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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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study we randomized 52 consenting patients who completed detoxification in St. Petersburg to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p

Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.

Introduction. An epidemic of syphilis and other sexually transmitted infections (STI) in the Russian Federation is believed to be related to the rise in injection drug use. A study was carried out in collaboration with a non-governmental organization, Foundation 'Vozvrastcheniye'. Methods: Nine hundred and ten injection drug users participating in the programme were tested for syphilis, HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV); 65 participants who had laboratory markers for syphilis and 45 syphilis-negative serosurvey subjects agreed to participate in a questionnaire study. Results: Syphilis, HIV, HBV and HCV were diagnosed in 12%, 0%, 48% and 79% of drug users, respectively. Prevalence of syphilis seromarkers was nine times higher in females than in males, and strongly associated with sex work. Conclusions: The results of the study indicate that resources to treat and prevent further infections including HIV should be prioritized toward risk reduction in drug injectors and sex workers in St Petersburg.

Recent evidence suggests that acute administration of opioid analgesic drugs (such as morphine or heroin) produces delayed hyperalgesia. This hyperalgesic response is likely to result from hyperactivation of NMDA receptors triggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioid-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that becomes spatiotemporally associated with environmental cues accompanying repeated opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphine tolerance, NMDA receptor antagonists have been shown to block development of analgesic tolerance induced by repeated exposures to morphine. The view of the conditioned nature of opioid tolerance may be significantly extended by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, consequentially, it may become empowered to elicit the later-onset effect itself. Such 'intra-drug' conditioning hypothesis is well in line with the current experimental evidence but further studies will be needed to verify it directly.

Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and crosstolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and crosstolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of d -CPPen (SDZ EAA 494; 1–5.6 mg/kg), dizocilpine (MK-801; 0.03–0.3 mg/kg), memantine (0.3–17 mg/kg), ACEA-1021 (10–56 mg/kg), and eliprodil (1–30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to d -CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with d -CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.

The reinstatement of extinguished cocaine self-administration behavior was studied in rats pretreated with N-methyl-D-aspartate receptor antagonists. Rats were trained to self-administer intravenous cocaine (0.32 mg/kg/infusion) during five consecutive daily sessions that were followed by five consecutive daily extinction sessions, during which cocaine was unavailable and cocaine-associated cues (sound and light) were absent. Neither the competitive N-methyl-D-aspartate receptor antagonist D-CPPene (0.3-3 mg/kg) nor the low-affinity N-methyl-D-aspartate receptor channel blocker memantine (1-10 mg/kg) reinstated extinguished responding. Priming injections of intravenous cocaine (Experiment 1), and exposures to cocaine-associated stimuli (buzzer and light; Experiment 2) engendered responding on the reinforced lever in excess of that on the non-reinforced lever. In Experiment 1, administration of D-CPPene or memantine prior to the priming injection of cocaine eliminated the difference between reinforced-lever and non-reinforced-lever response rates. For both D-CPPene and memantine, however, this effect was largely due to increased responding upon the non-reinforced lever rather than to decreased reinforced-lever responding. In Experiment 2, D-CPPene, but not memantine, abolished in a dose-dependent manner the selective increase in reinforced-lever over non-reinforced-lever responding that was induced by exposures to cocaine-related stimuli. This effect of D-CPPene was not due to increased non-reinforced-lever responding. These data help define the boundaries within which N-methyl-D-aspartate receptor antagonists can prevent reinstatement of cocaine-seeking behavior (e.g. type of antagonist used and reinstatement procedure).

The effect of dihydropyridine calcium channel antagonist isradipine (PN 200-110) on morphine reinforcement has been investigated using i.v. self-administration test in rats. Rats were given the opportunity to self-administer a solution of morphine (1 mg/Ml, i.v.) in a 1 hr limited access paradigm (FR = 1). Within 5–7 days rats had learned to self-administer approximately 1 mg of morphine in 1 hr as evidenced by a plateau of responding. The administration of isradipine (1.2, 2.5 and 5.0 mg/kg s.c.) 90 min before the morphine self-administration session, induced dose-dependent increase in the number of morphine self-infusions with respect to basal values. This response pattern was very similar to the one observed when morphine solution was substituted by saline in trained rats not treated with isradipine. The results indicate that isradipine inhibits partially the reinforcing properties of morphine in self-administration test.

