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NIDA Home > Publications > Director's Reports > May, 2008 Index    

Director's Report to the National Advisory Council on Drug Abuse - May, 2008

Research Findings - International Research

Publications by Former NIDA INVEST Drug Abuse Research Fellows

Pressure-Assisted Capillary Electrochromatography with Electrospray Ionization-Mass Spectrometry Based on Silica-Based Monolithic Column for Rapid Analysis of Narcotics
INVEST Fellow: Lan Zhang (China, 2004-2005)
A pressure-assisted CEC (pCEC) with ESI-MS based on silica-based monolithic column was developed for rapid analysis of narcotics. Combining the extremely high permeability and separation efficiency of silica-based monolithic column with the high selectivity and sensitivity of pCEC-ESI-MS, the developed system exhibited its prominent advantages in separation and detection. A systematic investigation of the pCEC separation and ESI-MS detection parameters was performed. Experiment results showed that the optimized separation efficiency could be obtained at 8 bar assisted pressure with 25 kV separation voltage, using the solution containing 65% ACN v/v and 20 mmol/L ammonium acetate with pH 6.0 as running buffer. 3 microL/min of sheath liquid was considered as the optimized flow rate since it could provide the maximum signal intensity. Under the optimum conditions, the five tested narcotics could be completely separated within 10 min with the detection limit in the range of 2.0-80 nmol/L. The proposed method has been successfully used for detection of narcotics in real urine samples. Lu, M., Zhang, L., Feng, Q., Xia, S., Chi, Y., Tong, P., and Chen, G. Electrophoresis. January 22, 2008, Epub ahead of print.

Neurokinin-1 Receptors in Cholinergic Neurons of the Rat Ventral Pallidum have a Predominantly Dendritic Distribution that is Affected by Apomorphine when Combined with Startle-Evoking Auditory Stimulation
INVEST Fellow: Elisa Mengual (Spain, 1999-2000)
Cholinergic neurons of the basal forebrain are implicated in startle reflex inhibition by a prior weak stimulus often referred to as prepulse inhibition (PPI) and used as an index of sensorimotor gating deficits in schizophrenia. Gating deficits can be produced in rodent models by acute systemic administration of apomorphine, a non-selective dopamine D1 and D2 receptor agonist that also affects trafficking of neurokinin-1 (NK(1)) receptors induced by startle evoking auditory stimulation (AS) in midbrain neurons. The authors used electron microscopic immunolabeling of NK(1) receptors and the vesicular acetylcholine transporter (VAchT) to test the hypothesis that the subcellular distributions of these receptors in cholinergic neurons of the rat ventral pallidum are subject to a similar regulation. In vehicle controls, NK(1) immunogold was often seen near cytoplasmic endomembranes in somata and large dendrites, but was more equally distributed in cytoplasmic and plasmalemmal compartments of medium dendrites, and principally located on the plasma membrane of small dendrites. These labeling patterns appeared to be largely independent of whether the NK(1) receptor was co-expressed with VAchT, however only the medium and small VAchT-labeled dendrites showed significant treatment-specific differences in NK(1) immunogold distributions. The NK(1) receptor immunogold particle density on the plasma membrane of medium cholinergic dendrites was significantly enhanced by combined apomorphine and AS, while neither alone affected either the plasmalemmal density or the equality of the plasmalemmal and cytoplasmic distributions of NK(1) receptors in these dendrites. Small cholinergic dendrites showed a significant AS-induced increase in both the plasmalemmal and cytoplasmic density of NK(1) gold particles, and an apomorphine-induced disruption of the preferential plasmalemmal targeting of the NK(1) receptors. These results provide ultrastructural evidence that NK(1) receptors in cholinergic neurons of the ventral pallidum have subcellular locations and plasticity conducive to active involvement in dopamine-dependent sensorimotor processing. Mengual, E., Chan, J., Lane, D., San Luciano Palenzuela, M., Hara, Y., Lessard, A., and Pickel, V.M. Neuroscience. December 4, 2007, Epub ahead of print.

Role of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) Receptor Subunit GluR1 in Spinal Dorsal Horn in Inflammatory Nociception and Neuropathic Nociception in Rat
INVEST Fellow: You Wan (China, 1989-1999)
The present study aims to investigate changes of spinal cord AMPA receptor GluR1 and its phosphorylation in inflammatory and neuropathic pain. Complete Freund's adjuvant (CFA) injection into the hind paw produced inflammatory thermal hyperalgesia that was assessed by decreased response latency to radiant heat; spinal nerve ligation (SNL) was used to induce mechanical allodynia that was evaluated with von Frey hairs. By method of Western blot, expression of GluR1 (the main subunit of the AMPA receptor) and its phosphorylated forms at serine 845 (pGluR1-Ser845) and at serine 831 (pGluR1-Ser831) in the spinal dorsal horn was observed. It was found that the expression of pGluR1-Ser845 and pGluR1-Ser831 increased significantly at 1 h after CFA injection, reached peak at 4 h and returned to the normal control level at 24 h, while no significant change was detected in GluR1 itself. In contrast, neither GluR1 nor pGluR1 showed any significant change in rats following SNL. These results suggest that phosphorylated GluR1 (pGluR1-Ser845 and pGluR1-Ser831) might play a role in the induction of inflammatory but not neuropathic pain. Lu, Y., Sun, Y.N., Wu, X., Sun, Q., Liu, F.Y., Xing, G.G., and Wan, Y. Brain Res. January 16, 2008, Epub ahead of print.

