Research Findings - International Research

U.S. - Netherlands Researchers Demonstrate that Manualized Behavior Therapy for Children May Prevent Adolescent Substance Use

A binational research team has published their findings that a cognitive-behavioral intervention, the Coping Power Program (CPP), may prevent children diagnosed with Disruptive Behavior Disorder (DBD) in middle childhood from progressing to substance abuse in early adolescence. In studies supported by a NIDA International Program - Netherlands administrative supplement to Dr. John E. Lochman, University of Alabama, and Dr. Walter Matthys, Rudolf Magnus Institute of Neuroscience, Utrecht, the CPP was adapted for use with Dutch children diagnosed with DBD and seen in outpatient psychiatry clinics and mental health centers. The Utrecht Coping Power Program (UCPP) randomly assigned children to either the UCPP or the care as usual (CU) conditions, and compared them to a matched healthy control sample. The researchers report that in a five-year follow-up, children in the UCPP group not only smoked fewer cigarettes and were less likely to have ever used marijuana than children in the CU group, the UCPP group's substance use rates also fit within the range of those reported for the control group. The authors conclude that manualized behavior therapy with DBD-diagnosed children may be a preventive tool for substance use later in adolescence. Journal of the American Academy of Child and Adolescent Psychiatry, 46(1), pp. 33-39, 2007.

DISCA-Supported Research Finds Depression Predicts Failure to Quit Smoking

2004 NIDA Distinguished International Scientist Ivan Berlin, Groupe Hospitalier Universitaire Pitie-Salpetriere, France, and his DISCA partner Dr. Lirio S. Covey, New York State Psychiatric Institute, report that a Beck Depression Inventory score > or = 10, even in smokers who do not meet a current diagnosis of major depression, directly predicts inability to quit smoking. The pair assessed 600 smokers without currently diagnosed depression who participated in a smoking cessation study at 8 centers. The researchers examined whether mood, personality, and coping predict smoking cessation and whether the associations of personality and coping are mediated through depressed mood. The researchers concluded that neither personality traits nor coping skills predicted directly smoking cessation. However, they found that low levels of problem focusing and social support seeking predicted a negative outcome via depressed mood, suggesting that clinicians assess depression symptoms in routine smoking cessation care. Addiction,101(12), pp. 1814-1821, 2006.

Research Publications by International Program Alumni

Alumni of the NIDA International Program research training and exchange programs authored or coauthored the following articles indexed by PubMed:

Former NIDA INVEST Drug Abuse Research Fellows

Habituation Deficits Induced by mGlu2/3 Receptor Blockade in Mice: Reversal by Antipsychotic Drugs
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
Cortical metabotropic glutamate receptors (mGluRs) appear to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist, LY-341495, thirty min prior to being placed into novel arenas for automatic motor activity recording (two-hour sessions). Administration of LY-341495 (1-10 mg/kg, s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min prior to the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist, SB-277011A (3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment (e.g., 5-HT2A, 5-HT3 and 5-HT6 antagonists, 5-HT1A agonist, D4 antagonist, CB1 antagonist, AMPAkines, glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs. Bespalov, A.Y., Jongen-Relom A.L., van Gaalen, M., Harich, S., Schoemaker, H., and Gross, G. J Pharmacol Exp Ther. November 29, 2006. [Epub ahead of print].

Naltrexone With or Without Fluoxetine for Preventing Relapse to Heroin Addiction in St. Petersburg, Russia
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
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. Krupitsky, E.M., Zvartau, E.E., Masalov, D.V., Tsoy, M.V., Burakov, A.M., Egorova, V.Y., Didenko, T.Y., Romanova, T.N., Ivanova, E.B., Bespalov, A.Y., Verbitskaya, E.V., Neznanov, N.G., Grinenko, A.Y., O'Brien, C.P. and Woody, G.E. J Subst Abuse Treat. 31(4), pp. 319-328, 2006. Epub July 24, 2006.