The aim of the present work was to clarify the role of calcium influx through L-type calcium channels in the rewarding and analgesic effects of morphine. Therefore the effects of Bay K-8644 and nimodipine, dihydropyridine calcium agonist and antagonist, respectively, on the analgesic and rewarding effects of morphine in mice were studied. Morphine-induced analgesia was measured with the aid of writhing test, hot plate test and tail clip test. The rewarding properties of morphine were studied using i.v. self-administration in drug-naive mice. Bay K-8644 potentiated morphine-induced analgesia in all the tests. The influence of nimodipine on morphine analgesia was more complicated and depended on the dose of morphine and test used. In self-administration experiments morphine exhibited the bell-shaped concentration-response curve. Bay K-8644 produced a shift of the curve to the left, while nimodipine had the opposite action indicating, respectively, facilitating and inhibitory influence on morphine rewarding effect. It is concluded that nimodipine exhibits partial antagonistic properties towards the rewarding action of morphine and slightly potentiates morphine-induced analgesia while Bay K-8644 increases either the rewarding or the analgesic effects of morphine.

To compare trends in opioid consumption in Israel and St. Petersburg/Russia (morphine, oxycodone, pethidine, fentanyl, methadone, buprenorphine, trimeperidine, and papaveretum) over the period 2000-2008, and to describe the regulatory barriers to their accessibility as an exploratory variable for between-country differences.Data were drawn from the databases maintained by the Israel Ministry of Health's Pharmaceutical Administration and the St. Petersburg Central Pharmaceutical Reserve. The data were converted into a defined daily dose (DDD)/1,000 inhabitants/day. Regulation was evaluated according to the WHO guidelines for the assessment of national opioid regulation.The opioid consumption rates in Israel were substantially higher than those in St. Petersburg. The excess in DDD/1,000 inhabitants/day was for fentanyl +0.287 in 2000 and +1.206 in 2008, for morphine +0.245 in 2000 and +0.122 in 2008, and for pethidine/trimeperidine +0.035 in 2000 and +0.007 in 2008. Oxycodone consumption increased in Israel from 0.31 DDD/1,000 inhabitants/day in 2000 to 0.46 DDD/1,000 inhabitants/day in 2008, whereas this analgesic is not available in St. Petersburg. Methadone and buprenorphine consumption rose in Israel, whereas these drugs are not available in Russia. Conversely, omnopon consumption decreased in St. Petersburg from 0.0206 DDD/1,000 inhabitants/day in 2000 to 0.00304 DDD/1,000 inhabitants/day in 2008, whereas the compound is not available in Israel. St. Petersburg differs from Israel with less opioid formulary availability and greater regulatory restrictions.The results suggest that strong opioid analgesics consumption rates in St. Petersburg yield those in Israel, and that the between-countries differences in opioid formularies availability and legal and regulatory barriers to opioids accessibility are responsible for the consumption discrepancies.

The effect of isradipine, a dihydropyridine calcium antagonist, on morphine-induced place preference and analgesia in rats and mice was studied. Isradipine (0.6–5.0 mg/kg s.c.) inhibited an acquisition of morphine-induced place preference in rats and mice in a dose-related manner. Isradipine did not affect or strengthen morphine-induced analgesia as measured by tail-clip and hot-plate tests in mice and tail-clip and tail-flick tests in rats. The results suggest that analgesic and reinforcing effects of morphine might be pharmacologically separated by isradipine.

AIM: To assess the effectiveness of a sexual risk reduction intervention in the Russian narcology hospital setting. DESIGN SETTING AND PARTICIPANTS: This was a randomized controlled trial from October 2004 to December 2005 among patients with alcohol and/or heroin dependence from two narcology hospitals in St Petersburg Russia. INTERVENTION: Intervention subjects received two personalized sexual behavior counseling sessions plus three telephone booster sessions. Control subjects received usual addiction treatment which did not include sexual behavior counseling. All received a research assessment and condoms at baseline. MEASUREMENTS: Primary outcomes were percentage of safe sex episodes (number of times condoms were used / by number of sexual episodes) and no unprotected sex (100% condom use or abstinence) during the previous 3 months assessed at 6 months. FINDINGS: Intervention subjects reported higher median percentage of safe sex episodes (unadjusted median difference 12.7%; P = 0.01; adjusted median difference 23% P = 0.07); a significant difference was not detected for the outcome no unprotected sex in the past 3 months [unadjusted odds ratio (OR) 1.6 95% confidence interval (CI) 0.8-3.1; adjusted OR 1.5 95% CI 0.7-3.3]. CONCLUSIONS: Among Russian substance-dependent individuals sexual behavior counseling during addiction treatment should be considered as one potential component of efforts to decrease risky sexual behaviors in this HIV at-risk population.

