Elena Blokhina

Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats.

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-naïve 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.

Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

CONTEXT Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. OBJECTIVE To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment. DESIGN Six-month double-blind, double-dummy, randomized trial. SETTING Addiction treatment programs in St Petersburg, Russia. PARTICIPANTS Three hundred six opioid-addicted patients recently undergoing detoxification. INTERVENTIONS Biweekly counseling and 1 of the following 3 treatments for 24 weeks: (1) 1000-mg naltrexone implant and oral placebo (NI+OP group; 102 patients); (2) placebo implant and 50-mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or (3) placebo implant and oral placebo (PI+OP group; 102 patients). MAIN OUTCOME MEASURE Percentage of patients retained in treatment without relapse. RESULTS By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P < .001) and 11 of 102 patients in the PI+OP group (10.8%) (P < .001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P = .07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P < .001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P = .02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P = .12), and all resolved with antiallergy medication treatment. Other nonlocal-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found. CONCLUSIONS The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00678418.

Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice

Previous studies have indicated that blockade of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors prevents acquisition of instrumental behaviors reinforced by food and drugs such as morphine and cocaine. The present study aimed to extend this evidence by testing whether NMDA receptor channel blocker, memantine, would exert similar effects on acquisition of cocaine and nicotine self-administration in mice. Inasmuch as memantine also acts as nicotinic receptor channel blocker, this study assessed the effects of mecamylamine and MRZ 2/621 that are more selective nicotinic blockers. Adult male Swiss mice were allowed to self-administer cocaine (0.8-2.4 microg/infusion) or nicotine (0.08-0.32 microg/infusion) during the 30-min test. Pretreatment with memantine (0.1-10 mg/kg) prevented acquisition of nicotine but not cocaine self-administration. Pretreatment with mecamylamine (0.3-3 mg/kg) and MRZ 2/621 (0.3-10 mg/kg) produced dose-dependent suppression of both cocaine and nicotine self-administration. Taken together with the previous reports, these results indicate that nicotinic receptor blockers antagonize acute reinforcing effects of cocaine while NMDA receptor blockade may have limited effectiveness.

Long-acting depot formulations of naltrexone for heroin dependence: a review.

Purpose of review The major problem with the oral formulation of naltrexone for heroin dependence is poor compliance (adherence). Long-acting sustained release formulations of naltrexone (implantable and injectable) might help to improve compliance and, thus, increase the efficacy of abstinence-oriented treatment of heroin dependence with naltrexone. Recent findings There have been several implantable and injectable formulations of naltrexone developed within the last decade. It was demonstrated that some of them are effective and relatively well tolerated medications for relapse prevention in heroin addicts. However, advantages and disadvantages of these new medications have never been systematically analyzed. Summary Long-acting sustained release formulations of naltrexone are well tolerated and more effective for relapse prevention in heroin addicts than the oral ones.

Pretreatment with morphine potentiates naloxone-conditioned place aversion in mice: effects of NMDA receptor antagonists

Acute pretreatment with opioid receptor agonists potentiates behavioral effects of opioid antagonists. This phenomenon was suggested to serve as an acute model of opioid dependence. Since antagonists acting at N-methyl-D-aspartate (NMDA) receptors were repeatedly shown to attenuate development, maintenance, and expression of opioid dependence, the present study evaluated the effects of competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), and low-affinity channel blocker, 1-amino-3,5-dimethyl adamantane hydrochloride (memantine), on establishment of naloxone-conditioned place aversion in mice that were pre-exposed to morphine. Morphine (20 mg/kg) pretreatment significantly potentiated the ability of naloxone (0.01-0.3 mg/kg) to produce place aversion. The place aversion produced by naloxone (0.1 mg/kg) was attenuated by D-CPPene (1 and 3 mg/kg but not 0.1 or 0.3 mg/kg) when it was administered 3.5 h after morphine (0.5 h prior to conditioning trial with naloxone) but not 0.5 h prior to morphine. Memantine (1-10 mg/kg) had no effect under any treatment condition (0.5 h prior to morphine, simultaneously with morphine, 2 or 3.5 h after morphine). Thus, the ability of NMDA receptor antagonist to affect development and/or expression of morphine dependence may not be a good predictor of their effects on establishment of morphine-potentiated naloxone-conditioned place aversion.

Naltrexone with or without guanfacine for preventing relapse to opiate addiction in St.-Petersburg, Russia

BACKGROUND 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. METHODS 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). RESULTS 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% (p<0.05 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. CONCLUSIONS 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.