Axonal Accumulation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Cation Channels Contributes to Mechanical Allodynia after Peripheral Nerve Injury in Rat
INVEST Fellow: You Wan (China, 1989-1999)
Peripheral nerve injury causes neuropathic pain including mechanical allodynia and thermal hyperalgesia due to central and peripheral sensitization. Spontaneous ectopic discharges derived from dorsal root ganglion (DRG) neurons and from the sites of injury are a key factor in the initiation of this sensitization. Numerous studies have focused primarily on DRG neurons; however, the injured axons themselves likely play an equally important role. Previous studies of neuropathic pain in rats with spinal nerve ligation (SNL) showed that the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel in DRG neuronal bodies is important for the development of neuropathic pain. Here, the authors investigate the role of the axonal HCN channel in neuropathic pain rats. Using the chronic constriction injury (CCI) model, they found abundant axonal accumulation of HCN channel protein at the injured sites accompanied by a slight decrease in DRG neuronal bodies. The function of these accumulated channels was verified by local application of ZD7288, a specific HCN blocker, which significantly suppressed the ectopic discharges from injured nerve fibers with no effect on impulse conduction. Moreover, mechanical allodynia, but not thermal hyperalgesia, was relieved significantly by ZD7288. These results suggest that axonal HCN channel accumulation plays an important role in ectopic discharges from injured spinal nerves and contributes to the development of mechanical allodynia in neuropathic pain rats. Jiang, Y.Q., Xing, G.G., Wang, S.L., Tu, H.Y., Chi, Y.N., Li, J., Liu, F.Y., Han, J.S., and Wan, Y. Pain, January 5, 2008, Epub ahead of print.

Delay and Failure in Treatment Seeking After First Onset of Mental Disorders in the World Health Organization's World Mental Health Survey Initiative
INVEST Fellow: Guilherme Borges (Mexico, 1997-1998)
Data are presented on patterns of failure and delay in making initial treatment contact after first onset of a mental disorder in 15 countries in the World Health Organization (WHO)'s World Mental Health (WMH) Surveys. Representative face-to-face household surveys were conducted among 76,012 respondents aged 18 and older in Belgium, Colombia, France, Germany, Israel, Italy, Japan, Lebanon, Mexico, the Netherlands, New Zealand, Nigeria, People's Republic of China (Beijing and Shanghai), Spain, and the United States. The WHO Composite International Diagnostic Interview (CIDI) was used to assess lifetime DSM-IV anxiety, mood, and substance use disorders. Ages of onset for individual disorders and ages of first treatment contact for each disorder were used to calculate the extent of failure and delay in initial help seeking. The proportion of lifetime cases making treatment contact in the year of disorder onset ranged from 0.8 to 36.4% for anxiety disorders, from 6.0 to 52.1% for mood disorders, and from 0.9 to 18.6% for substance use disorders. By 50 years, the proportion of lifetime cases making treatment contact ranged from 15.2 to 95.0% for anxiety disorders, from 7.9 to 98.6% for mood disorders, and from 19.8 to 86.1% for substance use disorders. Median delays among cases eventually making contact ranged from 3.0 to 30.0 years for anxiety disorders, from 1.0 to 14.0 years for mood disorders, and from 6.0 to 18.0 years for substance use disorders. Failure and delays in treatment seeking were generally greater in developing countries, older cohorts, men, and cases with earlier ages of onset. These results show that failure and delays in initial help seeking are pervasive problems worldwide. Interventions to ensure prompt initial treatment contacts are needed to reduce the global burdens and hazards of untreated mental disorders. Wang, P.S., Angermeyer, M., Borges, G., Bruffaerts, R., Tat Chiu, W., DE Girolamo, G., Fayyad, J., Gureje, O., Haro, J.M., Huang, Y., Kessler, R.C., Kovess, V., Levinson, D., Nakane, Y., Oakley Brown, M.A., Ormel, J.H., Posada-Villa, J., Aguilar-Gaxiola, S., Alonso, J., Lee, S., Heeringa, S., Pennell, B.E., Chatterji, S., and Ustuen, T.B. World Psychiatry 6(3), pp. 177-185, 2007.