The effect of 7-week forced oral nicotine exposure on acquisition of intravenous nicotine self-administration, nicotine place conditioning, and nicotine preference was studied in mice. The nicotine solution was given in stepwise increased concentrations as the sole source of liquid for 7 weeks. Nicotine exposed animals self-administered nicotine intravenously at lower unit dose than nicotine-naive ones, indicating that the forced 7-week nicotine exposure, followed by 7-day withdrawal, had rendered them more sensitive to nicotine's reinforcing effects. At the dose of 0.5 mg/kg, nicotine induced conditioned place preference both in drug-naive and nicotine exposed mice, but the 0.3 mg/kg dose of nicotine failed to do so. The forced nicotine pre-exposure did not alter the nicotine preference in the 2-bottle free-choice paradigm. In conclusion, these results suggest that nicotine pre-exposure enhances the reinforcing effects of acutely administered nicotine only in the intravenous self-administration model.

To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial.Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine.The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p0.0125).The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.Цель исследования. Выявление влияния полиморфных вариантов генов опиоидной и дофаминовой систем мозга на эффективность комбинированной терапии налтрексоном и гуанфацином у больных с опиоидной зависимостью в рамках двойного слепого рандомизированного плацебо-контролируемого исследования с двойной маскировкой. Материал и методы. Обследовали 301 больного с опиоидной зависимостью, которые были рандомизированы в четыре группы: налтрексон (NTX) 50 мг/день+гуанфацин (GFC) 1 мг/день (Н+Г); NTX+GFC-плацебо (Н+ГП); NTX-плацебо+GFC (НП+Г) и двойное плацебо (НП+ГП). Показателем эффективности терапии было удержание пациентов в программе лечения. Пациенты были генотипированы по полиморфным вариантам генов: опиоидных рецепторов типов µ (OPRM1) и каппа (OPRК1), фермента катехол-орто-метилтрансферазы (COMT), дофаминовых рецепторов 2-го (DRD2) и 4-го (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белка - трансмембранного переносчика дофамина (SLC6A3, DAT1) и альфа-2А-адренорецептора (ADRA2A)-фармакологической мишени гуанфацина. Результаты. Комбинация налтрексона и гуанфацина была сравнима по эффективности с монотерапией налтрексоном. Независимо от вида терапии ряд генетических вариантов повышает шанс завершения программы лечения: аллель Т DRD4 521 (rs1800955) (р=0,039; OR (95% ДИ)=3,7 (1,1-12,7); лог-ранк критерий: р=0,01); аллель С DRD2 С957Т (rs 6277) (р=0,03; HR=0,6 (0,34-0,95); сочетания генотипов: DRD4 VNTR (LL)+OPRM1 A118G (rs1799971)(AA), р=0,051; DRD2 C957T (ТТ)+OPRM1 (rs1074287) (СС), р=0,025; DRD2 - 141С (II)+OPRM1 (rs510769) (АА), р=0,035; DBH Fau(СС)+OPRM1 (rs1074287) (СС), р=0,0497. Независимо от вида терапии ряд генетических вариантов повышает риск рецидива: аллель Т (rs510769) OPRM1 (р=0,053), аллель А (rs1799971, A118G) OPRM1 (р=0,056), аллель S (количество повторов менее 7) экзон III 48 bp DRD4 VNTR (р=0,001; HR=3,1 (ДИ 95% 1,57-6,18); сочетания генотипов: DRD4 521 С/Т (ТТ)+DRD2 Nco I (TT), р=0,026; DRD4 521 С/Т (ТТ)+DRD2 -141 С (II), р=0,011; DRD4 521 С/Т (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,011; DRD2 Nco I (ТТ)+ADRA2A (СС), р=0,012; DRD2 Nco I (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,02. Эффекты, зависящие от вида терапии: 1) только в группе пациентов, получавших налтрексон и гуанфацин (Н+Г), носители генотипа ТT локуса DRD4 521(rs1800955) достоверно более длительное время удерживались в программе терапии, чем остальные пациенты (генотипы СС и СТ) (лог-ранк критерий: p=0,002); 2) только в группе двойного плацебо (НП+ГП) носители аллеля Т локуса rs510769 OPRM1 имели больший риск рецидива зависимости по сравнению с генотипом СС (р=0,016) и носители аллеля А локуса rs1799971 (A118G) OPRM1имели больший риск рецидива по сравнению с генотипом GG (р=0,008) (FDR р0,0125). Заключение. Показано совместное влияние генов дофаминовой и опиоидной систем мозга на эффективность налтрексона и гуанфацина и стабилизацию ремиссии у больных c опиоидной наркоманией. Генетические варианты локуса DRD4 521(rs1800955) гена дофаминового рецептора типа 4 проявляются только в группе пациентов, получавших активные препараты, и в наибольшей степени связаны именно с фармакологическим эффектом налтрексона и гуанфацина. Полиморфизм гена µ-опиоидного рецептора, в особенности функционального варианта rs1799971 (A118G), в наибольшей степени проявляется в группе двойного плацебо, что заставляет предполагать существенное влияние этого гена на черты личности, темперамента и характера, особенно в контексте комплаенса. По результатам генотипирования возможно выявление высокорезистентных к терапии пациентов, а предварительное проведение генотипирования перед назначением вариантов фармакотерапии может повысить эффективность лечения опиоидной зависимости.