Peri-response Pharmacokinetics of Remifentanil During a Self-administration Session Indicates that Neither Blood nor Brain Levels are Titrated
INVEST Fellow: Gerald Zernig, Austria, 1993-1994
An individual's drug abuse pattern is determined by a multitude of factors. Among these, simple pharmacological determinants of within-binge drug consumption are sorely under investigated. The authors therefore determined if within-session operant responsing to the ultra-short-acting mu opioid agonist remifentanil (RMF) was determined by blood or brain RMF levels or changes thereof. A peri-response analysis did not detect any "threshold" RMF level, either in blood or in the nucleus accumbens (NAc) core as a deep brain region that might determine a rat's "decision" to re-emit a response during a multiple-injection drug self-administration session. The peri-response analysis also failed to find any peak RMF level, either in blood or in the NAc core, which could serve as a "ceiling" level. Thus, these findings strongly suggest that titration of blood or brain RMF levels does not determine a rat's intra-session operant response. Crespo, J.A., Panlilio, L.V., Schindler, C.W., Sturm, K., Saria, A., Zernig, G. Ann N Y Acad Sci. 1074, pp. 497-504, 2006.

4-Amino-5-aryl-6-arylethynylpyrimidines: Structure-activity Relationships of Non-Nucleoside Adenosine Kinase Inhibitors
INVEST Fellow: Steve McGaraughty, Canada, 1995-1996
A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed. Matulenko, M.A., Paight, E.S., Frey, R.R., Gomtsyan, A., Didomenico, S. Jr., Jiang, M., Lee, C.H., Stewart, A.O., Yu, H., Kohlhaas, K.L., Alexander, K.M., McGaraughty, S., Mikusa, J., Marsh, K.C., Muchmore, S.W., Jakob, C.L., Kowaluk, E.A., Jarvis, M.F. and Bhagwat, S.S. Bioorg Med Chem. December 20, 2006 [Epub ahead of print].

Culturally Specific Adaptation of a Prevention Intervention: An International Collaborative Research Project
INVEST Fellow: Tatiana Tsarouk, Russia, 2001-2002
This study adapted a U.S. drug use prevention program for use with Russian at-risk adolescents, and explored directions for further development of programs addressing prevention of substance abuse and other health risk behaviors including risk of HIV infection. The adaptation process was conducted in phases, initially carried out in Seattle with 23 bilingual (English-Russian) youth and then further adapted in two Moscow schools with 44 "typical" youth. In the final phase, program adaptation for the Russian at-risk adolescents was achieved by conducting a pilot test of the adapted program lessons with Moscow at-risk adolescents (n=10), who met criteria of poor school performance and/or truancy. Observations and experience were used throughout to adapt and refine the program for at-risk youth. Modifications were made to represent more accurately colloquial Russian and to capture teen experiences common to Russian culture. Both U.S. and Russian youth characterized the lessons as engaging and valuable. They also expressed a need to learn about sexuality, drug use, and health; peer and romantic relationships; and problem-solving strategies. Tsarouk, T., Thompson, E.A., Herting, J.R., Walsh, E. and Randell, B. Addict Behav. December 29, 2006 [Epub ahead of print].

Different Effects of Opioid Antagonists on _, D, and _ Opioid Receptors With and Without Agonist Pretreatment
INVEST Fellow: Danxin Wang, China, 1996-1997
Opioid receptors display basal signaling (constitutive, agonist-independent activity), which appears to be regulated by agonist exposure. Whereas agonist pretreatment desensitizes receptors to subsequent agonist stimulation, basal signaling of micro opioid receptor (MOR) was shown to increase. Moreover, agonist pretreatment converts the neutral antagonists naloxone and naltrexone into inverse agonists, suppressing basal signaling, while analogues with reduced C-6 position, e.g., 6beta-naltrexol, remain neutral antagonists at MOR under any condition. This study compares the regulation of basal signaling of MOR, delta (DOR), and kappa (KOR) opioid receptors after pretreatment with morphine or receptor-selective agonists, in transfected HEK293 cell membranes. Moreover, naloxone, naltrexone and related antagonists were compared for binding potency and effect on basal and agonist-stimulated receptor signaling, measuring (35)S-GTPgammaS binding. The results demonstrate basal activity for each opioid receptor, which is modulated by pretreatment with agonists. Even closely related opioid antagonists display distinct patterns of neutral and inverse effects before and after agonist pretreatment, including distinct efficacies between naloxone and naltrexone at agonist-pretreated DOR and KOR. Pretreatment with different agonists has varying effects on inverse and neutral activities of some analogues tested. These results demonstrate that antagonist efficacy is context-dependent, possibly accounting for paradoxical pharmacological effects. Activity profiles at the three opioid receptors under different conditions could lead to antagonists with optimal clinical properties in treatment of addiction and adverse opioid effects. Wang, D., Sun, X. and Sadee, W. J Pharmacol Exp Ther. January 31, 2007 [Epub ahead of print].