Cross-National Prevalence and Risk Factors for Suicidal Ideation, Plans and Attempts
INVEST Fellow: Guilherme Borges (Mexico, 1997-1998)
Suicide is a leading cause of death worldwide; however, the prevalence and risk factors for the immediate precursors to suicide - suicidal ideation, plans and attempts - are not well known, especially in low- and middle-income countries. The aim of this study was to report on the prevalence and risk factors for suicidal behaviors across 17 countries. A total of 84, 850 adults were interviewed regarding suicidal behaviors and socio-demographic and psychiatric risk factors. Results showed that the cross-national lifetime prevalence of suicidal ideation, plans, and attempts is 9.2% (s.e.=0.1), 3.1% (s.e.=0.1), and 2.7% (s.e.=0.1). Across all countries, 60% of transitions from ideation to plan and attempt occur within the first year after ideation onset. Consistent cross-national risk factors included being female, younger, less educated, unmarried and having a mental disorder. Interestingly, the strongest diagnostic risk factors were mood disorders in high-income countries but impulse control disorders in low- and middle-income countries. The authors conclude that there is cross-national variability in the prevalence of suicidal behaviors, but strong consistency in the characteristics and risk factors for these behaviors. These findings have significant implications for the prediction and prevention of suicidal behaviors. Nock, M.K., Borges, G., Bromet, E.J., Alonso, J., Angermeyer, M., Beautrais, A., Bruffaerts, R., Chiu, W.T., de Girolamo, G., Gluzman, S., de Graaf, R., Gureje, O., Haro, J.M., Huang, Y., Karam, E., Kessler, R.C., Lepine, J.P., Levinson, D., Medina-Mora, M.E., Ono, Y., Posada-Villa, J., and Williams, D. Br. J. Psychiatry.192, pp. 98-105, 2008.

The Epidemiology of Suicide-Related Outcomes in Mexico
INVEST Fellow: Guilherme Borges (Mexico, 1997-1998)
Nationally representative data from the Mexican National Comorbidity Survey are presented on the lifetime prevalence and age-of-onset (AOO) distributions of suicide ideation, plan and attempt and on temporally prior demographic and DSM-IV psychiatric risk factors. Lifetime ideation was reported by 8.1% of respondents, while 3.2% reported a lifetime plan and 2.7% a lifetime suicide attempt. Onset of all outcomes was highest in adolescence and early adulthood. The risk of transition from suicide ideation to plan and attempt was highest within the first year of onset of ideation. The presence of one or more temporally prior DSM-IV/CIDI (Composite International Diagnostic Instrument) disorder was strongly related to each suicide-related outcome. Suicidal outcomes are prevalent, have an early AOO, and are strongly related to temporally prior mental disorders in Mexico. Given the early AOO, intervention efforts need to focus more than currently on children and adolescents with mental disorders to be effective in prevention. Borges, G., Nock, M.K., Medina-Mora, M.E., Benjet, C., Lara, C., Chiu, W.T., and Kessler, R.C. Suicide Life Threat. Behav. 37(6), pp. 627-640, 2007.

Suicide Ideation, Plan, and Attempt in the Mexican Adolescent Mental Health Survey
INVEST Fellow: Guilherme Borges (Mexico, 1997-1998)
No representative data among adolescents in Mexico exist on the prevalence and risk factors for suicide ideation, plan, and attempt despite a recent increase in suicide deaths. Data are presented from the Mexican Adolescent Mental Health Survey, a representative household survey of 3,005 adolescents ages 12 to 17 in metropolitan Mexico City who were gathered in 2005, regarding lifetime prevalence and age-of-onset distributions of suicide ideation, plan, and attempt and demographic and psychiatric disorders risk factors. Lifetime ideation was reported by 11.5% of respondents, whereas 3.9% reported a lifetime plan and 3.1% a lifetime suicide attempt. Onset of suicidality started around age 10 and at age 15 showed the highest hazards. Suicide ideators were more likely to report a plan and attempt within the first year of onset of ideation. Suicidality was more likely to occur among females. The presence of one or more mental disorders was strongly related to suicide ideation, plan, and attempt. Among ideators only dysthymia was consistently related to a plan and attempt. The authors conclude that intervention efforts should focus on assessment and target adolescents with mental disorders, particularly mood disorders, to be effective in prevention. Borges, G., Benjet, C., Medina-Mora, M.E., Orozco, R., and Nock, M. J. Am. Acad. Child Adolesc. Psychiatry. 47(1), pp. 41-52, 2008.

Polymorphisms in Human Dopamine D2 Receptor Gene Affect Gene Expression, Splicing, and Neuronal Activity During Working Memory
INVEST Fellow: Danxin Wang (China, 1996-1997)
Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect of DRD2 variants remains ambiguous. The authors measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of the DRD2 locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studied DRD2 variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproduced in vitro by using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. These results identify regulatory DRD2 polymorphisms that modify mRNA expression and splicing and working memory pathways. Zhang, Y., Bertolino, A., Fazio, L., Blasi, G., Rampino, A., Romano, R., Lee, M.L., Xiao, T., Papp, A., Wang, D., and Sadee, W. Proc. Natl. Acad. Sci. U S A. 104(51), pp. 20552-20557, 2007.