Цель исследования. Выявление влияния полиморфных вариантов генов опиоидной и дофаминовой систем мозга на эффективность комбинированной терапии налтрексоном и гуанфацином у больных с опиоидной зависимостью в рамках двойного слепого рандомизированного плацебо-контролируемого исследования с двойной маскировкой. Материал и методы. Обследовали 301 больного с опиоидной зависимостью, которые были рандомизированы в четыре группы: налтрексон (NTX) 50 мг/день+гуанфацин (GFC) 1 мг/день (Н+Г); NTX+GFC-плацебо (Н+ГП); NTX-плацебо+GFC (НП+Г) и двойное плацебо (НП+ГП). Показателем эффективности терапии было удержание пациентов в программе лечения. Пациенты были генотипированы по полиморфным вариантам генов: опиоидных рецепторов типов μ (OPRM1) и каппа (OPRК1), фермента катехол-орто-метилтрансферазы (COMT), дофаминовых рецепторов 2-го (DRD2) и 4-го (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белка — трансмембранного переносчика дофамина (SLC6A3, DAT1) и альфа-2А-адренорецептора (ADRA2A)-фармакологической мишени гуанфацина. Результаты. Комбинация налтрексона и гуанфацина была сравнима по эффективности с монотерапией налтрексоном. Независимо от вида терапии ряд генетических вариантов повышает шанс завершения программы лечения: аллель Т DRD4 521 (rs1800955) (р=0,039; OR (95% ДИ)=3,7 (1,1—12,7); лог-ранк критерий: р=0,01); аллель С DRD2 С957Т (rs 6277) (р=0,03; HR=0,6 (0,34—0,95); сочетания генотипов: DRD4 VNTR (LL)+OPRM1 A118G (rs1799971)(AA), р=0,051; DRD2 C957T (ТТ)+OPRM1 (rs1074287) (СС), р=0,025; DRD2 — 141С (II)+OPRM1 (rs510769) (АА), р=0,035; DBH Fau(СС)+OPRM1 (rs1074287) (СС), р=0,0497. Независимо от вида терапии ряд генетических вариантов повышает риск рецидива: аллель Т (rs510769) OPRM1 (р=0,053), аллель А (rs1799971, A118G) OPRM1 (р=0,056), аллель S (количество повторов менее 7) экзон III 48 bp DRD4 VNTR (р=0,001; HR=3,1 (ДИ 95% 1,57—6,18); сочетания генотипов: DRD4 521 С/Т (ТТ)+DRD2 Nco I (TT), р=0,026; DRD4 521 С/Т (ТТ)+DRD2 —141 С (II), р=0,011; DRD4 521 С/Т (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,011; DRD2 Nco I (ТТ)+ADRA2A (СС), р=0,012; DRD2 Nco I (ТТ)+OPRM1 A118G (rs1799971) (AA), р=0,02. Эффекты, зависящие от вида терапии: 1) только в группе пациентов, получавших налтрексон и гуанфацин (Н+Г), носители генотипа ТT локуса DRD4 521(rs1800955) достоверно более длительное время удерживались в программе терапии, чем остальные пациенты (генотипы СС и СТ) (лог-ранк критерий: p=0,002); 2) только в группе двойного плацебо (НП+ГП) носители аллеля Т локуса rs510769 OPRM1 имели больший риск рецидива зависимости по сравнению с генотипом СС (р=0,016) и носители аллеля А локуса rs1799971 (A118G) OPRM1имели больший риск рецидива по сравнению с генотипом GG (р=0,008) (FDR р0,0125). Заключение. Показано совместное влияние генов дофаминовой и опиоидной систем мозга на эффективность налтрексона и гуанфацина и стабилизацию ремиссии у больных c опиоидной наркоманией. Генетические варианты локуса DRD4 521(rs1800955) гена дофаминового рецептора типа 4 проявляются только в группе пациентов, получавших активные препараты, и в наибольшей степени связаны именно с фармакологическим эффектом налтрексона и гуанфацина. Полиморфизм гена μ-опиоидного рецептора, в особенности функционального варианта rs1799971 (A118G), в наибольшей степени проявляется в группе двойного плацебо, что заставляет предполагать существенное влияние этого гена на черты личности, темперамента и характера, особенно в контексте комплаенса. По результатам генотипирования возможно выявление высокорезистентных к терапии пациентов, а предварительное проведение генотипирования перед назначением вариантов фармакотерапии может повысить эффективность лечения опиоидной зависимости.

