Research Findings - International Research

Publications by Former NIDA INVEST Drug Abuse Research Fellows

Former NIDA INVEST Drug Abuse Research Fellows

AMPA Receptor Antagonists Reverse Effects of Extended Habit Training on Signaled Food Approach Responding in Rats
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
Dopamine D1 receptor stimulation is critically involved in early appetitive phases of learning in various behavioral paradigms. However, extended habit training was previously shown to reduce the ability of dopamine D1 receptor antagonists such as R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) to disrupt behavioral performance. The present study aimed to evaluate whether coadministration of glutamate alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor antagonists restores sensitivity to acute blockade of D1 receptors. Adult male Wistar rats were presented with 45-mg food pellets delivered to the food tray, which was immediately preceded by a 400-ms tone (2.8 kHz, 78 dB). During each training and test session, there were 28 food-tone presentations with an average intertrial interval of 70 s, and each head entry into the food tray was recorded. Drug tests were conducted on either day 3 or 9 of the training using independent groups of animals. The main dependent variable was the number of trials during which no head-entry response was made during the 10-s period immediately after the food delivery. Longer training duration enhanced the resistance of the signaled food approach behavior to extinction and to disrupting effects of supplementary food ration. Similarly, acute administration of SCH-23390 (0.04-0.16 mg/kg) dose-dependently reduced the number of omitted trials when given before the test session on day 3 but much less so when injected on day 9. AMPA receptor antagonists, NBQX (10 mg/kg) or GYKI-52466 (3-10 mg/kg), had no effects on their own but significantly enhanced the disrupting effects of SCH-23390 (0.08 and 0.16 mg/kg) when given on day 9 but not on day 3 of the training. These results indicate that AMPA receptor blockade restores sensitivity to appetitive behavior-disrupting effects of SCH-23390 in subjects exposed to extended training protocol. Bespalov, A.Y., Harich, S., Jongen-Relo, A.L., van Gaalen, M.M., and Gross, G. Psychopharmacology (Berl). July 19, 2007 (e-pub ahead of print).

Delay of First Treatment of Mental and Substance Use Disorders in Mexico
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Authors studied failure and delay in making initial treatment contact after the first onset of a mental or substance use disorder in Mexico as a first step to understanding barriers to providing effective treatment in Mexico. Data were from the Mexican National Comorbidity Survey (2001-2002), a representative, face-to-face household survey of urban residents aged 18 to 65 years. The age of onset for disorders was compared with the age of first professional treatment contact for each lifetime disorder (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Many people with lifetime disorders eventually made treatment contact, although the proportions varied for mood (69.9%), anxiety (53.2%), and substance use (22.1%) disorders. Delays were long: 10 years for substance use disorders, 14 years for mood disorders, and 30 years for anxiety disorders. Failure and delay in making initial treatment contact were associated with earlier ages of disorder onset and being in older cohorts. The authors conclude that failure to make prompt initial treatment contact is an important reason explaining why there are unmet needs for mental health care in Mexico. Meeting these needs will likely require expansion and optimal allocation of resources as well as other interventions. Borges, G., Wang, P.S., Medina-Mora, M.E., Lara, C., and Chiu, W.T. Am. J. Public Health. July 31, 2007 (e-pub ahead of print).

Prevalence and Socio-demographic Correlates of Drug Use Among Adolescents: Results from the Mexican Adolescent Mental Health Survey
The aims of the study were to estimate the life-time and 12-month prevalence of illicit drug use among Mexican adolescents, the age of onset of first drug use and the socio-demographic correlates. A multi-stage probability survey of adolescents aged 12-17 years residing in the Mexico City Metropolitan Area was carried out in 2005. Adolescents were administered the computer-assisted adolescent version of the World Mental Health Composite International Diagnostic Interview by trained lay interviewers in their homes. The response rate was 71% (n = 3005). Descriptive and logistic regression analyses were performed considering the multi-stage and weighted sample design of the survey. Of the adolescents, 5.2% have ever tried illicit drugs, 2.9% in the last 12 months. The most frequently used drugs are marijuana, followed by tranquilizers/ stimulants. The median age of first use is 14 years. Correlates of life-time drug use are older age, having dropped out of school, parental drug problems, low religiosity and low parental monitoring. The authors conclude that while drug use among Mexican adolescents is lower than among adolescents from other developed countries, its increasing prevalence with age and the narrowing male/female ratio calls for firm public health actions, particularly prevention strategies. Benjet, C., Borges, G., Medina-Mora, M.E., Fleiz, C., Blanco, J., Zambrano, J., Rojas, E., Ramirez, M. Addiction. 102(8), pp. 1261-1268, 2007.

Subcutaneous, Intrathecal and Periaqueductal Grey Administration of Asimadoline and ICI-204448 Reduces Tactile Allodynia in the Rat
INVEST Fellow: Silvia Cruz, Mexico, 1996-1997
The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. These results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, these data suggest that these drugs could be useful to treat neuropathic pain in human beings. Caram-Salas, N.L., Reyes-Garcia, G., Bartoszyk, G.D., Araiza-Saldana, C.I., Ambriz-Tututi, M., Rocha-Gonzalez, H.I., Arreola-Espino, R., Cruz, S.L., and Granados-Soto, V. Eur. J. Pharmacol. June 29, 2007 (Epub ahead of print).