The Metabotropic Glutamate Receptor 7 (mGluR(7)) Allosteric Agonist AMN082 Modulates Nucleus Accumbens GABA and Glutamate, but not Dopamine, in Rats
INVEST Fellow: Zhengxiong Xi (China, 1995-1996)
The group III metabotropic glutamate receptor 7 (mGluR(7)) has been implicated in many neurological and psychiatric diseases, including drug addiction. However, it is unclear whether and how mGluR(7) modulates nucleus accumbens (NAc) dopamine (DA), l-glutamate or gamma-aminobutyric acid (GABA), important neurotransmitters believed to be involved in such neuropsychiatric diseases. In the present study, the authors found that systemic or intra-NAc administration of the mGluR(7) allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose-dependently lowered NAc extracellular GABA and increased extracellular glutamate, but had no effect on extracellular DA levels. Such effects were blocked by (R,S)-alpha-methylserine-O-phosphate (MSOP), a group III mGluR antagonist. Intra-NAc perfusion of tetrodotoxin (TTX) blocked the AMN082-induced increases in glutamate, but failed to block the AMN082-induced reduction in GABA, suggesting vesicular glutamate and non-vesicular GABA origins for these effects. In addition, blockade of NAc GABA(B) receptors by 2-hydroxy-saclofen itself elevated NAc extracellular glutamate. Intra-NAc perfusion of 2-hydroxy-saclofen not only abolished the enhanced extracellular glutamate normally produced by AMN082, but also decreased extracellular glutamate in a TTX-resistant manner. The authors interpret these findings to suggest that the increase in glutamate is secondary to the decrease in GABA, which overcomes mGluR(7) activation-induced inhibition of non-vesicular glutamate release. In contrast to its modulatory effect on GABA and glutamate, the mGluR(7) receptor does not appear to modulate NAc DA release. Li, X., Gardner, E.L., and Xi, Z.X. Neuropharmacology. November 19, 2007, Epub ahead of print.

Effects of Gabapentin on Cocaine Self-Administration, Cocaine-Triggered Relapse and Cocaine-Enhanced Nucleus Accumbens Dopamine in Rats
INVEST Fellow: Zhengxiong Xi (China, 1995-1996)
Gabapentin is a gamma-aminobutyric acid (GABA) analogue, with GABAmimetic pharmacological properties. Gabapentin is used for the treatment of seizures, anxiety and neuropathic pain. It has been proposed that gabapentin may be useful in the treatment of cocaine dependence. However, clinical trials with gabapentin have shown conflicting results, while preclinical studies are sparse. In the present study, the authors investigated the effects of gabapentin on intravenous cocaine self-administration and cocaine-triggered reinstatement of drug-seeking behavior, as well as on cocaine-enhanced dopamine (DA) in the nucleus accumbens (NAc). They found that gabapentin (25-200mg/kg, i.p., 30min or 2h prior to cocaine) failed to inhibit intravenous cocaine (0.5mg/kg/infusion) self-administration under a fixed-ratio reinforcement schedule or cocaine-triggered reinstatement of cocaine-seeking behavior. In vivo microdialysis showed that the same doses of gabapentin produced a modest increase (approximately 50%, p<0.05) in extracellular NAc GABA levels, but failed to alter either basal or cocaine-enhanced NAc DA. These data suggest that gabapentin is a weak GABA-mimic drug. At the doses tested, it has no effect in the addiction-related animal behavioral models here tested. This is in striking contrast to positive findings in the same animal models shown by another GABAmimetic - gamma-vinyl GABA (see companion piece to present article). Peng, X.Q., Li, X., Li, J., Ramachandran, P.V., Gagare, P.D., Pratihar, D., Ashby, C.R. Jr., Gardner, E.L., and Xi, Z.X. Drug Alcohol Depend. December 5, 2007, Epub ahead of print.

Gamma-Vinyl GABA Inhibits Cocaine-Triggered Reinstatement of Drug-Seeking Behavior in Rats by a Non-Dopaminergic Mechanism
INVEST Fellow: Zhengxiong Xi (China, 1995-1996)
Relapse to drug use is a core feature of addiction. Previous studies demonstrate that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive drugs. The authors here report that systemic administration of GVG (25-300mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-seeking behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naive rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-seeking behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to GVG's action on the NAc. Peng, X.Q., Li, X., Gilbert, J.G., Pak, A.C., Ashby, C.R. Jr., Brodie, J.D., Dewey, S.L., Gardner, E.L., and Xi, Z.X. Drug Alcohol Depend. December 4, 2007, Epub ahead of print.

Incidence of Fatal Adverse Drug Reactions: A Population Based Study
INVEST Fellow: Henrik Druid (Sweden, 2000-2001)
Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden. The aim of this study was to determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population. Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001-31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centers and medicolegal files) were reviewed to identify suspected drug-related fatalities. Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal hemorrhages (n = 18; 37%), central nervous system hemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other hemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs. The authors conclude that the medical burden of FADRs is significant. Hemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs. Wester, K., Jnsson, A.K., Spigset, O., Druid, H., and Hgg, S. Br. J. Clin. Pharmacol. December 7, 2007, Epub ahead of print.

A Selective Nav1.8 Sodium Channel Blocker, A-803467, Attenuates Spinal Neuronal Activity in Neuropathic Rats
INVEST Fellow: Steven McGaraughty (Canada, 1995-1996)
The authors have recently reported that systemic delivery of A-803467, a selective Nav1.8 sodium channel blocker, reduces behavioral measures of chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and spinal nerve ligated (SNL) rats. Administration of A-803467 (10-30 mg/kg, i.v.) reduced mechanically evoked (10 g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg, i.v.) transiently reduced evoked, but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pre-treatment with the TRPV1 receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. In order to determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30-100 nmol/1 microl) or into the hind paw receptive field (300 nmol/50 microl) reduced evoked but not spontaneous WDR firing. In contrast, intra-spinal (50-150 nmol/ 0.5 microl) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Nav1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low threshold mechanical signals to spinal WDR neurons, but Nav1.8 sodium channels on central terminals appear to be key to the modulation of spontaneous firing in SNL rats. McGaraughty, S., Chu, K.L., Scanio, M.J., Kort, M.E., Faltynek, C.R., and Jarvis, M.F. J. Pharmacol. Exp. Ther. December 18, 2007, Epub ahead of print.