CCK(B) Receptor Antagonist L365,260 Potentiates the Efficacy to and Reverses Chronic Tolerance to Electroacupuncture-induced Analgesia in Mice
INVEST FELLOW: You Wan, China, 1998-1999
Cholecystokinin octapeptide (CCK-8) is a physiological antagonist of endogenous opioids in the central nervous system (CNS). The authors' previous work has shown that CCK-8 plays an important role in the development of tolerance to morphine analgesia and electroacupuncture (EA) analgesia in the rat. The present studies were designed to examine whether the CCK(B) receptor is involved in the modulation of EA analgesia and the development of EA tolerance in mice. The latency to flick the tail in the radiant heat was used as index to assess the efficacy of EA analgesia. Subcutaneous (s.c.) injection of the CCK(B) receptor antagonist L365,260 produced a dose-dependent (0.125-2.0mg/kg) potentiation of the analgesia induced by 100Hz EA, with a maximal effect occurred at 0.5mg/kg. In addition, L365,260 (0.5mg/kg) significantly reversed chronic tolerance to 100Hz EA in mice. These results suggest that the CCK(B) receptor might play a role in the tonic inhibition of 100Hz EA-induced analgesia and in the mediation of chronic tolerance to 100Hz EA in mice. The results opened a way for further investigation of the function of CCK-8 in pain modulation using inbred strains of mice. Huang, C., Hu, Z.P., Jiang, S.Z., Li, H.T., Han, J.S. andWan, Y. Brain Res Bull. 71(5), pp. 447-451, 2007. Epub December 11, 2006.

Effect of Memantine on Cue-induced Alcohol Craving in Recovering Alcohol-dependent Patients
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
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. Results indicatec that 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. Krupitsky, E.M., Neznanova. O., Masalov, D., Burakov, A.M., Didenko, T., Romanova, T., Tsoy, M., Bespalov, A., Slavina, T.Y., Grinenko, A.A., Petrakis, I.L., Pittman, B., Gueorguieva, R., Zvartau, E.E. and Krystal, J.H. Am J Psychiatry. 164(3), pp. 519-523, 2007.

Stimulation of the Metabotropic Glutamate 2/3 Receptor Attenuates Social Novelty Discrimination Deficits Induced by Neonatal Phencyclidine Treatment
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
RATIONALE: Glutamatergic mechanisms are implicated in psychiatric disorders such as schizophrenia. Modulation of glutamatergic neurotransmission via stimulation of the metabotropic glutamate 2/3 receptors (mGluR2/3) has been shown to reverse a number of behavioral effects of NMDA receptor antagonists thus indicating potential antipsychotic activity of mGluR2/3 agonists. The present study aimed to evaluate the effects of LY-354740 (mGluR2/3 agonist) and LY-487379 (mGluR2 potentiator) on social novelty discrimination in male Wistar rats that were treated with PCP (10 mg/kg, s.c.) on postnatal days 7, 9, and 11. During each test session (twice a week, postnatal days 70-100), an adult experimental rat was presented with a juvenile, untreated rat (4 weeks old) for a period of 30 min. At the end of this period, a second (novel) juvenile rat was introduced for 5 min. Adult rats spent more time exploring the novel than the familiar juvenile. This capacity for social novelty discrimination was impaired in rats that received neonatal PCP treatment and the impaired discrimination could be reversed by acute treatment with antipsychotic drugs such as clozapine (0.3-3 mg/kg) and the glycine transporter GlyT1 inhibitor SSR-504734 (1-10 mg/kg). Acute pretreatment with LY-354740 (1-10 mg/kg) or LY-487379 (3-30 mg/kg) facilitated social discrimination in rats with PCP administration history without having appreciable effects in controls and without affecting total time spent in social interaction. These results suggest that targeting glutamatergic functions may reverse long-term developmental cognitive deficits produced by PCP. Harich, S., Gross, G. and Bespalov, A. Psychopharmacology (Berl). February 23, 2007 [Epub ahead of print].