Pharmacological Actions of NGB 2904, a Selective Dopamine D(3) Receptor Antagonist, in Animal Models of Drug Addiction
INVEST Fellow: Zhengxiong Xi, China, 1995-1996
As a continuation of the authors' work with SB-277011A, they have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Their results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction. Xi, Z.X., and Gardner, E.L. CNS Drug Rev. 13(2), pp. 240-259, 2007.

Effects of mGlu1 Receptor Blockade on Working Memory, Time Estimation, and Impulsivity in Rats
INVEST Fellow: Anton Bespalov, Russia, 1994-1995
Metabotropic glutamate 1 (mGlu1) receptor antagonists were reported to induce cognitive deficits in several animal models using aversive learning procedures. The present study aimed to further characterize behavioral effects of mGlu1 receptor antagonists using appetitively motivated tasks that evaluate working memory, timing, and impulsivity functions. Separate groups of adult male Wistar rats were trained to perform four food-reinforced operant tasks: delayed non-matching to position (DNMTP), differential reinforcement of low rates of responding 18 s (DRL 18-s), signal duration discrimination (2-s vs 8-s bisection), and tolerance to delay of reward. Before the tests, rats were pretreated with (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM; 2.5-10 mg/kg, i.p.; JNJ16567083). In DNMTP task, EMQMCM produced delay-dependent increases in performance accuracy so that, at 10 mg/kg dose level, percentage of correct lever choices was enhanced at 8- and 16-s delays. In DRL task, at all three tested doses, response rates were higher, and reinforcement rates were lower than under control conditions. In signal duration discrimination tasks, EMQMCM did not have any specific effects on temporal control. In tolerance to delay of reward, EMQMCM (5 and 10 mg/kg) facilitated choice of the lever associated with large reward at longer delay levels. The authors conclude that blockade of mGlu1 receptors improves working memory and reduces impulsive choice at the doses that have no effects on time perception but appear to facilitate impulsive action. Sukhotina, I.A., Dravolina, O.A., Novitskaya, Y., Zvartau, E.E., Danysz, W., and Bespalov, A.Y. Psychopharmacology (Berl). October 2, 2007 (e-pub ahead of print).

The Effect of Migration to the United States on Substance Use Disorders Among Returned Mexican Migrants and Families of Migrants
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Authors examined the association between substance use disorders and migration to the United States in a nationally representative sample of the Mexican population. They used the World Mental Health version of the Composite International Diagnostic Interview to conduct structured, computer-assisted, face-to-face interviews with a cross-sectional sample of household residents aged 18 to 65 years who lived in Mexico in cities with a population of at least 2,500 people in 2001 and 2002. The response rate was 76.6%, with 5,826 respondents interviewed. Respondents who had migrated to the United States and respondents who had family members who migrated in the United States were more likely to have used alcohol, marijuana, or cocaine at least once in their lifetime; to develop a substance use disorder; and to have a current (in the past 12 months) substance use disorder than were other Mexicans. Authors conclude that international migration appears to play a large role in transforming substance use norms and pathology in Mexico. Future studies should examine how networks extending over international boundaries influence substance use. Borges, G., Medina-Mora, M.E., Breslau, J., and Aguilar-Gaxiola, S. Am. J. Public Health. 97(10), pp. 1847-1851, 2007. e-pub August 29, 2007.

Use of Mental Health Services for Anxiety, Mood, and Substance Disorders in 17 Countries in the WHO World Mental Health Surveys
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
Mental disorders are major causes of disability worldwide, including in the low-income and middle-income countries least able to bear such burdens. Authors describe mental health care in 17 countries participating in the WHO world mental health (WMH) survey initiative and examine unmet needs for treatment. Face-to-face household surveys were undertaken with 84,850 community adult respondents in low-income or middle-income (Colombia, Lebanon, Mexico, Nigeria, China, South Africa, Ukraine) and high-income countries (Belgium, France, Germany, Israel, Italy, Japan, Netherlands, New Zealand, Spain, USA). Prevalence and severity of mental disorders over 12 months, and mental health service use, were assessed with the WMH composite international diagnostic interview. Logistic regression analysis was used to study sociodemographic predictors of receiving any 12-month services. The number of respondents using any 12-month mental health services (57 [2%; Nigeria] to 1477 [18%; USA]) was generally lower in developing than in developed countries, and the proportion receiving services tended to correspond to countries' percentages of gross domestic product spent on health care. Although seriousness of disorder was related to service use, only five (11%; China) to 46 (61%; Belgium) of patients with severe disorders received any care in the previous year. General medical sectors were the largest sources of mental health services. For respondents initiating treatments, 152 (70%; Germany) to 129 (95%; Italy) received any follow-up care, and one (10%; Nigeria) to 113 (42%; France) received treatments meeting minimum standards for adequacy. Patients who were male, married, less-educated, and at the extremes of age or income were treated less. Unmet needs for mental health treatment are pervasive and especially concerning in less-developed countries. Alleviation of these unmet needs will require expansion and optimum allocation of treatment resources. Wang, P.S., Aguilar-Gaxiola, S., Alonso, J., Angermeyer, M.C., Borges, G., Bromet, E.J., Bruffaerts, R., de Girolamo, G., de Graaf, R., Gureje, O., Haro, J.M., Karam, E.G., Kessler, R.C., Kovess, V., Lane, M.C., Lee, S., Levinson, D., Ono, Y., Petukhova, M., Posada-Villa, J., Seedat, S., and Wells, J.E. Lancet. 370(9590), pp. 841-850, 2007.

