure. The rate-independent method of ICSS allows researchers to assess the “pure” rewarding effect of cocaine without influence of nonspecific motor reactions. The present study aimed to estimate effects of estradiol and a combination of estradiol and cocaine on ICSS in ovariectomized female rats. 17-β-estradiol (5 μg/animal/day, 2 days) produced a long-lasting gradual lowering of the thresholds for ICSS. The ability of estradiol to decrease thresholds for ICSS has never been shown previously. Combination of 17-β-estradiol and cocaine (5.0 mg/kg, 5 days) produced a greater effect on ICSS thresholds than the effect of either compound alone. No tolerance or sensitization to cocaine developed during the study. Present findings suggest estradiol increases sensitivity of the brain reward system in rats, which may have an important implication in understanding sex differences in cocaine effects.

Opioid dependence is one of the most severe drug dependencies. Naltrexone is a medication that completely blocks the subjective and other effects of opioids and, when administered to detoxified opioid addicts and taken as directed, prevents relapse and helps maintain abstinence. The major problem with naltrexone is poor compliance, particularly in countries in which there is a treatment alternative based on substitution of illicit opioids such as heroin with orally administered opioid agonists (methadone) or partial agonist/antagonists (buprenorphine). In Russia, substitution therapy is forbidden by law, and naltrexone is the only available pharmacotherapy for heroin dependence. Due to the lack of alternatives to naltrexone and stronger family control of compliance (adherence), naltrexone is more effective for relapse prevention and abstinence stabilization in Russia than in Western countries. Long-acting, sustained-release formulations (injectable and implantable) seem particularly effective compared with oral formulations. This article summarizes the results of studies conducted in Russia during the past 10 years that demonstrate these points.

Glutamate, the main excitatory neurotransmitter in the mammalian CNS, acts via ionotropic and metabotropic receptors. Results from in vitro studies demonstrating tight interactions between ionotropic NMDA receptors and subtype 5 metabotropic glutamate receptors (mGlu5) have shown that blockade of mGlu5 receptors increases the behavioral effects of NMDA receptor antagonists. The aim of the present work was to study the actions of the highly selective mGlu5 receptor antagonist MTEP alone and in combination with MK-801, a blocker of the NMDA receptor-associated ion channel, on performance of a delayed selection task (a test of working memory) in rats. MK-801 (0.1 mg/kg) induced a specific impairment to working memory, with proactive interference (degradation of the ability to remember current information because of the effects of previously learned material). Administration of MTEP (5.0 mg/kg) combined with both solvent and with MK-801 had no significant effects, demonstrating the small or nonexistent involvement of mGlu5 receptors in the mechanisms of working memory.

The purpose of this study was to assess the association between binge alcohol use and unprotected sex in Russian substance users. Participants ( N = 181) were narcology hospital patients assessed on demographics, alcohol use, risky sex, and sexually transmitted disease/human immunodeficiency virus (STD/HIV) diagnoses. Adjusted generalized estimating equations (GEEs) logistic regression analysis examined the association between binge drinking and same-day unprotected sex across each of the past 30 days, per participant ( N = 5430 observations). Participants were age 18 to 55 years, 75% male, and 64% binge drinking. Sex trade was reported by 27%; history of STDs by 43%; and HIV by 15%. One fourth of daily observations included sex; 88% of these involved unprotected sex. Binge drinking was not associated with same-day unprotected sex (adjusted odds ratio [ORadj] = 1.0, 95% confidence interval [CI] = 0.7–1.4, χ2(1, N = 5219) = 0.01, ns). Findings document substantial HIV/STD risk and prevalence among Russian narcology patients, but no link between binge drinking and unprotected sex in this population, possibly due to very low rates of condom use generally.

Aims: We studied whether verapamil, a Ca2+ channel blocker, affects cardiovascular symptoms in alcohol withdrawal. Methods: Cardiovascular effects of verapamil (5 mg intravenously) were compared in 20 alcohol-dependent subjects during alcohol withdrawal (n = 10) on days 1, 2 and 10 and during early recovery (n = 10; duration 45 ± 4.1 days). The heart rate was obtained from the electrocardiogram. Systolic and diastolic blood pressures were measured with a sphygmomanometer by Korotkoff. Stroke volume was studied by impedance cardiography. Results: Significant differences in verapamil effects on systolic and diastolic blood pressure and stroke volume and total peripheral resistance were observed in patients with withdrawal when compared with those in early recovery. Conclusion: L-type Ca2+ channels may modify vascular tone in alcohol withdrawal.