Validity of Self-reported Drinking Before Injury Compared with a Physiological Measure: Cross-national Analysis of Emergency-department Data from 16 Countries
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Self-reports of alcohol consumption among patients visiting an emergency department (ED) have been used extensively in the investigation of the relationship between drinking and injury. Little is known, however, about the associations between validity of self-reports with patient and injury characteristics and whether these relationships vary across regions or countries. Both of these issues are explored in this article. In the construct of a multilevel logistical model, validity of self-reports was estimated as the probability of a positive self-report given a positive blood alcohol concentration (BAC). The setting included 44 EDs across 28 studies in 16 countries. Participants included 10,741 injury patients from the combined Emergency Room Collaborative Alcohol Analysis Project (ERCAAP) and the World Health Organization Collaborative Study of Alcohol and Injuries. Data were analyzed on self-reported drinking within 6 hours before injury compared with BAC results obtained from breath-analyzer readings in all but two studies, which used urine screens. Covariates included demographic, drinking, and injury characteristics and aggregate-level contextual variables. At the individual level, a higher BAC measurement was associated with a higher probability of reporting drinking, as was heavy drinking and sustaining injuries in traffic accidents or violence-related events. At the study level, neither aggregate BAC nor other sociocultural variables affected the validity of self-reported drinking. This study provides further evidence of the validity of self-reported drinking measures in crossnational ED studies based on the objective criterion of BAC estimates. Cherpitel, C.J., Ye, Y., Bond, J., Borges, G., Macdonald, S., Stockwell, T., Room, R., Sovinova, H., Marais, S. and Giesbrecht, N. J Stud Alcohol Drugs. 68(2), pp. 296-302, 2007.

Cannabinoid Receptor Antagonists Counteract Sensorimotor Gating Deficits in the Phencyclidine Model of Psychosis
Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. The authors also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. These findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia. Ballmaier, M., Bortolato, M., Rizzetti, C., Zoli, M., Gessa, G., Heinz, A. and Spano, P. Neuropsychopharmacology. February 14, 2007 [Epub ahead of print].

Analysis of Yearly Variations in Drug Expenditure for One Patient Using Data Warehouse in a Hospital
INVEST Fellow: Yufeng Chen, China, 2003-2004
Medical expense has grown rapidly in Japan. It could be caused by the increase of the patient number and the increase of medical expense per patient. The authors studied the latter factor on drug expenditure from 1996 to 2002 using the prescription data stored in the data warehouse of one hospital. They found that the drug expenditure per patient had increased 1.32 times. The mean number of prescriptions per patient increased 1.23 times and the mean expenditure of one medicine increased 1.08 times. These results demonstrated that drug expenditure for one patient had gradually increased. This was caused by both the rise in the number of medicines taken by one patient and the rise in the prices of medicines. The data warehouse in the hospital was useful for the analysis of the trends in medical expenditure for one patient. Chen, Y., Matsumura, Y., Nakagawa, K., Ji, S., Nakano, H., Teratani, T., Zhang, Q., Mineno, T. and Takeda, H. J Med Syst. 31(1), pp. 17-24, 2007.

Roles of 5-HT Receptor Subtypes in the Inhibitory Effects of 5-HT on C-Fiber Responses of Spinal Wide Dynamic Range Neurons in Rats
INVEST Fellow: You Wan, China, 1998-1999
5-Hydroxytryptamine (5-HT, or serotonin) plays an important role in the descending control of nociception. 5-HT and its receptors have been extensively studied in the modulation of nociceptive transmission at the spinal level using behavioral tests that may be affected by the effects of 5-HT on motor performance and skin temperature. Using electrophysiological methods, the present study aimed to systematically investigate the roles of 5-HT receptor subtypes on the inhibitory effects of 5-HT on responses of the spinal wide dynamic range (WDR) neurons to C-fiber inputs in rats. Under basal conditions, topical application of 5-HT to the spinal cord inhibited the C-fiber responses of WDR neurons dose-dependently, whereas antagonists of 5-HT1A (WAY 100635), 5-HT1B (GR 55562), 5-HT2A (ketanserin), 5-HT2C (RS 102221), 5-HT3 (MDL 72222) and 5-HT4 (GR 113808) had no effect on their own. The inhibitory effects of 5-HT were reversed by antagonists of 5-HT1B (GR 55562), 5-HT2A (ketanserin), 5-HT2C (RS 102221), 5-HT3 (MDL 72222) and 5-HT4 (GR 113808), but not by 5-HT1A (WAY 100635), receptor antagonists. Topical administration of agonists of 5-HT1A (8-OH-DPAT), 5-HT1B (CGS 12066), 5-HT2A (alpha-m-5-HT), 5-HT2C (MK 212), 5-HT3 (mCPBG) and 5-HT4 (BZTZ) also inhibited the C-responses. These results suggest that under basal conditions there is no tonic serotonergic inhibition on the C-responses of dorsal horn neurons and multiple 5-HT receptor subtypes including 1B, 2A, 2C, 3 and 4 may be involved in mediating the inhibitory effects of 5-HT. Liu, F.Y., Xing, G.G., Qu, X.X., Xu, I.S., Han, J.S. and Wan, Y. J Pharmacol Exp Ther. February 28, 2007 [Epub ahead of print].