Pharmacological MRI in Awake Rats Predicts Selective Binding of Alpha(4)beta(2) Nicotinic Receptors
INVEST Fellow: Steven McGaraughty (Canada, 1995-1996)
Neuronal nicotinic receptors are the subject of intensive research focused on developing novel therapies for drug abuse, neurocognitive disorders, neurodegenerative diseases, and pain. In this study, the authors have applied pharmacological magnetic resonance imaging (phMRI) in awake rats to map functional brain responses to the selective alpha(4)beta(2) nicotinic receptor agonists, A-85380, and ABT-594. Moreover, they have validated their methods by comparison with autoradiography using [(3)H]-A-85380 and [(3)H]-ABT-594. Under awake conditions (no anesthesia during scanning) where rats were habituated to the imaging environment, both compounds increased regional cerebral blood volume (rCBV) across multiple brain regions that closely matched regional brain receptor distribution with the same tritiated compounds. In addition, regional ABT-594-induced rCBV changes under awake conditions were also derived and characterized using a pharmacological model. Area-under-curve and maximum rCBV changes in brain were found to be dose-related and region-specific, and corresponded well with the known preclinical behavioral profile of this drug. In contrast, under conditions of alpha-chloralose anesthesia where physiological variables were maintained within normal ranges, increases in rCBV induced by ABT-594 were primarily restricted to some cortical areas and did not agree well with autoradiography data. These data demonstrate the utility of using phMRI in awake animals to characterize selective pharmacological action but also highlight an important confound (anesthesia) that is rarely considered in preclinical phMRI studies. Synapse 62:159-168, 2008. (c) 2007 Wiley-Liss, Inc. Chin, C.L., Pauly, J.R., Surber, B.W., Skoubis, P.D., McGaraughty, S., Hradil, V.P., Luo, Y., Cox, B.F., and Fox, G.B. Synapse. 62(3), pp. 159-168, 2007, Epub ahead of print.

Role of Nociceptin/Orphanin FQ and the Pseudopeptide [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) and Their Interaction with Classic Opioids in the Modulation of Thermonociception in the Land Snail Helix Aspersa
INVEST Fellow: Silvia Cruz (Mexico, 1996-1997)
The role in nociception of nociceptin/orphanin FQ (N/OFQ) and its receptor, the opioid receptor-like 1 (NOP), remains unclear because this peptide has been implicated in both suppression and enhancement of nociception. The present work characterizes the effects of N/OFQ and the NOP receptor antagonist, the pseudopeptide [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) (Phe(1)Psi), on thermonociception in the snail Helix aspersa using the hot plate assay. Additionally, the possible interaction of each of these compounds with morphine or dynorphin A(1-17) and naloxone was studied. Compounds were administered into the hemocoel cavity of H. aspersa and the latency to the aversive withdrawal behavior recorded. Dose-response and time course curves were done. N/OFQ and naloxone produced a similar dose-dependent pronociceptive effect; however, N/OFQ reached its peak effect earlier and was 30 times more potent than naloxone. [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) and the opioid agonists, morphine and dynorphin A(1-17) produced antinociception with a similar efficacy, but [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) reached its peak effect more rapidly and lasted longer than that of dynorphin A(1-17) and morphine. [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) was 50 times less potent than dynorphin A(1-17), but 30 times more potent than morphine. N/OFQ significantly reduced morphine and dynorphin A(1-17)-induced antinociception. Combined administration of low doses of [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) and morphine or dynorphin A(1-17) produced a potent antinociceptive effect. Sub-effective doses of naloxone and N/OFQ also synergized to produce pronociception. Data suggest that these two opioid classes regulate nociception through parallel systems. The H. aspersa model appears as a valuable experimental preparation to continue the study of these opioid receptor systems. Miller-Perez, C., Sanchez-Islas, E., Pellicer, F., Rodriguez-Manzo, G., Cruz, S.L., and Leon-Olea, M. Eur. J. Pharmacol. November 28, 2007, Epub ahead of print.