NMDA Receptor Surface Trafficking and Synaptic Subunit Composition are Developmentally Regulated by the Extracellular Matrix Protein Reelin
INVEST Fellow: Olivier Manzoni, France, 1997-1998
During postnatal development, changes in the subunit composition of glutamate receptors of the NMDA subtype (NMDARs) are key to the refinement of excitatory synapses. Hypotheses for maturation of synaptic NMDARs include regulation of their expression levels, membrane targeting, and surface movements. In addition, several members of extracellular matrix (ECM) proteins such as Reelin are involved in synaptic plasticity. However, it is not known whether and how ECM proteins regulate synaptic NMDAR maturation. To probe the participation of NMDARs to synaptic currents and NMDARs surface dynamics, the authors used electrophysiological recordings and single-particle tracking in cultured hippocampal neurons. Their results show that, during maturation, Reelin orchestrates the regulation of subunit composition of synaptic NMDARs and controls the surface mobility of NR2B subunits. During postnatal maturation, we observed a marked decrease of NR1/NR2B receptor participation to NMDAR-mediated synaptic currents concomitant with the accumulation of Reelin at active synapses. Blockade of the function of Reelin prevented the maturation-dependent reduction in NR1/NR2B-mediated synaptic currents. The reduction of NR1/NR2B receptors was not inhibited by blocking synaptic activity but required beta1-containing integrin receptors. Single-particle tracking showed that inhibition of Reelin decreased the surface mobility of native NR2B-containing NMDARs, whereas their synaptic dwell time increased. Conversely, recombinant Reelin dramatically reduced NR2B-mediated synaptic currents and the time spent by NR2B subunits within synapses. These data reveal a new mode of control of synaptic NMDAR assembly at postnatal hippocampal synapses and an unprecedented role of ECM proteins in regulating glutamate receptor surface diffusion. Groc, L., Choquet, D., Stephenson, F.A., Verrier, D., Manzoni, O.J., and Chavis, P. J. Neurosci. 27(38), pp. 10165-10175, 2007.

Molecular Components and Functions of the Endocannabinoid System in Mouse Prefrontal Cortex
INVEST Fellow: Olivier Manzoni, France, 1997-1998
BACKGROUND: Cannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown. Here, using electron microscopy authors found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+) as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, these data show that 2-AG mediates LTD at these synapses. These data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate in the etiology of PFC-related pathologies. Lafourcade, M., Elezgarai, I., Mato, S., Bakiri, Y., Grandes, P., and Manzoni, O.J. PLoS ONE. 2(1), pp. e709, 2007.

KCNMB1 Genotype Influences Response to Verapamil SR and Adverse Outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST)
INVEST Fellow: Danxin Wang, China, 1996-1997
Authors sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel beta1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES). KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed. Genetic samples were collected from 5,979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed. Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P=0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47-0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33-1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56-1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype. These findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes. Beitelshees, A.L., Gong, Y., Wang, D., Schork, N.J., Cooper-Dehoff, R.M., Langaee, T.Y., Shriver, M.D., Sadee, W., Knot, H.J., Pepine, C.J., and Johnson, J.A; INVEST Investigators. Pharmacogenet. Genomics. 17(9), pp. 719-729, 2007.

Levo-tetrahydropalmatine Inhibits Cocaine's Rewarding Effects: Experiments with Self-administration and Brain-stimulation Reward in Rats
INVEST Fellow: Zhengxiong Xi, China, 1995-1996
It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D(1) and D(2) receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THP's effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THP's effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10mg/kg) increased, while a high dose (20mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaine's rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10mg/kg, but not 1-3mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THP's actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction. Xi, Z.X., Yang, Z., Li, S.J., Li, X., Dillon, C., Peng, X.Q., Spiller, K., and Gardner, E.L. Neuropharmacology. 53(6), pp. 771-782, 2007. e-pub August 15, 2007.

Cannabinoid CB1 Receptor Antagonists Attenuate Cocaine's Rewarding Effects: Experiments with Self-Administration and Brain-Stimulation Reward in Rats
INVEST Fellow: Zhengxiong Xi, China, 1995-1996
Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, the authors found that blockade of CB1 receptors by AM 251 (1-10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30-70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1-3 mg/kg) also significantly and dose-dependently inhibited (by 25-90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications. Xi, Z.X., Spiller, K., Pak, A.C., Gilbert, J., Dillon, C., Li, X., Peng, X.Q., and Gardner, E.L. Neuropsychopharmacology. August 29, 2007 (e-pub ahead of print).