Cocaine-Induced Brain Activation Detected by Dynamic Manganese-enhanced Magnetic Resonance Imaging (MEMRI)
INVEST Fellow: Zhengxiong Xi, China, 1995-1996
Dynamic manganese-enhanced magnetic resonance imaging (MEMRI) detects neuronal activity based on the passage of Mn(2+) into active neurons. Because this mechanism is independent of any hemodynamic response, it is potentially ideal for pharmacological studies and was applied to investigate the acute CNS effects of cocaine in the rat. Dose-dependent, region-specific MEMRI signals were seen mostly in cortical and subcortical mesocorticolimbic structures. To verify the spatial accuracy and physiological mechanisms of MEMRI, neuronal activation following electrical forepaw stimulation revealed somatotopic signal enhancement in the primary and secondary somatosensory cortices, which was blocked by diltiazem, a Ca2+ channel antagonist. These data suggest that MEMRI may serve as a tool for investigating the effects of pharmacological agents and opens an application of MRI to study CNS drug effects at a systems level. Lu, H., Xi, Z.X., Gitajn, L., Rea, W., Yang, Y. and Stein, E.A. Proc Natl Acad Sci U S A. 104(7), pp. 2489-2494, 2007. Epub February 7, 2007.

Former Hubert H. Humphrey Drug Abuse Research Fellows

Predictors of HIV Sero-status Among Drug Injectors at Three Ukraine Sites
HHH Fellow: Sergey Dvoryak, Ukraine, 1999-2000
The objective of this study was to assess the HIV serostatus of injection drug users (IDU) in Ukraine, as well as associations between serostatus and selected demographic and risk factors. IDU were recruited from the streets in Kiev, Odessa and Makeevka/Donesk. Participants were interviewed using an HIV risk behavior assessment and tested for HIV with a finger-stick rapid test. Multiple logistic regression was used to identify determinants of HIV infection. Of the 891 IDUs surveyed, one-third came from each site and 22% were female. Their mean age was 29 years and on average they had been injecting for slightly more than 10 years. Seven hundred and seventy-eight of the total sample did not know their HIV status when first interviewed; they are the participants in this investigation. Overall, 33% tested positive for HIV, including 34% in Kiev, 51% in Odessa and 17% in Makeevka/Donesk. Independent predictors of HIV included injecting a sedative/opiate mixture, female sex, having sex with a person who was HIV positive or whose HIV status was unknown and injecting daily. HIV-negative IDU were significantly younger than those infected, they were more likely to be from Makeevka/Donesk and they were more likely to have been sexually active. Rates of HIV infection among IDU vary considerably across Ukraine, although even in the site with the lowest rate nearly one in five was infected. The extent of drug and sex-related risk behaviors calls for interventions to reduce the spread of HIV and other infectious diseases. Booth, R.E., Kwiatkowski, C.F., Brewster, J.T., Sinitsyna, L. and Dvoryak, S. AIDS. 20(17), pp. 2217-2223, 2006.