Publications by Former NIDA Hubert H. Humphrey Drug Abuse Research Fellows

Comparing Serial and Nonserial Sexual Offenders: Alcohol and Street Drug Consumption, Impulsiveness and History of Sexual Abuse
HHH Fellow: Arthur Guerra de Andrade (Brazil, 1991-1992)
The objectivwe of this study was to evaluate the differences between serial and nonserial sexual offenders in terms of alcohol and drug consumption, impulsivity, and personal history of being sexually abused. A sectional and retrospective study was carried out by the team of the outpatient clinic for the treatment of sexual disorders at Faculdade de Medicina do ABC - Santo Andre, Brazil. Three groups of subjects (n = 198) consisting of sexual offenders against one victim, two victims and three or more victims were examined. Convicts sentenced only for sexual crimes were evaluated with the Drug Addiction Screening Test, the CAGE, the Short Alcohol Dependence Data, the Barratt Impulsiveness Scale, the Sexual Addiction Screening Test, and the Static-99. Sexual offenders against three or more victims showed more frequent history of being sexually abused than the sexual offenders against one victim. A one-way analysis of variance indicated that sexual offenders against three or more victims evidenced significantly higher scores on the Barratt Impulsiveness Scale and on the Sexual Addiction Screening Test than did the sexual aggressors against one victim. After a multinomial logistic regression analysis, the Barratt Impulsiveness Scale and the history of being sexually abused were predicting factors for the group of aggressors against three or more victims in relation to the aggressors against one victim. The authors conclude that sexual offenders against three or more victims present different characteristics from other groups of sexual offenders and these findings can help to create proposals for the management of this type of inmates. Baltieri, D.A., and Andrade, A.G. Rev. Bras. Psiquiatr. December 20, 2007, Epub ahead of print.

Urban Rural Differences in Prevalence of Self-Reported Diabetes in India-The WHO-ICMR Indian NCD Risk Factor Surveillance
HHH Fellow: Nimesh Desai (India, 1999-2000)
Recent reports show strikingly high prevalence of diabetes among urban Asian Indians; however, there are very few studies comparing urban, peri-urban and rural prevalence rates of diabetes and their risk factors at the national level. This study is a part of the national non-communicable diseases (NCD) risk factor surveillance conducted in different geographical locations (North, South, East, West/Central) in India between April 2003 and March 2005. A total of 44,523 individuals (age: 15-64 years) inclusive of 15,239 from urban, 15,760 from peri-urban/slum and 13,524 from rural areas were recruited. Major risk factors were studied using modified WHO STEPS approach. Diabetes was diagnosed based on self-reported diabetes diagnosed by a physician. The lowest prevalence of self-reported diabetes was recorded in rural (3.1%) followed by peri-urban/slum (3.2%) and the highest in urban areas (7.3%, odds ratio (OR) for urban areas: 2.48, 95% confidence interval (CI): 2.21-2.79, p<0.001). Urban residents with abdominal obesity and sedentary activity had the highest prevalence of self-reported diabetes (11.3%) while rural residents without abdominal obesity performing vigorous activity had the lowest prevalence (0.7%). In conclusion, this nation-wide NCD risk factor surveillance study shows that the prevalence of self-reported diabetes is higher in urban, intermediate in peri-urban and lowest in rural areas. Urban residence, abdominal obesity and physical inactivity are the risk factors associated with diabetes in this study. Mohan, V., Mathur, P., Deepa, R., Deepa, M., Shukla, D.K., Menon, G.R., Anand, K., Desai, N.G., Joshi, P.P., Mahanta, J., Thankappan, K.R., and Shah, B. Diabetes Res. Clin. Pract. January 29, 2008, Epub ahead of print.

Hypotension Caused by Therapeutic Doses of Venlafaxine: Case Report and Proposed Pathophysiological Mechanisms
HHH Fellow: Arthur Guerra de Andrade (Brazil, 1991-1992)
Although venlafaxine is usually associated with modest increases in blood pressure and not so often clinical hypertension, there are a few reported cases of hypotension related to overdoses of this specific antidepressant. The case study of a young female patient with a history of Major Depressive Disorder who initiated treatment with venlafaxine 75 mg/day and developed hypotension when the dosage was titrated up to 225 mg/day is described. The patient did not present comorbid diseases nor use other medication. A temporal association and a dose-dependent relationship between the hypotension and the use of venlafaxine is shown. To the best of the knowledge of the authors, this is the first case report that specifically associates regular doses of venlafaxine with the presence of hypotension. A pathophysiological mechanism is proposed, involving the participation of presynaptic alpha2-adrenergic receptors and the presence of a possible genetic polymorphism of cytochrome P4502D6, which is associated with lower drug metabolization, to explain the relationship between venlafaxine in regular dosage and development of hypotension. Alexandrino-Silva, C., Maua, F.H., De Andrade, A.G., and De Toledo Ferraz Alves, T.C. J. Psychopharmacol. January 21, 2008, Epub ahead of print.

Drugs and Fatal Traffic Accidents in the Czech Republic
HHH Fellow: Tomas Zabransky (Czech Republic, 2003-2004)
The aim of the study was to determine the prevalence of psychotropic drug use in active participants in traffic accidents who died during the accident or shortly after it due to injuries resulting from the accident. A special mortality register containing data of all forensic autopsies was analyzed. The studied sample consisted of persons who died during traffic accidents and were active participants in those ones (pedestrians, cyclists, or drivers), and were toxicologically tested during the forensic examination. The sample consisted of 1,213 cases, 1,039 (85.7%) males and 174 (14.3%) females who died in 2003-2005. Ethanol was found in 34.7% of cases, however a significant declining trend over the years was noted. The proportion of positive detections for any psychotropic drug other than alcohol was 7.2%; benzodiazepines were found most frequently (3.6%), followed by cannabis (2.2%), and stimulants (1.7% of the sample). Positive findings of ethanol were significantly more common among males, whereas positive benzodiazepine tests were more frequent in females. Positive cases were significantly younger than negative ones for ethanol, volatile substances, stimulants, and cannabis; in cases of positive medicaments tests, the positive cases were significantly older than the negatives. Mravci-k, V., Vorel, F., and Zabransky, T. Cent. Eur. J. Public Health. 15(4), pp. 158-162, 2007.