An endogenous natriuretic and vasoconstrictor Na/K-ATPase inhibitor, marinobufagenin (MBG), is implicated in NaCl-induced hypertension and in ethanol addiction. In rats, MBG suppresses voluntary alcohol intake, while immunization against MBG induces alcohol-seeking behavior. Since alcohol withdrawal is associated with elevation of blood pressure (BP) and renal sodium retention, we hypothesized that MBG mediates pressor response to ethanol withdrawal. In male Sprague-Dawley rats, forced ethanol intake (20% v/v, 2.8+/-0.2 g/day for 7 days) did not affect BP and MBG excretion. Ethanol withdrawal was associated with a 21 mm Hg increase in BP, a 10% decrease in hematocrit, and a three-fold increase in renal MBG excretion. In vivo administration of anti-MBG antibody to rats prevented withdrawal-induced BP elevation. Therefore, MBG mediates pressor response to ethanol withdrawal, and may link mechanisms of ethanol dependence and hypertension.

The influence of verapamil and nifedipine after single and subchronic treatment on morphine-induced subjective responses were studied in opiate addicts. Heroin-dependent subjects were injected via an antecubetal vein with 20 mg of morphine or placebo using a randomized cross-over design. In Experiment one, either verapamil 80 mg or nifedipine 60 mg or placebo was administered per os 1 hour prior morphine or placebo injection. In experiment two calcium blockers were administered weekly prior morphine administration. Administration of nifedipine (40 mg) reduced, not significantly, the subjective scaling of morphine effects and shifted the discrimination of morphine effects towards those of weak opiates. Acute treatment with verapamil (80 mg) increased, not significantly, the subjective rating of morphine effects. Pre-treatment of heroin abusers with nifedipine 60 mg daily for a week resulted in a remarkable inhibition of opiate-induced effects both expression and duration in comparison with placebo and verapamil pre-treatment. Patients pre-treated with nifedipine were also unable to discriminate properly morphine from other psychotropic compounds. Thus, nifedipine but not verapamil markedly inhibited but did not reduce completely the central effects of morphine. It is concluded that nifedipine can potentially offer a new interesting approach to the treatment programmes of opiate abuse.

Research on the neurocognitive characteristics of heroin addiction is sparse and studies that do exist include polydrug abusers; thus, they are unable to distinguish neurocognitive effects of heroin from those of other drugs. To identify neurocognitive correlates specific to heroin addiction, the present study was conducted in St. Petersburg, Russia where individuals typically abuse and/or become addicted to only one substance, generally alcohol or heroin. Heroin addicts were recruited from an inpatient treatment facility in St. Petersburg. Three comparison groups included alcoholics, addicts who used both alcohol and heroin, and non-abusers. Psychiatric, background, and drug history evaluations were administered after detoxification to screen for exclusion criteria and characterize the sample. Executive Cognitive Functions (ECF) that largely activate areas of the prefrontal cortex and its circuitry measured include complex visual pattern recognition (Paired Associates Learning), working memory (Delayed Matching to Sample), problem solving (Stockings of Cambridge), executive decision making (Cambridge Decision Making Task), cognitive flexibility (Stroop Color-Word Task) and response shifting (Stop Change Task). In many respects, the heroin addicts were similar to alcohol and alcohol+heroin dependent groups in neurocognitive deficits relative to controls. The primary finding was that heroin addicts exhibited significantly more disadvantageous decision making and longer deliberation times while making risky decisions than the other groups. Because the nature and degree of recovery from drug abuse are likely a function of the type or pattern of neurocognitive impairment, differential drug effects must be considered.