Obstetric and Neonatal Outcomes in Women Who Live in an Urban Resettlement Area of Delhi, India: A Cohort Study
HHH Fellow: Arun Kumar Sharma, India, 2004-2005
The aim of the present research was to study the pregnancy outcome, namely mode and place of delivery, attendant at birth and perinatal mortality in an urban resettlement area of Delhi, India, and to determine factors that affect the outcome. Methods: All the pregnant women (n = 909) in the area were enrolled and followed until 7 days after delivery. The authors calculated the crude and adjusted odds ratios for predictors of pregnancy related obstetric and neonatal outcomes, using logistic regression analysis. A total of 884 (97.3%) women could be followed up. Approximately two-thirds of deliveries took place at home. Primigravida, more educated mothers and mothers with non-cephalic presentation or complications were more likely to deliver in a health facility (P < 0.05). Most deliveries (97%) were vaginal, 2.5% were cesarean and 0.5% forceps deliveries. Primigravida mothers, mothers with short stature, mothers with non-cephalic presentation or complications had cesarean and forceps delivery more often (P < 0.05). A perinatal mortality rate of 74.5 per 1000 live births was observed. Presentation of the fetus and complications in the mother remained important factors. The authors conclude that the majority of deliveries in the under-privileged sections in urban Delhi take place at home and the perinatal mortality remains high. Chhabra, P., Sharma, A.K. and Tupil, K.A. J Obstet Gynaecol Res. 32(6), pp. 567-573, 2006.

Alcohol Abuse-Duration Dependent Decrease in Plasma Testosterone and Antioxidants in Males
HHH Fellow: Amit Chakrabarti, India, 2002-2003
Ethanol is a testicular toxin and it causes fertility abnormalities with low sperm count and impaired sperm motility in men. The present study was designed to investigate plasma testosterone level and hypothalamic pituitary gonadal (HPG) axis function in alcoholic men and also effect of ethanol on systemic oxidative stress. Forty six male alcohol abusers in the age group 20-40 years were selected. Fifty five males in the same age group served as control. Alcohol abusers had significantly low plasma testosterone with low luteinizing hormone and follicle stimulating hormone. In addition they had significantly high thiobarbituric acid reactive substances (TBARS), superoxide dismutase and glutathione S-transferase, and low glutathione, ascorbic acid, catalase, glutathione reductase and glutathione peroxidase. Moreover, serum testosterone level in alcoholics negatively correlated with duration of alcohol abuse, and TBARS. Duration dependent decreased serum testosterone level in alcohol abusers might be due to 1) increased oxidative stress which can damage Leydig and supporting Sertoli cells and 2) impaired HPG axis. Maneesh, M., Dutta, S., Chakrabarti, A. and Vasudevan, D.M. Indian J Physiol Pharmacol. 50(3), pp. 291-296, 2006.

Exposure to HIV in Brazilian Adolescents: The Impact of Psychiatric Symptomatology
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
The objective of this study was to examine associations between psychiatric symptomatology and HIV-positive status in adolescents who sought HIV testing at a public health center in Brazil. In a cross-sectional study, 388 adolescents assessed for their HIV status were also evaluated for psychiatric symptomatology using the Symptom Checklist-90-R (SCL-90-R). The impact of potential confounding variables such as risk behaviors was ascertained using the Brazilian version of the Risk Assessment Battery (RAB). Overall seropositivity rate was 6.2%. Seropositives had significantly higher scores in all dimensions of psychiatric symptomatology in the SCL-90-R (P < 0.05 and effect sizes > 0.5 in all dimensions). In multiple analyses, with the inclusion of 3 composite variables (sex-risk, drug-risk, and psychiatric symptomatology), only psychiatric symptoms were associated with positive HIV status (OR = 1.88, CI95% = 1.06-3.34; P = 0.032). The authors findings suggest that amongst young people asking for HIV testing in Brazil, seropositivity is associated with psychological symptoms and that screening for the latter would therefore be appropriate in this context. Bassols, A.M., Santos, R.A., Rohde, L.A. and Pechansky, F. Eur Child Adolesc Psychiatry. January 2, 2007 [Epub ahead of print].