Gender Differences in the Relationship Between Alcohol and Violent Injury: An Analysis of Cross-national Emergency Department Data
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
The objectives of the present study were twofold: (1) to determine whether gender differences exist in the roles of drinking in the event (i.e., self-reported drinking before the injury and estimated blood alcohol concentration [BAC] captured after injury) and drinking pattern (i.e., heavy episodic drinking) in explaining violent versus nonviolent injuries and (2) to assess whether these gender differences vary by country. Emergency department data were analyzed from 30 hospitals in 15 countries, as part of the Emergency Room Collaborative Alcohol Analysis Project and the World Health Organization Collaborative Study of Alcohol and Injuries. Interaction effects between gender and alcohol were tested in the prediction of violent versus nonviolent injury for each country. The bivariate analyses revealed significantly larger effects of drinking-in-the-event variables for men than for women in three countries (i.e., 6 hours before the injury in Argentina and having a positive BAC in Belarus and Spain). In the multivariate analyses, restricted to countries with sufficient sample sizes (i.e., Mexico, South Africa, and the United States), no significant gender differences were found between the drinking-in-the-event variables and violent injury. In the bivariate and multivariate analyses, a significant interaction effect between gender and heavy episodic drinking was found in the United States, indicating that heavy episodic drinking predicted violent injury for women but not for men. Although the results are preliminary, treatment and prevention programs may need to target both genders equally or perhaps even focus more on heavy-drinking women, particularly in the United States. Wells, S., Thompson, J.M., Cherpitel, C., Macdonald, S., Marais, S., and Borges, G. J. Stud. Alcohol Drugs. 68(6), pp. 824-833, 2007.

Comorbidity for Alcohol Use Disorders and Drug Use in Mexican-origin Groups: Comparison of Data from National Alcohol Surveys in the U.S. and Mexico
INVEST Fellow: Guilherme Borges, Mexico, 1997-1998
The comorbidity, separately, of alcohol dependence and consequences of drinking with illicit drug use is compared between Mexicans and Mexicans Americans, using data from the 1995 and 2000 U.S. National Alcohol Surveys (n = 830) and the 1998 Mexico National Household Survey on Addictions (n = 3313). Among drinkers, comorbidity was significantly more prevalent among Mexican Americans than among Mexicans and was positively associated with level of acculturation among Mexican Americans. Although data may not be generalizable, they are important for a better understanding of cultural influences on the development of comorbid substance abuse conditions among Mexicans immigrating to the United States and their substance abuse treatment needs. Cherpitel, C.J., Robertson, M., Ye, Y., Borges, G., Bautista, C.F., Lown, A., Greenfield, T., and Bond, J. Subst. Use Misuse 42(11), pp. 1685-1703, 2007.

Effects of Nitric Oxide Synthase Inhibitors in Attenuating Nicotine Withdrawal in Rats
INVEST Fellow: Raka Jain, India, 1996-1997
This study evaluates the effects of three nitric oxide synthase (NOS) inhibitors (L-NNA, L-NAME, L-NMMA) in attenuating the precipitated nicotine withdrawal syndrome in rats. Male albino Wistar rats were made dependent on nicotine by subcutaneous infusion of nicotine (9.0 mg/kg/day) via a 7 day osmotic pump, whereas control rats received saline via osmotic pumps. Test doses of each NOS inhibitor were administered 30 min prior to mecamylamine (1 mg/kg) challenge in control and test rats on the 7th day. Somatic signs of withdrawal were scored for 15 min by using the global Gellert-Holtzman rating scale followed by a measurement of motor activity. A comparison of NOS inhibitors treated rats with the mecamylamine-precipitated nicotine rats showed that at highest dose L-NNA appears to produce a more complete attenuation of all aspects of withdrawal syndrome. On the other hand, L-NAME appears to do so both at moderate and highest doses. This could be due to an incomplete reversal of some signs of withdrawals by L-NMMA. However, motor activity increased in nicotine dependent rats with the administration of NOS inhibitors. This study demonstrates that NO plays an important role in the expression of behavioral signs of nicotine withdrawal syndrome and suggests a potential use of NOS inhibitors as an aid in tobacco smoking cessation. Jain, R., Mukherjee, K., and Mohan, D. Pharmacol. Biochem. Behav. October 22, 2007 (e-pub ahead of print).

Painful Purinergic Receptors
INVEST Fellow: Steven McGaraughty, Canada, 1995-1996
Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies including genetic disruption studies and the development of selective antagonists has indicated that the activation of P2X receptor subtypes, including P2X3, P2X2/3, P2X4 and P2X7, and P2Y (e.g. P2Y2) receptors can modulate pain. For example, administration of a selective P2X3 antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X4 receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X7 receptor also reduce sensitization in animal models of inflammatory and neuropathic pain providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Additionally, activation of P2Y2 receptors leads to sensitization of polymodal TRPV1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g. P2X3, P2X2/3 and P2Y receptors) or indirectly through neural-gial cell interactions (P2X4 and P2X7 receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity. Donnelly-Roberts, D., McGaraughty, S., Shieh, C.C., Honore, P., and Jarvis, M.F. J. Pharmacol. Exp. Ther. November 27, 2007 (e-pub ahead of print).