Cannabis and heavy alcohol use potentially increase HIV transmission by increasing risky drug behaviors. We studied 404 subjects entering treatment for heroin dependence, in St. Petersburg, Russia. We used the HIV Risk Assessment Battery (RAB) drug subscale to measure risky drug behavior. Although all heavy alcohol users had risky drug behaviors, their drug RAB scores did not differ from non-heavy alcohol users in unadjusted or adjusted analyses. Cannabis use was significantly associated with drug RAB scores in unadjusted analyses (mean difference 1.7 points) and analyses adjusted for age, sex, and employment (mean difference 1.3 points). When also adjusting for stimulant use, the impact of cannabis use was attenuated and no longer statistically significant (mean difference 1.1 points). Because of the central role of risky drug behaviors in the Russian HIV epidemic, it is important to understand how the use of multiple substances, including cannabis and alcohol, impacts risky drug behaviors.

One of the reasons of growing incidence of tuberculosis (TB) is spread of AIDS, drug dependence, and alcoholism. To investigate their mutual influence the authors examined 185 lung TB patients (of them, 124 males) admitted to TB hospitals of St-Petersburg in 2003-2005. Inclusive criteria were age of 18 to 79 yrs, recent admission to the hospital, the patient's consent to participate the study. Patients were excluded if they were severely ill or had psychiatric disorders. The lung TB was evaluated using medical history, physical, clinic, laboratory, radiologic, and bacteriologic data. Alcohol and drug abuse was assessed with Addiction Severity Index (ASI), retrospective analysis of alcohol and substance use for previous 90 days, Michigan Alcohol Screening Test (MAST), measurement of alcohol in exhaled air and detection of substances in urine. Somatic and psychic health was evaluated using ASI, Beck Depression Inventory, and Spielberger Trait Anxiety Inventory. Risk of HIV-infection was determined in a test of HIV risk assessment and with HIV risk questionnaire developed at Johns Hopkins University. The average age of the participants was 40.5 yrs. More than 60 % of them had abuse-related disorders: alcohol abuse in 51.9 %, alcoholism plus drug dependence in 8.6 %, and drug dependence in 3.8 %. Alcohol dependence facilitated development of TB multiple drug resistance (21 % vs 7.6 % in patients without alcohol dependence, p < 0.05), extensive (73.9 % and 40.9 %, respectively, p < 0.001) and chronic (28.6 % and 16.7 %, respectively) forms of TB. Most of TB patients with abuse-related disorders tended to have psychiatric disorders (depression, anxiety). The risk of HIV-infection was significantly higher in TB patients with drug abuse (3.51 vs 0.07). Thus, it is necessary to consider co-morbidity in TB patients for more effective treatment of lung tuberculosis.

Synaptic actions of gamma-amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism. We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD). We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals. Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls. These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G. These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009). We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310). Analyses in these populations did not support a role for GAD2 in alcoholism. In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs. The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.

Ethanol blocks N-methyl-d-aspartic acid (NMDA) glutamate receptors. Increased NMDA receptor function may contribute to motivational disturbances that contribute to alcoholism. The authors assessed whether the NMDA receptor antagonist memantine reduces cue-induced alcohol craving and produces ethanol-like subjective effects.Thirty-eight alcohol-dependent inpatients participated in three daylong testing sessions in a randomized order under double-blind conditions. On each test day, subjects received 20 mg of memantine, 40 mg of memantine, or placebo, and subjective responses to treatment were assessed. The level of alcohol craving was assessed before and after exposure to an alcohol cue.Memantine did not stimulate alcohol craving before exposure to an alcohol cue, and it attenuated alcohol cue-induced craving in a dose-related fashion. It produced dose-related ethanol-like effects without adverse cognitive or behavioral effects.These data support further exploration of whether well-tolerated NMDA receptor antagonists might have a role in the treatment of alcoholism.

Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-d-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. Methods: This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately. Results: All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam. Conclusions: This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal.

Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.