Stimulant Injectors in Ukraine: The Next Wave of the Epidemic?
HHH Fellow: Sergey Dvoryak (Ukraine, 1999-2000)
This study was designed to assess differences in drug and sex-related risk behaviors between injectors of opiates only, opiate/sedative mix only and stimulants only. Participants were current out-of-treatment injection drug users (IDUs), unaware of their HIV status, recruited through street outreach in Kiev, Odessa and Makeevka/Donetsk, Ukraine. Overall, 22% tested positive for HIV, including 39% among opiate/sedative injectors, 19% among opiate injectors and 17% among stimulant injectors. Despite these differences, stimulant injectors were at higher risk than other IDUs in sharing a used needle/syringe, always injecting with others, injecting a drug solution drawn from a common container, having an IDU sex partner, not using condoms during vaginal or anal sex and on composite measures of injection and sex risks. After controlling for age differences, stimulant injectors remained at higher risk in their needle and sex risk behaviors. The authors conclude that without intervention, it is likely that HIV will increase among stimulant injectors. Booth, R.E., Lehman, W.E., Kwiatkowski, C.F., Brewster, J.T., Sinitsyna, L., and Dvoryak, S. AIDS Behav. February 9, 2008, Epub ahead of print.

Socio-Cultural, Psychosexual and Biomedical Factors Associated with Genital Symptoms Experienced by Men in Rural India
HHH Fellow: Nimesh Desai (India, 1999-2000)
Biomedical, anthropological and psychiatric frameworks have been used to research different elements of men's sexual health - sexually transmitted infections, psychosexual concerns and psychological distress - but rarely within the same study. The authors combined these in a study in rural north India. In Tehri Garhwal and Agra districts, they explored male perceptions of genital and sexual symptoms through focus group discussions and then conducted a clinic-based survey of 366 symptomatic men who presented at rural private provider clinics. Men's urine specimens were tested for gonorrhea and chlamydia infection using polymerase chain reaction techniques. Researchers screened them for probable psychological distress by administering the General Health Questionnaire (12- items). Results revealed that local and traditional notions of health influenced men's symptom perceptions, with semen loss their predominant concern. Dhat, commonly perceived as an involuntary semen loss, corresponded most closely with the symptom of urethral discharge, but was attributed mainly to non-infectious causes. It could also manifest as a syndrome with physical weakness and mental lethargy. FGD participants lacked correct and complete information on reproductive health. Around 75% of the symptomatic men presented with dhat, but only 5.5% tested positive for gonorrhea or chlamydia. Application of syndromic sexually transmitted infection (STI) guidelines in these settings could result in over diagnosis and over treatment with antibiotics. In contrast, there was a significant association between dhat and probable psychological distress as detected by the GHQ (Adjusted OR, GHQ case positive: 2.66, 95% CI: 1.51-4.68). This study confirms the existence of a dhat syndrome in rural India, which is culturally influenced and reflects heightened psychosexual concerns as well as mental distress states. Comprehensive health services for men should include assessments of their psychosexual needs and be supported by reproductive/sexual health education. STI treatment guidelines for urethral symptoms should be revised and be based on epidemiological data. Gautham, M., Singh, R., Weiss, H., Brugha, R., Patel, V., Desai, N.G., Nandan, D., Kielmann, K., and Grosskurth, H. Trop. Med. Int. Health February 19, 2008, Epub ahead of print.

Methylphenidate DAT Binding in Adolescents with Attention-Deficit/ Hyperactivity Disorder Comorbid with Substance Use Disorder - a Single Photon Emission Computed Tomography with [Tc(99m)]TRODAT-1 Study
HHH Fellow: Flavio Pechansky (Brazil, 1993-1994)
Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent among adolescents with Substance Use Disorders (SUD). Effects of methylphenidate (MPH) on ADHD are attributed to its properties of blocking the dopamine transporter (DAT) in the striatum. However, it has been demonstrated that drug addiction is associated with dopaminergic system changes that may affect MPH brain effects, emphasizing the need to better understand MPH actions in subjects with ADHD+SUD. The objective of this study was to evaluate the effect of an extended release formulation of MPH (MPH-SODAS) on DAT availability in 17 stimulant-naive ADHD adolescents with comorbid SUD (cannabis and cocaine). Subjects underwent two single photon emission computed tomography (SPECT) scans with [Tc(99m)]TRODAT-1, at baseline and after 3 weeks on MPH-SODAS. Clinical assessment for ADHD relied on the Swanson, Nolan and Pelham Scale - version IV (SNAP-IV). Caudate and putamen DAT binding potential (BP) was calculated. After 3 weeks on MPH-SODAS, there was a significant reduction of SNAP-IV total scores (p<0.001), and approximately 52% reductions of DAT BP at the left and right caudate. Similar decreases were found at the left and right putamen (p<0.001 for all analyses). This study shows that the magnitude of DAT blockade induced by MPH in this population is similar to what is found in ADHD patients without SUD comorbidity, providing neurobiological support for trials with stimulants in adolescents with ADHD+SUD, an important population excluded from studies. Szobot, C.M., Shih, M.C., Schaefer, T., Junior, N., Hoexter, M.Q., Fu, Y.K., Pechansky, F., Bressan, R.A., and Rohde, L.A. Neuroimage. January 10, 2008, Epub ahead of print.