HERMITAGE—a randomized controlled trial to reduce sexually transmitted infections and HIV risk behaviors among HIV-infected Russian drinkers

AIMS This study assessed the effectiveness of HERMITAGE (HIVs 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. DESIGN We conducted a single-blinded, two-armed, randomized controlled trial with 12-month follow-up. SETTING The study was conducted in St Petersburg, Russia. Participants were recruited from four HIV and addiction clinical sites. The intervention was conducted at Botkin Infectious Disease Hospital. PARTICIPANTS HIV-infected individuals with past 6-month risky sex and heavy alcohol consumption (n = 700) were randomized to the HERMITAGE intervention (n = 350) or an attention control condition (n = 350). INTERVENTION A Healthy Relationships Intervention stressing disclosure of HIV serostatus and condom use, adapted for a Russian clinical setting with two individual sessions and three small group sessions. MEASUREMENTS The primary outcome was incident STI by laboratory test at 12-month follow-up. Secondary outcomes included change in unprotected sex and several alcohol and injection drug use (IDU) variables. FINDINGS Participants had the following baseline characteristics: 59.3% male, mean age 30.1, 60.4% past year IDU, 15.4% prevalent STI and mean CD4 cell count 413.3/μl. Assessment occurred among 75 and 71% of participants at 6 and 12 months, respectively. STIs occurred in 20 subjects (8.1%) in the intervention group and 28 subjects (12.0%) in the control group at 12-month follow-up; logistic regression analyses found no significant difference between groups (adjusted odds ratio 0.63; 95% confidence interval = 0.34-1.18; P = 0.15). Both groups decreased unsafe behaviors, although no significant differences were found between groups. CONCLUSIONS The HERMITAGE HIV risk reduction intervention does not appear to reduce sexually transmitted infections and HIV risk behaviors in Russian HIV-infected heavy drinkers compared with attention controls.

Punitive policing and associated substance use risks among HIV-positive people in Russia who inject drugs

Drug law enforcement is part of the HIV risk environment among people who inject drugs (PWID). Punitive policing practices such as extrajudicial arrests for needle possession and police planting of drugs have been described anecdotally in Russia, but these experiences and their associations with risky drug behaviours have not been quantified. This study aims to quantify the burden of extrajudicial police arrests among a cohort of HIV‐positive PWID in Russia and to explore its links to drug‐related health outcomes.

Pain is associated with heroin use over time in HIV-infected Russian drinkers

AIMS To evaluate whether pain was associated with increased risk of using heroin, stimulants or cannabis among HIV-infected drinkers in Russia. DESIGN Secondary analysis of longitudinal data from the HERMITAGE study (HIVs Evolution in Russia-Mitigating Infection Transmission and Alcoholism in a Growing Epidemic), a behavioral randomized controlled trial, with data collected at baseline, 6-month and 12-month visits. SETTING Recruitment occurred at HIV and addiction treatment sites in St Petersburg, Russian Federation. PARTICIPANTS Six hundred and ninety-nine HIV-infected adult drinkers. MEASUREMENTS The primary outcome was past month illicit drug use; secondary outcomes examined each drug (heroin, stimulants and cannabis) separately. The main predictor was pain that interfered at least moderately with daily living. General estimating equations (GEE) logistic regression models were used to evaluate the association between pain and subsequent illicit drug use, adjusting for potential confounders. FINDINGS Participants reporting pain appeared to have higher odds of using illicit drugs, although the results did not reach statistical significance [adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 0.99, 1.76, P = 0.06]. There was a significant association between pain and heroin use (OR = 1.54; 95% CI = 1.11-2.15, P = 0.01) but not use of other drugs (OR = 0.75; 95% CI =0.40-1.40, P = 0.35 for stimulants and OR = 0.70; 95% CI = 0.45-1.07, P = 0.09 for cannabis). CONCLUSIONS HIV-infected Russian drinkers who report pain are more likely to use heroin over time than HIV-infected Russian drinkers who do not report pain. Pain may be an unrecognized risk factor for persistent heroin use with implications for HIV transmission in Russia.

Associations between partner violence perpetration and history of STI among HIV-infected substance using men in Russia.

Abstract Studies document a significant association between victimization from intimate partner violence (IPV) and sexually transmitted infections (STIs) and HIV among substance using women in Russia and elsewhere, but no study has examined IPV perpetration and STI among Russian men or HIV-infected men in Eastern Europe. This study was designed to assess the association between lifetime history of IPV perpetration and STI (lifetime and current) among substance using HIV-infected men in Russia. Cross-sectional analyses were conducted with baseline data from 415 male participants enrolled in a randomized HIV intervention clinical trial [the HERMITAGE Study]. Participants were HIV-infected men reporting recent heavy alcohol use and unprotected sex in St. Petersburg, Russia. Baseline surveys assessed demographics, IPV perpetration, risk behaviors, and STI history. Current STI was assessed via blood testing for syphilis and urine testing for gonorrhea, Chlamydia and Trichomonas. Multiple logistic regression analyses were used to assess the association between history of IPV with lifetime and current STI. Participants were aged 20–57 years. Almost half of participants (46%) reported a history of IPV perpetration; 81% reported past 30-day binge alcohol use, and 43% reported past 30-day injection drug use. Past and current STI was 41% and 12%, respectively. Men reporting a history of IPV perpetration had significantly higher odds of reporting ever having an STI (AOR=1.6, 95% CI=1.1, 2.4) but lower odds of testing positive for a current STI (AOR=0.50, 95% CI=0.26, 0.96). These findings demonstrate that a history of male IPV perpetration is common in HIV-infected Russian men and associated with a history of STI. Programmatic work toward IPV prevention is needed in Russia and may be beneficial in mitigating STIs, but more research is needed to understand how and why the association between IPV and STI changes over time in this population.