Alcohol consumption in Russia is reportedly high for both men and women; most studies of Russian drinking have used questionnaires not designed specifically to measure alcohol consumption or to interview women. This study was designed specifically to measure drinking patterns among pregnant and nonpregnant Russian women. Eight hundred ninety-nine women of child-bearing age in St. Petersburg Russia were interviewed in employment centers educational centers and at obstetric and gynecologic (OB/GYN) clinics and hospitals. Measurement of drinking used several types of drinking questions and time frames. Nearly all nonpregnant Russian women (95.9%) reported consuming alcohol in the last 12 months. Among nonpregnant women drinkers 7.6% reported drinking heavily (29.58 mL or more ethanol/d) and 18.4% reported drinking = 5 on at least 1 occasion. Contrary to expectations of Russian obstetricians pregnant Russian women readily answered detailed questions about their drinking behavior during pregnancy. Nearly all pregnant women drank in the year before they became pregnant; of these 60.0% reported drinking when they knew they were pregnant and 34.9% drank in the past 30 days. Among pregnant women who drank in the past 30 days 7.4% reporting having = 5 drinks on at least 1 occasion. Nevertheless more than 90% of pregnant and nonpregnant Russian women believed that alcohol has a detrimental effect on pregnancy outcomes. Pregnant and nonpregnant Russian women were willing to answer detailed questions about their drinking behavior. Although most pregnant women studied reduced their drinking during pregnancy one-third of the pregnant women did not stop drinking. It is important to find out what enabled two-thirds of the pregnant women to stop drinking before or during their pregnancy. (authors)

Poor validity of preclinical animal models is one of the most commonly discussed explanations for the failures to develop novel drugs in general and in neuroscience in particular. However, there are several areas of neuroscience such as injury-induced spasticity where etiological factor can be adequately recreated and models can focus on specific pathophysiological mechanisms that likely contribute to spasticity syndrome in humans (such as motoneuron hyperexcitability and spinal hyperreflexia). Methods used to study spasticity in preclinical models are expected to have a high translational value (e.g., electromyogram (EMG)-based electrophysiological tools) and can efficiently assist clinical development programs. However, validation of these models is not complete yet. First, true predictive validity of these models is not established as clinically efficacious drugs have been used to reverse validate preclinical models while newly discovered mechanisms effective in preclinical models are yet to be fully explored in humans (e.g., 5-HT2C receptor inverse agonists, fatty acid amid hydrolase inhibitors). Second, further efforts need to be invested into cross-laboratory validation of study protocols and tools, adherence to the highest quality standards (blinding, randomization, pre-specified study endpoints, etc.), and systematic efforts to replicate key sets of data. These appear to be readily achievable tasks that will enable development not only of symptomatic but also of disease-modifying therapy of spasticity, an area that seems to be currently not in focus of research efforts.

Constitutively active 5-HT2 receptors have been suggested to contribute to motoneuronal excitability, muscle spasms and spasticity. Accordingly, 5-HT2C receptor inverse agonists have been demonstrated in pilot experiments to reduce spasticity in animal model of spasticity and patients with spinal cord injuries. Thus, 5-HT2C receptor inverse agonists may represent a novel class of anti-spasticity agents justifying a search for compounds with robust 5-HT2C receptor inverse agonist activity either among the existing medications or via a dedicated drug discovery program. Morphine-induced Straub tail response in mice is regarded as a model of transient spasticity that may be suitable for supporting such drug discovery efforts. Subcutaneous injection of morphine (10-60mg/kg) induced a dose-dependent Straub tail reaction in male Swiss mice with maximum response obtained 15-30min after the morphine administration. When given prior to morphine, 5-HT2B/2C receptor inverse agonists cyproheptadine (1-10mg/kg, i.p.) and SB206553 (0.3-3mg/kg, i.p.) diminished Straub tail reaction dose-dependently without affecting spontaneous locomotor activity. In contrast, 5-HT2B/2C receptor antagonist methysergide (1-5.6mg/kg, i.p.) and 5-HT2C receptor antagonist SB242084 (1-5.6mg/kg, i.p.) as well as 5-HT2A receptor inverse agonist pimavanserin (1-10mg/kg, i.p.) had no appreciable effects on Straub tail response. Taken together, the findings indicate that constitutive activity of 5-HT2B/2C receptor may be involved in the mechanisms of morphine-induced spasticity. Thus, morphine-induced Straub tail response may be evaluated further as a candidate higher throughput test to identify 5-HT2C receptor inverse agonists with anti-spasticity effects in vivo.