Schizophrenia Modifying the Expression of Gender Identity Disorder
HHH Fellow: Arthur Guerra de Andrade (Brazil, 1991-1992)
According to the Brazilian Federal Medical Association, transsexualism is recognized as a gender identity disorder if a long-term diagnostic therapeutic process has demonstrated that the transposition of gender roles is irreversible, and if only hormonal and surgical procedures are appropriate to relieve the stress associated with the gender identity. Although such treatment will only be initiated with caution and after a long phase of intense diagnostic screening, the differentiation between pure identity disorders and transsexual feelings secondary to an ongoing psychopathologic process, such as schizophrenia, can be arduous for many health professionals. The aim of this article was to report a case of a female patient with schizophrenia and transsexualism and the risks of a potential diagnostic confusion. A 19-year-old black woman, with an 8-year history of undifferentiated schizophrenia and intense gender dysphoria, was referred for sex reassignment surgery evaluation in the Ambulatory for the Treatment of Sexual Disorders of the ABC Medical School. After a more adequate antipsychotic treatment, her masculine behavior has persisted, but her desire to change her own genital organs has decreased. A better acceptance of the multiplicity of possible genders should neither contribute to inadequate interpretations of the signs and symptoms of our patients nor facilitate dangerous clinical or surgical recommendations. Baltieri, D.A., and De Andrade, A.G. J. Sex Med. December 7, 2007, Epub ahead of print.

Outcomes and Adherence in Syria's First Smoking Cessation Trial
HHH Fellow: Fadi Hammal (Syria, 2005-2006)
The objective of this study was to determine the feasibility of implementing cessation interventions in Syria. The authors randomized 50 smokers to either a brief or intensive behavioral cessation intervention. Adherence to treatment and cessation through 3 months postcessation were calculated. Adherence in the intensive group was only moderate and was associated with smoking for more years and higher self-efficacy. Cessation rates in the brief and intensive intervention groups were 16% and 4%, respectively. Nicotine dependence predicted abstinence at 3 months. Important barriers to cessation included perceived dependence, lack of access to pharmacotherapy, poor social support, and water pipe smoking. Asfar, T., Weg, M.V., Maziak, W., Hammal, F., Eissenberg, T., and Ward, K.D. Am. J. Health Behav. 32(2), pp. 146-156, 2008.

Tobacco Control in Developing Countries: Tanzania, Nepal, China, and Thailand as Examples
HHH Fellow: Stephen Nsimba (Tanzania, 2005-2006)
This paper illustrates case studies of four developing countries and compares them as to relative advancement in tobacco control as prescribed by the Framework Convention on Tobacco Control. Tobacco-control efforts first seem to involve assessment of tobacco use prevalence and passage of tobacco-control legislation (e.g., warning labels). Tanzania, Nepal, and China serve as examples. Eventually, an integrated tobacco-control stance that demonstrates several cycles of tobacco-control activities occurs, as is shown in Thailand. Through these case studies, one can achieve a sense of the direction of progress in tobacco control in developing countries. Sussman, S., Pokhrel, P., Black, D., Kohrman, M., Hamann, S., Vateesatokit, P., and Nsimba, S.E. Nicotine Tob. Res. 9 Suppl 3, pp. 447-457, 2007.

The Association between Disability and Residual Symptoms in Depressive Patients: A 3-Month Follow-Up
HHH Fellow: Berna Ulug (Turkey, 1995-1996)
In this 3-month naturalistic follow-up the authors aimed to investigate depression treatment outcome and the correlation between improvement of depressive symptoms and level of disability. The study included 104 patients with depression that presented to the Hacettepe Psychiatry Outpatient Clinic. The course was defined operationally using the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Structured Clinical Interview for DSM-IV Axis I Disorders. The World Health Organization Disability Assessment Schedule (WHO-DAS II) was administered to determine level of disability. Patients received follow-up assessments using the same instruments 3 months after receiving antidepressant treatment. Follow-up assessments showed that improvement in Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale total scores was statistically significant, and lower anxiety and depression ratings were correlated with lower disability levels. The patients that had severe depression and anxiety at the beginning of the course had residual depressive symptoms. The results showed that severity of depression was a predictor of residual symptoms in this cohort. Psychological anxiety was the most common residual symptom (consistent with other studies) and the patients with a psychological anxiety score >/= 2 had higher disability levels (Z = -3.570, P < 0.05). Severity of depression was a predictor of residual symptoms and partial remission after a depressive episode appeared to be strongly associated with disability. These findings highlight the importance of adequate treatment of depression. Ozyuksel, B., and Ulug, B. Turk. Psikiyatri. Derg.18(4), pp. 323-332, 2007 (Turkish).


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