Physical Design Analysis and Mainstream Smoke Constituent Yields of the New Potential Reduced Exposure Product, Marlboro UltraSmooth
INVEST Fellow: Vaughan Rees, Australia, 1999-2000
Potential reduced exposure products (PREPs) purport to lower toxicant emissions, but without clinical and long-term health outcome data, claims for reduced harm status of PREPs depend heavily on standard machine yield smoke constituent data. Two prototypes of the new carbon-filtered PREP Marlboro UltraSmooth (MUS) were investigated using both standard (FTC/ISO) and intensive (Health Canada) machine methods to measure gas/vapor- and particulate-phase smoke constituents. Basic physical design characteristics that may influence smoke constituent yields, such as ventilation, pressure drop (resistance to draw), quantity of tobacco, and quantity and type of carbon, were measured. The possible presence of added chemical flavorant compounds was investigated using gas chromatography-mass spectroscopy. MUS prototypes were found to have several key differences in physical design compared with a conventional cigarette, including higher ventilation, lower draw resistance, and in the case of the Salt Lake City prototype, the use of vitreous carbon beads and the presence of chemical flavorants on both the beads and an embedded filter fiber. When tested under the standard regimen, gas-phase constituents of MUS prototypes were reduced compared with a conventional low-yield cigarette. However, far smaller reductions in gas-phase constituents were observed under the intensive regimen, suggesting that the carbon technology used in MUS is less effective when smoked under more intensive conditions. Particulate-phase constituents were not reduced by the carbon filter under either machine-smoking regimen. The data suggest that MUS has been designed to reduce toxic yields while preserving consumer appeal. However, MUS is less effective in reducing toxic smoke constituents when smoked under intensive conditions. Rees, V.W., Wayne, G.F., Thomas, B.F., and Connolly, G.N. Nicotine Tob. Res. 9(11), pp. 1197-1206, 2007.

Internal Tobacco Industry Research on Olfactory and Trigeminal Nerve Response to Nicotine and Other Smoke Components
INVEST Fellow: Vaughan Rees, Australia, 1999-2000
Evidence has shown that factors other than the central pharmacological effects of nicotine are important in promoting smoking behavior. One such non-nicotine effect includes sensory stimulation, which may promote smoking by developing learned associations with nicotine's rewarding effects, or by constituting a rewarding experience independent of nicotine. The present study used internal tobacco industry documents to examine industry efforts to understand and manipulate stimulation of the sensory nerves by tobacco smoke, and the influence of sensory stimulation on smoker behavior. Research focused on sensory nerves of the head and neck, including the olfactory nerve, which carries flavor and odor, and the trigeminal nerve, which carries irritant information. The tobacco industry maintained a systematic research program designed to elucidate an understanding of responses of sensory nerves to nicotine and other components of tobacco smoke, and attempted to develop nicotine-like compounds that would enhance sensory responses in smokers. Industry research appeared intended to aid in the development of new products with greater consumer appeal. The potential influence of sensory response in enhancing nicotine dependence through an associative mechanism was acknowledged by the tobacco industry, but evidence for research in this area was limited. These findings add to evidence of industry manipulation of sensory factors to enhance smoking behavior and may have implications for development of more effective treatment strategies, including more "acceptable" nicotine replacement therapies. Megerdichian, C.L., Rees, V.W., Ferris, Wayne G., and Connolly, G.N. Nicotine Tob. Res. 9(11), pp. 1119-1129, 2007.

Long-term Synaptic Plasticity in the Spinal Dorsal Horn and its Modulation by Electroacupuncture in Rats with Neuropathic Pain
INVEST Fellow: You Wan, China, 1998-1999
The authors previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, the authors investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). They found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from the present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz. Xing, G.G., Liu, F.Y., Qu, X.X., Han, J.S., and Wan, Y. Exp. Neurol. 208(2), pp. 323-332, 2007. e-pub September 12, 2007.

The Selective Dopamine D(3) Receptor Antagonists SB-277011A and NGB 2904 and the Putative Partial D(3) Receptor Agonist BP-897 Attenuate Methamphetamine-enhanced Brain Stimulation Reward in Rats
INVEST Fellow: Zhengxiong Xi, China, 1995-1996
The authors have previously reported that selective antagonism of brain D(3) receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR). In the present study, the authors investigated whether the selective D(3) receptor antagonists SB-277011A and NGB 2904 and the putative partial D(3) agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR. Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate-frequency curve shift paradigm was used to measure brain-reward threshold (theta (0)). METH (0.1-0.65 mg/kg, i.p.) dose-dependently lowered ( approximately 10-50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1-1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1-5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation-response curve to the right (inhibited BSR itself) in the presence or absence of METH. Selective antagonism of D(3) receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D(3) and non-D(3) receptors. These findings support a potential use of selective D(3) receptor antagonists for the treatment of METH addiction. Spiller, K., Xi, Z.X., Peng, X.Q., Newman, A.H., Ashby, C.R. Jr., Heidbreder, C., Gaal, J., and Gardner, E.L. Psychopharmacology (Berl). November 6, 2007 (e-pub ahead of print).