Naltrexone is an antagonist that binds tightly to μ-opioid receptors and blocks the subjective and analgesic effects of opioids. It does not produce physiologic dependence and precipitates withdrawal if administered to an opioid dependent person, thus starting it must begin with detoxification. It was first available in the mid-1970s as a 50 mg tablet that blocked opioids for 24–36 h if taken daily, or every 2–3 days at higher doses - for example: 100 mg Monday and Wednesday, 150 mg on Friday. From a pharmacological perspective it worked very well and was hoped to be an effective treatment but results were disappointing due to low patient interest and high dropout followed by relapse. Interest in it waned but rose again in the late 1990’s when injecting opioid use and the rapid spread of HIV in the Russian Federation converged with an international interest in reducing the spread of HIV. One result was a series of meetings sponsored by the U.S. National Institute on Drug Abuse (NIDA) and Pavlov State Medical University in St. Petersburg, Russian Federation, on ways to reduce the spread of HIV in that country. Addiction treatment was a clear priority and discussions showed that naltrexone could have a role since agonist treatment is against Russian law but naltrexone is approved and the government funds over 25,000 beds for detoxification, which is the first step in starting naltrexone treatment. These meetings were followed by NIDA studies that showed better compliance to oral naltrexone than in prior U.S. studies with the expected reductions in HIV injecting risk for those that stayed in treatment. These events and findings provided a background and identified an infrastructure for the study that led to FDA approval of extended release injectable naltrexone for preventing relapse to opioid dependence. This paper will briefly review findings from these studies and end with comments on the potential role of extended release naltrexone as a meaningful addition to current pharmacotherapies for treating opiod dependence and reducing HIV risk.

To evaluate the effect of opioid receptor genes and dopamine system genes polymorphisms on treatment outcomes of opioid dependence with implantable and oral naltrexone.Authors carried out a randomized double-blind, double-dummy, placebo-controlled clinical trial. Three hundred and six patients with opioid dependence were randomized into 3 equal treatment groups. The first group received implantation of 1000 mg naltrexone every 2 months during 6 months + oral naltrexone placebo; the second group - placebo implant every 2 months + oral naltrexone (50mg/day) and the third group - placebo implant + oral naltrexone placebo. It was genotyped polymorphisms in the following genes: mu-opioid receptor (OPRM1), kappa-opioid receptor (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (DAT1).Regardless of treatment several polymorphisms of these genes were associated with high risk of relapse: an allele L (2R) DRD4 120bp (p=0.05; OR (95% CI)=3.3(1.1-10.1)); an allele С DRD2 NcoI (р=0,051; OR (95% CI)=2,86 (1,09-7,52)); the genotype 9.9 DAT VNTR 40bp (р=0,04; OR (95% CI)=1,4 (1,3-1,5)); on the contrary, (СС+СТ)-(ТТ)) variants of OPRK1-DRD2Ncol increased a chance to complete treatment program (р=0,004; OR (95% CI)=7.4 (1.8-30.4)), Kaplan-Meier survival analysis (р=0,016). The probability of completing treatment program by the carriers of these variants was higher in the oral naltrexone group (p=0.016), lower in the double placebo group (p=0.015), but did not influence on treatment outcomes in the naltrexone-implant group.Naltrexone-implant is a highly effective medication for treatment of opioid dependence and its effectiveness exceeds that of oral naltrexone and placebo. The study has shown the joint influence of opioid receptor genes and genes of dopaminergic system on treatment outcomes of opioid dependence. Genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.Цель исследования - выявить влияние полиморфных вариантов генов опиоидной и дофаминовой систем на эффективность противорецидивной терапии опийной наркомании имплантируемой и пероральной лекарственных форм налтрексона. Материал и методы. Было проведено двойное слепое рандомизированное плацебо-контролируемое исследование с двойной маскировкой. 306 больных опийной наркоманией были рандомизированы в 3 группы по 102 человека в каждой. Больным 1-й группы назначались имплант 1000 мг налтрексона (3 имплантации с интервалом 2 мес, всего на 6 мес) и таблетки плацебо, больным 2-й группы - плацебо-имплант и пероральный налтрексон (50 мг в сутки), больным 3-й группы - двойное плацебо (имплант и таблетки). Генотипирование больных проводили по следующим вариантам полиморфизма генов: опиоидных рецепторов типов мю (OPRM1) и каппа (OPRК1), фермента катехол-орто-метил-трансферазы (COMT), дофаминовых рецепторов 2 (DRD2) и 4 (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белка - трансмембранного переносчика дофамина (SLC6A3, DAT1). Результаты. Было установлено, что вне зависимости от вида противорецидивной терапии ряд полиморфных вариантов повышает риск рецидива зависимости: аллель L (2 повтора по 120 н.п.) DRD4120bp (р=0,05; OR (95% ДИ)=3,3(1,1-10,1)); аллель С DRD2NcoI (р=0,051; OR (95% ДИ)=2,86 (1,09-7,52)); генотип 9,9 DATVNTR40bp (р=0,04; RR (95% ДИ)=1,4(1,3-1,5)); напротив, варианты полиморфизма (СС+СТ)-(ТТ)) по сочетанию генов (OPRK1-DRD2Ncol) повышают вероятность завершения программы лечения (р=0,004; OR (95% ДИ)=7,4 (1,8-30,4)), анализ выживаемости Каплана-Мейера (р=0,016). В группе перорального налтрексона носители этих же вариантов (OPRK1-DRD2Ncol) имели более высокую вероятность завершения программы лечения (р=0,016), однако эффект был обратным в группе двойного плацебо (р=0,015) и не проявлялся вообще в группе с имплантом налтрексона (р=0,33). Заключение. Имплант налтрексона является высокоэффективным препаратом для лечения опийной наркомании, превосходящим по эффективности пероральный налтрексон и плацебо-имплант. По результатам генотипирования вероятно выявление потенциальных респондеров при терапии пациентов, что может повысить эффективность лечения.