Aims: The present study utilized female cynomolgus monkeys and examined whether estrogen (E2), progesterone (P4) and total testosterone (T) predicted eventual social rank, changed following hierarchy establishment, or was associated with susceptibility to cocaine self-administration. Methods: Blood serum was collected for three months prior to social housing, then for one month once hierarchies were stable. Following stable hierarchy formation, monkeys were trained to respond for food under a fixed-ratio 30 schedule of reinfocement and then given access to ascending doses of cocaine (0.0003–0.1mg/kg/inj). Results: Prior to social housing, E2 exposure across the menstrual cycle was greater in eventual subordinate compared to eventual dominantmonkeys, while therewere no differences in P4 concentrations. After stable hierarchies formed (4 monkeys/pen), E2 in subordinates decreased and differences between groupswere no longer observed. Furthermore, dominant animals had decreases in P4 after hierarchies stabilized, whereas subordinate animals showed increases in P4 following stable social group formation. T concentrations did not predict or differ between ranks; decreases in T concentrations were observed across all ranks following stable hierarchy formation. Subordinate monkeys acquired cocaine self-administration at lower doses than dominant monkeys. This effect could be driven by higher circulating E2 since there was an inverse relationshipbetweenE2concentrations anddoseof cocaine at which acquisition occurred. Conclusions: These results enhance our understanding of an individual’s response to environmental manipulations, such as attainment and occupation of social ranks and between-rank variation in hormone dysregulation as well as their relationship to cocaine self-administration. Such informationwill aid in the developmentof pharmacological treatment strategies for drugaddiction. Financial support: DA017763, DA036973.

The Russian health care system is organized around specific diseases, with relatively little focus on integration across specialties to address co-morbidities. This organizational structure presents new challenges in the context of the recent epidemics of injection drug use (IDU) and HIV. This paper uses existing and new data to examine the prevalence of reported new cases of drug dependence (heroin) and HIV over time as well as associations between drug dependence and alcoholism, hepatitis B and C, and tuberculosis in the City of St. Petersburg and the Leningrad region. We found a sharp rise in reported cases of IDU beginning in 1991 and continuing until 2002/2003, followed by a sharp rise in newly reported cases of HIV. These rises were followed by a drop in new cases of HIV and drug addiction in 2002/2003 and a drop in the proportion of HIV-positve individuals with IDU as a risk factor. Infection with hepatitis B and C were common, especially among injection drug users (38 and 85%, respectively), but also in alcoholics (7 and 14%). Tuberculosis was more common in alcoholics (53%) than in persons with alcoholism and drug dependence (10%), or with drug dependence alone (4%). Though these data have many limitations, they clearly demonstrate that drug dependence and/or alcoholism, HIV, hepatitis, and tuberculosis frequently co-occur in St. Petersburg and the Leningrad Region. Prevention and treatment services across medical specialties should be integrated to address the wide range of issues that are associated with these co-morbidities.

The cardiovascular effects of the beta-adrenergic receptor antagonist propranolol (40 mg) were compared in 20 alcohol-dependent subjects during alcohol withdrawal syndrome (WS; n=10) on days 1, 2, 3, and 10 to those during remission (n=10; 50 +/- 7.7 days). Significant differences were observed in negative chronotropic and hypotensive effects during withdrawal compared to remission. The initial level of hemodynamics prior to propranolol administration was the most important factor modifying the drug responses. The amount of daily consumption of alcohol also predicted to some extent the effects of propranolol. The WS-related changes in peripheral and central beta-adrenergic system were most likely responsible for the differences in propranolol actions.