Age and Gender Effects on Olanzapine and Risperidone Plasma Concentrations in Children and Adolescents
INVEST Fellow: Gerald Zernig, Austria, 1993-1994
Risperidone and olanzapine are second-generation antipsychotics that are increasingly used in child and adolescent psychiatry. So far, little is known about plasma concentrations and concentration-to-dose (C/D) ratios of these agents in children and adolescents compared to adults. This study investigated whether age and gender influence risperidone and olanzapine plasma concentration by determining risperidone and olanzapine plasma levels by tandem mass spectrometry in 162 Caucasian patients (98 risperidone and 64 olanzapine). For risperidone and 9-hydroxyrisperidone, the C(total)/D ratio was almost identical in both age groups (10-18 and 19-45 years, respectively). In the younger age group, females exhibited significantly higher total plasma levels than males while receiving similar doses of risperidone. For olanzapine, in adolescents significantly higher C/D ratios were detected by an average of 43% (after adjustment for weight: 34%) compared to adults. This study demonstrates an age effect for olanzapine but not for risperidone resulting in higher olanzapine plasma levels in younger patients. For risperidone, the authors found a gender effect as female adolescent patients had significantly higher risperidone plasma concentrations than male adolescent patients. Future prospective studies are necessary to clarify whether the prescribed dosage should be different in young and older patients. Aichhorn, W., Marksteiner, J., Walch, T., Zernig, G., Hinterhuber, H., Stuppaeck, C., and Kemmler, G. J. Child Adolesc. Psychopharmacol. 17(5), pp. 665-674, 2007.

Study on the Association between Vaginal Douching and Sexually Transmitted Diseases among Female Sex Workers in a County of Yunnan Province
INVEST Fellow: Lan Zhang, China, 2004-2005
The objective of the present study was to explore the epidemic characteristics of vaginal douching, human immunodeficiency virus (HIV) and other sexually transmitted diseases(STD) among female sex workers (FSWs) in Yunnan province. FSWs were recruited to be investigated on their demographic data, drug abuse and sexual behavior, HIV/AIDS knowledge and procreation health status. Venous blood were collected to test for HIV, herpes simplex virus 2 (HSV-2) and syphilis while urine specimen was for morphine, cervical secretion for Gonorrhoea and Chlamydia trachomatis, and vaginal secretion for Trichomonas. A total number of 833 blood specimen were collected, in which 84 specimen were confirmed to be HIV positive with a prevalence rate of 10.1%. The prevalence rates of syphilis and HSV-2 were 8.2% and 68.4% respectively. 832 vaginal and cervical secretion specimen were collected with the prevalence rates of Gonorrhoea, Chlamydia trachomatis and Trichomonas were 11.5%, 28.2% and 11.9% respectively. In multivariate logistic analysis, the factors associated with vaginal douching were: being Han nationality, locations of sex work at middle/high level, ever heard of HIV/AIDS, emerged hypogastric pain last year, the number of sex work location > or =4. Vaginal douching was shown a risk factor for HIV and some STD. Wang, H.B., Wang, N., Ma, J.G., Wang, G.X., Chang, D.F., Ding, G.W., Xu, J.J., Zhang, G.L., Dong, R.L., Zhang, L., Wu, Z.L., and Zheng, X.W. Zhonghua Liu Xing Bing Xue Za Zhi. 28(6), pp. 558-561, 2007. [Article in Chinese]

Publications by Former NIDA Hubert H. Humphrey Fellows

Personality Traits and Sensitivity to Pain in Male Chronic Opioid Addicts
HHH Fellow: Eli Lawental, Israel, 1993-1994
Previous evidence concerning pain mechanisms, long-term opioids use, and personality traits evolve the possibility that pain perception and opioid abuse are two related phenomena and there is a need to take into account the specific personality traits as well, in examining the relationships among them. Opioid addicts (OAs) have been shown to exhibit different personality traits and pain perception as compared with healthy subjects. The aim of the present study was to examine the relations between personality traits and pain perception among in-treatment OAs in comparison with controls. Participants (54 OAs, 59 controls), all males, were exposed to the cold pressor test and were evaluated for latency of pain onset (seconds); pain intensity (0-100 visual analogue scale [VAS)]); and pain tolerance (time for hand withdrawal). Personality traits were evaluated using Cloninger's Tridimensional Personality Questionnaire, TPQ; harm avoidance, HA; reward dependence, RD; novelty seeking, NS. In comparison with controls, OAs exhibited longer latencies, lower VAS scores, and shorter tolerance, and significantly higher NS, bigher HA, and lower RD. Control group, but not OAs, showed a significant positive correlation between HA and VAS (r = 0.31, p = 0.02) and significant negative correlation between HA and tolerance (r = - 0.29, p = 0.03). It is concluded that in contrast to healthy population, personality traits, as measured by the TPQ, do not predict pain perception in OAs. Eisenberg, E., Cohen, D., Lawental, E., and Pud, D. J. Opioid Manag. 3(4), pp. 225-230, 2007.