This randomized placebo-controlled trial tested the efficacy of oral naltrexone with or without fluoxetine for preventing relapse to heroin addiction and for reducing HIV risk, psychiatric symptoms, and outcome. All patients received drug counseling with parental or significant-other involvement to encourage adherence. Patients totaling 414 were approached, 343 gave informed consent, and 280 were randomized (mean age, 23.6 +/- 0.4 years). At 6 months, two to three times as many naltrexone patients as naltrexone placebo patients remained in treatment and had not relapsed, odds ratio (OR) = 3.5 (1.96-6.12), p < .0001. Overall, adding fluoxetine did not improve outcomes, OR = 1.35 (0.68-2.66), p = .49; however, women receiving naltrexone and fluoxetine showed a trend toward a statistically significant advantage when compared to women receiving naltrexone and fluoxetine placebo, OR = 2.4 (0.88-6.59), p = .08. HIV risk, psychiatric symptoms, and overall adjustment were markedly improved among all patients who remained on treatment and did not relapse, regardless of group assignment. More widespread use of naltrexone could be an important addition to addiction treatment and HIV prevention in Russia.

Previous studies suggested that adenosine A1 and A2A receptor agonists counteract behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists while adenosine receptor antagonists may produce opposite effects enhancing the actions of NMDA receptor antagonists. To further evaluate the effects of combined administration of adenosine receptor antagonist caffeine and various NMDA and non-NMDA glutamate receptor antagonists on brain stimulation reward (discrete-trial threshold current intensity titration procedure), rats with electrodes implanted into the ventral tegmental area were tested after pretreatment with NMDA receptor channel blocker MK-801 (0.01-0.3 mg/kg), competitive antagonist D-CPPene (0.3-5.6 mg/kg), glycine site antagonist L-701,324 (1.25-5 mg/kg), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist GYKI-53655 (1-10 mg/kg), metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (1-10 mg/kg) alone and in combination with caffeine (1-30 mg/kg). MK-801 (0.056 and 0.1 mg/kg) was the only tested glutamate antagonist that lowered self-stimulation thresholds, while D-CPPene (5.6 mg/kg) and MPEP (5.6 and 10 mg/kg) had the opposite effects. Threshold-increasing effects of D-CPPene, but not of MPEP, however, were associated with marked impairment of operant performance, reflected by longer latencies to respond and higher rates of responding during the inter-trial intervals. Operant performance was also disrupted by the highest dose of MK-801 (0.3 mg/kg). For subsequent experiments, caffeine (1-30 mg/kg) was combined with the highest doses of NMDA receptor antagonists that did not lower the brain stimulation reward thresholds and did not impair operant performance. Caffeine had no appreciable effects on self-stimulation behavior when given alone. A low dose of caffeine (3 mg/kg) significantly lowered self-stimulation thresholds only when given together with MK-801 (0.03 mg/kg) or D-CPPene (3 mg/kg). Combined with the same antagonist drugs, higher doses of caffeine (10 and 30 mg/kg) facilitated time-out responding. These results indicate that, within a limited dose range, caffeine in combination with an NMDA receptor channel blocker and a competitive antagonist significantly lowers brain stimulation reward thresholds in rats.