Changing Patterns of Cocaine Use and HIV Risks in the South of Brazil
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
For well over a decade, researchers in Porto Alegre, Brazil, have been documenting the extent of the AIDS epidemic in the region, with a specific focus on the linkages between drug use and HIV seropositivity. Virtually all of the studies conducted during those years found injection drug use (IDU) to be the major vector for HIV seropositivity in this population. However, recent research found that the number of IDUs had declined significantly. Qualitative interviews and focus groups suggested many reasons for this decline: (1) many had died, because they had never heard of AIDS or HIV, and were unaware of how HIV is transmitted. As a result, they had become infected through the sharing of injection paraphernalia. (2) The quality of street cocaine had declined, making injection difficult. (3) Because of a fear of AIDS, some shifted to the smoking of crack, which had become a newly availability commodity in the street culture. Within this context, this article describes the qualitative data describing the decline of cocaine injecting and the corresponding emergence of crack use in Porto Alegre, Brazil, and related HIV risks. Inciardi, J.A., Surratt, H.L., Pechansky, F., Kessler, F., von Diemen, L., da Silva, E.M. and Martin, S.S. J Psychoactive Drugs. 38(3), pp. 305-310, 2006.

Influence of Clozapine on Platelet Serotonin, Monoamine Oxidase and Plasma Serotonin Levels
HHH Fellow: Berna Ulug, Turkey, 1995-1996
The purpose of this study was to investigate the influence of clozapine on plasma serotonin, platelet serotonin and monoamine oxidase (MAO) levels in schizophrenic patients and to compare their results with those of unmedicated healthy controls. Groups of 20 outpatients with schizophrenia and 20 healthy controls matched for age, sex and smoking status were recruited for the study. Psychopathology, neurocognitive functioning, plasma serotonin, platelet serotonin and MAO levels were assessed after 1-week drug free interval, and 8 weeks after initiation of clozapine treatment in an open design. The mean clozapine dose at week 8 was 382.5+/-96.4 (range: 250-600) mg/day. In the patient group, at baseline, plasma serotonin and platelet MAO levels were significantly lower, and platelet serotonin levels were significantly higher than in controls. After 8 weeks of clozapine treatment, plasma serotonin and platelet MAO levels increased significantly, while a significant decrease in platelet serotonin levels was detected compared with baseline values. Baseline platelet MAO levels explained 22% of the variance in Clinical Global Impression-Improvement (CGI-I) and improvement in attention, while baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms during clozapine treatment. These data indicate that clozapine may be reversing or compensating for a pre-existing alteration in serotonergic neurotransmission in schizophrenic patients. The prediction of response to clozapine through peripheral biochemical markers may have important clinical implications if repeated in larger samples. Ertugrul, A., Ucar, G., Basar, K., Demir, B., Yabanoglu, S. and Ulug, B. Psychiatry Res. December 6, 2006 [Epub ahead of print].

Conformation-Dependent Stability of Junctophilin 1 (JP1) and Ryanodine Receptor Type 1 (RyR1) Channel Complex is Mediated by their Hyper-reactive Thiols
HHH FELLOW: Jozsef Lango, Hungary, 1997-1998
Junctophilin 1 (JP1), a 72 kDa protein localized at skeletal muscle triad, is essential for stabilizing the close apposition of T-tubule (TT) and sarcoplasmic reticulum (SR) membranes to form junctions. In the present study the authors report that rapid and selective labeling of hyper-reactive thiols found in both JP1 and ryanodine receptor type 1 (RyR1) with CPM, a fluorescent thiol reactive probe, proceeded 12-fold faster under conditions that minimize RyR1 gating (e.g., 10mM Mg(2+)) compared with conditions that promote high channel activity (e.g., 100microM Ca(2+)/10mM caffeine/5mM ATP). The reactivity of these thiol groups was very sensitive to oxidation by naphthoquinone, H(2)O{sub}2, NO, or O(2), all known modulators of the RyR1 channel complex. Using preparative SDS-PAGE, in-gel tryptic digestion, HPLC, and mass spectrometric based peptide sequencing, the authors identified CPM-thioether adducts on 3 cysteine residues of JP1 (101, 402 and 628); the remaining 5 cysteines of JP1 were unlabeled. Co-immunoprecipitation experiments demonstrated a physical interaction between JP1 and RyR1 that, like thiol reactivity, was sensitive to RyR1 conformation and chemical status of the hyper-reactive cysteines of JP1 and RyR1. These findings support a model in which JP1 interacts with the RyR1 channel complex in a conformationally sensitive manner and may contribute integral redox sensing properties through reactive sulfhydryls chemistry. Phimister, A.J., Lango, J., Lee, E.H., Ernst-Russell, M., Takeshima, H., Ma, J., Allen, P.D. and Pessah, I.N. J Biol Chem. January 19, 2007 [Epub ahead of print].