The Effect of Clozapine on Neuroimaging Findings in Schizophrenia
HHH Fellow: Berna Ulug, Turkey, 1995-1996
Functional and structural neuroimaging help us to compare the brains of schizophrenic patients and controls, moreover they let us observe the changes with treatment. Longitudinal studies comparing patients with typical and atypical antipsychotics have been useful in understanding the effects of these antipsychotic medications on brain function. In general, atypical antipsychotics are suggested to have greater normalizing effects on brain function than typicals, although the results are controversial. In particular, clozapine appears to act more selectively than typical antipsychotics on the prefrontal region, an area of special relevance in higher cognitive functions and schizophrenia. The study of anatomic and functional brain variables associated with clozapine response in schizophrenia may help to identify patients who are most likely to benefit from clozapine treatment. The authors investigated the effect of clozapine on regional cerebral blood flow and (1)H MRS findings and studied their relationship with treatment response. Clozapine increased frontal/basal ganglia perfusion ratio in treatment-responders. In addition, NAA/Cre ratio has increased and Cho/Cre has decreased in dorsolateral prefrontal cortex after 8 weeks of clozapine treatment. The results of the study will be discussed in the light of current literature. These findings can contribute to better understanding of mechanism of action of clozapine. Ertugrul, A., and Ulu_, B. Psychiatr. Danub. 19(4), pp. 367-369, 2007.

HIV Treatment Access and Scale-up for Delivery of Opiate Substitution Therapy with Buprenorphine for IDUs in Ukraine--programme Description and Policy Implications
HHH Fellow: Sergiy Dvoryak, Ukraine, 1999-2000
Injection drug use (IDU) accounts for 70 percent of HIV cases in Ukraine. Until buprenorphine maintenance therapy (BMT) was introduced, few effective strategies aimed at achieving reduction in illicit drug use were available as a conduit to anti-retroviral therapy (ARV) among IDUs. In October 2005, BMT was scaled-up using Global Fund resources in six regions within Ukraine. Entry criteria included opioid dependence, HIV-1 seropositivity, age >or=18 years and reported interest in BMT. All sites included a multidisciplinary team. To date, 207 patients have been initiated on BMT. The existing infrastructure allows for further scale-up of and administration of BMT and the possibility of co-administration with ARV. The process for prescription and administration of buprenorphine and ARV is at times cumbersome and constrained by current regulations. More IDU need BMT to improve overall health outcomes. Central to expanding access will be legislative changes to existing drug policy. Moreover, the cost of buprenorphine is prohibitively expensive. Sustainable substitution therapy in Ukraine requires lower negotiated prices for buprenorphine, the addition of methadone, or both to the existing formulary for HIV+ drug users. Bruce, R.D., Dvoryak, S, Sylla, L., and Altice, F.L. Int. J. Drug Policy. 18(4), pp. 326-328, 2007. e-pub February 5, 2007.

Using Thought Mapping and Structured Stories to Decrease HIV Risk Behaviors among Cocaine Injectors and Crack Smokers in the South of Brazil
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
The objectves of this study were to compare changes in AIDS knowledge and risk behaviors among Brazilian cocaine users in an intervention trial. 119 participants were randomly assigned to either a standard or a standard plus "thought mapping" intervention, and re-interviewed 2 and 8 weeks after intake using standardized data collection instruments. Intervention effects were examined using generalized estimated equation model. Significant increases in AIDS knowledge and condom use were observed in the experimental group, as well as significant changes in the subscores for sexual and drug risks. The experimental intervention was less successful in decreasing mean days of cocaine use when compared to the standard. Although not robust, the findings nevertheless suggest that components of the experimental thought-mapping model might be useful in combination with other approaches. Pechansky, F., Bassani, D.G., von Diemen, L., Kessler, F., Leukefeld, C.G., Surratt, H.L., Inciardi, J.A., and Martin, S.S. Rev. Bras. Psiquiatr. 29(3), pp. 233-240, 2007. e-pub September 18, 2007.

Alcohol and Drug Use Among University Students: Gender Differences
HHH Fellows: Arthur Guerra de Andrade, Brazil, 1991-1992, and Vladimir
Stempliuk, Brazil, 2003-2004
This study compared the pattern of alcohol, legal and illegal drugs use among students of the Universidade de Sao Paulo (Brazil) in 1996 and 2001. Samples of 2.564 (1996) and 2.837 (2001) students answered a questionnaire proposed by the World Health Organization, which characterizes the consumption of alcohol, legal and illegal drugs in lifetime, in the last 12 months and in the last 30 days. Men showed a significant increase in lifetime use of tobacco (44.8% to 50.9%), marijuana (33.7% to 39.5%) and hallucinogens (6.6% to 14.1%) between 1996 and 2001. No significant change was observed among women between 1996 and 2001 in tranquilizer use. Concerning the consumption reported in the last 12 months, both genders displayed significant increases in the consumption of marijuana (22.3% to 27.1% for men and 12.9% to 16.9% for women), amphetamines (1.9% to 5.0% for men and 3.4% to 5.6% for women), and inhalants (9.8% to 15.7% for men and 5.4% to 10.6% for women). The greatest gender difference was observed in consumption reported in the last 30 days with significant increases in male use of tobacco (19.6% to 23.5%), marijuana (15.8% to 20.5%), amphetamines (1.1% to 3.2%), and inhalants (4.0% to 7.9%). Substance use reported in the last 30 days remained stable among women between the 2 surveys. Rates of substance use among university students increased. These gender differences in substance consumption should be taken into account in the development of preventive and treatment strategies for undergraduate university students. Wagner, G.A., Stempliuk, Vde A., Zilberman, M.L, Barroso, L.P., and de Andrade, A.G. Rev. Bras. Psiquiatr. 29(2), pp. 123-129, 2007.