Background: Two recent large genetic studies in the US population have reported association between genetic variation in γ-amino butyric acid α2 receptor subtype (GABRA2) and risk for alcohol dependence. The goal of this study was to test whether GABRA2 is associated with alcohol dependence in a sample of Russian alcohol-dependent men. Methods: A total of 113 Russian alcohol-dependent men and 100 male population control subjects were recruited in St. Petersburg and genotyped for seven GABRA2 single-nucleotide polymorphisms (SNPs) using real-time PCR (TaqMan). Six SNPs were located in a GABRA2 haplotype block previously associated with alcohol dependence (AD) in the US population. SNPs and haplotypes were tested for an association to AD using χ2 analysis and a likelihood ratio-based statistic implemented in the software COCAPHASE. Results: Significant associations between two SNPs and AD were observed (p < 0.05). In addition, a trend-level association was observed between AD and three adjacent SNPs (p < 0.1). Associated alleles were carried in a haplotype that was present at frequencies of 0.37 and 0.48 in the control and alcohol-dependent populations, respectively (p < 0.06). Tight linkage disequilibrium spanning from the central portion of the gene to the 3′ end was observed in this population. Comparison of the findings to the previously published studies in the US population revealed a highly similar linkage disequilibrium pattern in this population. Conclusions: These findings suggest that genetic variants of GABRA2 increase risk for AD in the Russian population and provide additional support to the hypothesis that polymorphic variation at the GABRA2 locus plays an important role in predisposing to AD at least in European-ancestry populations.

Previous studies suggested that metabotropic glutamate 5 (mGlu5) receptors play an important role in the reinforcing effects of abused drugs. The present experiments evaluated the effects of the mGlu5 receptor antagonist, MPEP (2-methyl-6-(phenylethynyl)-pyridine hydrochloride; 1–10 mg/kg, salt, i.p.), in rat models of nicotine-seeking behavior that may have relevance to relapse to drug-taking. Male Wistar rats (with restricted access to food) were trained to nose-poke to receive intravenous infusions of nicotine (0.03 mg/kg per infusion, base) under a fixed ratio 5 time out 60 s schedule of reinforcement. After stable nicotine self-administration was acquired, nose-poking behavior was extinguished in the absence of nicotine-associated cues. During the reinstatement test phase, independent groups of animals were exposed to: (a) response-contingent nicotine-associated cues (cue-induced reinstatement); or (b) response-noncontingent presentations of 45-mg food pellets under fixed time 2 min schedule (schedule-induced reinstatement). Additional control experiments were conducted to demonstrate that in nicotine-naive animals MPEP does not affect cue-induced reinstatement of food-seeking behavior and has no effects on operant behavior maintained by a simple fixed interval 2 min schedule of food reinforcement. Pretreatment with MPEP (10 mg/kg) significantly attenuated the reinstatement of nicotine-seeking in both experiments. Further, MPEP (10 mg/kg) significantly attenuated polydipsia induced by a fixed time 2 min food schedule. In conclusion, the present findings indicate that the blockade of mGlu5 receptors attenuates cue-induced reinstatement of nicotine self-administration behavior (but not food-seeking) and may produce a general inhibition of schedule-induced behaviors, including schedule-induced nicotine-seeking.

In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior—a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists. # 2004 Elsevier Ltd. All rights reserved.