Gender Differences in Sex Risk Behaviors Among Ukraine Injection Drug Users
HHH Fellow: Sergiy Dvoryak, Ukraine, 1999-2000
The objective of this study was to assess gender differences in drug and sex risk behaviors and evaluate predictors of HIV-related sex risk behaviors among heterosexual injection drug users (IDUs) in Ukraine. Street-recruited IDUs from Kiev, Odessa, and Makeevka/ Donesk, Ukraine. From June 2004 through November 2006, outreach workers recruited 1557 IDUs, including 526 from Kiev, 494 from Odessa, and 537 from Makeevka/Donesk. Participants were administered a standardized computer-assisted interview assessing HIV-related drug and sex risk behaviors, self-efficacy for practicing safe sex, and HIV knowledge. Overall, 80% of the participants were sexually active in the 30-day period before their interview. They also engaged in high-risk sex behaviors during this brief 30-day window: 53% reported anal or vaginal sex without a condom, 27% had sex with more than 1 partner, 41% had an IDU sex partner, and 37% had an HIV-positive sex partner or a partner whose HIV status they did not know. Overall, women were at higher risk than men and were more likely to have been told they were HIV-positive. The extremely high HIV prevalence rate in Ukraine and in this cohort, combined with their recent high-risk sex behaviors, forecasts not only a continuance of the epidemic in the region but an escalation. Booth, R.E., Lehman, W.E., Brewster, J.T., Sinitsyna, L., and Dvoryak, S. J. Acquir. Immune Defic. Syndr. July 19, 2007 (e-pub ahead of print).

Adaptation and Construct Validation of the Barratt Impulsiveness Scale
(BIS 11) to Brazilian Portuguese for Use in Adolescents
HHH Fellow: Flavio Pechansky, Brazil, 1993-1994
Impulsivity is associated with different psychiatric disorders. The Barratt Impulsiveness Scale version 11 is one of the scales mostly used to measure impulsivity and it does not have a validated version for Brazilian Portuguese. The objective of this study is to adapt and conduct the construct validation of the Barratt Impulsiveness Scale version 11 for adolescents. The scale was translated and adapted into Portuguese and then back-translated into English. The psychometric proprieties, factor analysis and construct validity were evaluated in two samples: 18 bilingual undergraduate medical students and 464 male adolescents between 15 and 20 years old from a well-delimited geographical area in the city of Canoas, southern Brazil. The adolescent sample had a mean age of 17.3 +/- 1.7 years. Intra-class correlation coefficient achieved a value of 0.90, and internal consistency had a of 0.62. Factor analysis did not identify the 3 factors of the original scale. Impulsivity scores from the Barratt Impulsiveness Scale version 11 had a correlation with scores for attention deficit/hyperactive disorder and oppositional defiant disorder and with number of symptoms of conduct disorder, suggesting an appropriate construct validity of the scale. Even considering some limitations in the Portuguese version, Barratt Impulsiveness Scale version 11 can be used in male adolescents and should be tested in other populations. von Diemen, L., Szobot, C.M., Kessler, F., and Pechansky, F. Rev. Bras. Psiquiatr. 29(2), pp. 153-156, 2007.

Brain Injury Markers (S100B and NSE) in Chronic Cocaine Dependents
Studies have shown signs of brain damage caused by different mechanisms in cocaine users. The serum neuron specific enolase and S100B protein are considered specific biochemical markers of neuronal and glial cell injury. This study aimed at comparing blood levels of S100B and NSE in chronic cocaine users and in volunteers who did not use cocaine or other illicit drugs. Twenty subjects dependent on cocaine but not on alcohol or marijuana, and 20 non-substance using controls were recruited. Subjects were selected by consecutive and non-probabilistic sampling. Neuron specific enolase and S100B levels were determined by luminescence assay. Cocaine users had significantly higher scores than controls in all psychiatric dimensions of the SCL-90 and had cognitive deficits in the subtest cubes of WAIS and the word span. Mean serum S100B level was 0.09 +/- 0.04 microg/l among cocaine users and 0.08 +/- 0.04 microg/l among controls. Mean serum neuron specific enolase level was 9.7 +/- 3.5 ng/l among cocaine users and 8.3 +/- 2.6 ng/l among controls. In this first study using these specific brain damage markers in cocaine users, serum levels of S100B and neuron specific enolase were not statistically different between cocaine dependent subjects and controls. Kessler, F.H., Woody, G., Portela, L.V., Tort, A.B., De Boni, R., Peuker, A.C., Genro, V., von Diemen, L., de Souza, D.O., and Pechansky, F. Rev. Bras. Psiquiatr. 29(2), pp. 134-139, 2007.