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Director's Report to the National Advisory Council on Drug Abuse - September, 2004

Research Findings - Human Development and Clinical Neuroscience Research

Impact of Cannabis Use on Brain Function in Adolescents

Dr. Leslie Jacobsen and colleagues reported on a pilot study to determine the potential effect of cannabis exposure in adolescents. Seven adolescent marijuana users that also used tobacco, seven tobacco users with a minimal history of cannabis use, and seven non-smokers with no history of cannabis use were compared. Participants were tested on a number of assessments of attention and working memory while fMRI was used to assess hippocampal activation patterns, since both preclinical and clinical evidence suggests that cannabis modulates hippocampal function. Cannabis users were found to have significantly more errors on a continuous performance task, which tests sustained attention, than participants that did not use tobacco and had not used cannabis. Cannabis users also had more errors than tobacco users, although the difference did not reach statistical significance. The performance of cannabis users on the most difficult working memory task used (the 2-back task) was found to differ significantly from both the tobacco-using group and those individuals that used neither tobacco nor cannabis. Analysis across all tasks showed that, overall, cannabis users performed worse than the individuals in the other two groups and also differed in their hippocampal activation pattern from non-using adolescents. Although a pilot study with relatively few participants, the data from this investigation do suggest that adolescent use of cannabis may affect memory and attention and that these effects are reflected in neurobiological alterations. Jacobsen, L.K., Mencl, E.W., Westerveld, M. and Pugh, K.R., Annals of the New York Academy of Sciences. 1021, pp. 384-390, 2004.

Mapping Changes in the Human Cortex Throughout the Span of Life

Dr. Elizabeth Sowell and her colleagues recently published an article in which they described their findings on changes in the morphology of the human cerebral cortex as a function of age, using sophisticated, quantitative analyses of MRI images, and compared them with data from previous imaging and postmortem studies. Dr. Sowell's research group has developed a method of anatomical analysis that incorporates pattern matching, which provides an advance over other currently used morphometric techniques in that it can more reliably take into account individual differences in cortical anatomy. Their findings using these techniques demonstrate quantitatively the variation in patterns of development, maturation and aging in the many areas that make up the human cerebral cortex. These data can serve as the basis for defining relationships between brain morphology and cognitive changes over the human lifespan. Sowell, E.R., Thompson, P.M., and Toga, A.W., The Neuroscientist.10(4), pp. 372-392, 2004.

Acute No-Effect Dose for in Ova Exposure to C3F7 Tagged 5-Hydroxytryptophan, a Novel Probe for Investigating Neural Development

Many of the neurotransmitters that are known to be affected by exposure to abused drugs are present in the brain in quantities too small to be detected with magnetic resonance imaging methods. In an effort to increase the detectability of these transmitters, Dr. Sherry Dingman and colleagues have developed isomers of 5-hydroxytryptophan (5-HTP) tagged with multiple fluorine atoms that have the potential to be used in studies of the effects of drugs of abuse during development. Previous work by this group has demonstrated that the tagged molecules accumulate in the expected areas of the brain during chick development. In this most recent publication, this research team has demonstrated that the injection of up to 5 micrograms of the labeled compound, which results in the accumulation of 0.5 to 1.0 micrograms in the developing brain, does not cause any detectable deleterious effects. This lack of neurotoxicity for the modified transmitter precursor provides additional evidence supporting its potential utility in studies of the neurodevelopmental effects of abused drugs. Dingman, S., Hurlburt, R., and Branch, C. Molecular Imaging and Biology 6(1), pp. 12-16, 2004.

Assessing the Sensitivity of fMRI Group Maps

A significant problem in conducting functional magnetic resonance imaging studies is the variability in the strength of activation in any specific brain region among individuals. Typically, when group comparisons are made, the mean activation of one group is compared with that of the other. Dr. McNamee and colleagues have compared a number of statistical analysis methods to determine how much the activation pattern of any individual in a group affects the mean and, therefore, the conclusions from such studies. They have demonstrated that methods used for combining fMRI data for the performance of group comparisons involve compromises between sensitivity to changes in activation and the chance that individual differences in activation pattern will be detected. McNamee, R.L. and Lazar, N.A., NeuroImage. 22, pp. 920-931, 2004.

Relationship of Ethnicity, Gender, and Ambulatory Blood Pressure to Pain Sensitivity: Effects of Individualized Pain Rating Scales

There have been many reports that the sensation of pain is modulated by blood pressure, but no systematic studies had been performed to determine whether this phenomenon is consistent across genders and ethnicities. Dr. Susan Girdler and her colleagues have investigated this issue in a study of 135 African American and white men and women. Their findings confirm the inverse relationship between blood pressure and the perception of pain. They also found that, when using a standardized scale for pain assessment, both African American men and women reported higher levels of pain intensity than white men and women. However, they also found that this difference was not present when using a scale in which each participant ranked the descriptors, rather than using a standardized scale. Beyond confirming previous findings relating blood pressure to the perception of pain, the results of this investigation emphasize that demographic differences may need to be taken into account in clinical pain assessment and management. Campbell, T.S., Hughes, J.W, Girdler S.S., Maixner, W., and Sherwood, A. The Journal of Pain. 5(3), pp. 183-191, 2004.

Prenatal Marijuana Exposure and Academic Achievement at Age 10 Years

University of Pittsburgh researchers have reported their latest findings from a longitudinal cohort study of children exposed to marijuana in utero. In this study, women were interviewed about their substance use at the end of each trimester of pregnancy, and at multiple times during the child's development. The children were assessed on physical, emotional, and cognitive development at 8 and 18 months, and at 3, 6, 10, 14, and 16 years postpartum. This report provides findings on academic achievement at age 10 (606 children were assessed), using the Wide Range Achievement Test-Revised (WRAT-R), the reading comprehension subtext of the Peabody Individual Achievement Test-Revise (PIAT-R), and teacher reports of child performance in school. As a group, the women were of lower socioeconomic status, high-school-educated, light-to-moderate users of marijuana and alcohol, and equally distributed in terms of race/ethnicity (Caucasian and African-American). Exposure to one or more marijuana joints per day during the first trimester predicted deficits in WRAT-R reading and spelling scores, and a lower rating on the teachers' evaluations of the children's performance. These associations existed when home environment, race/ethnicity, socioeconomic status, and other prenatal substance exposure were controlled. However, these associations were mediated by effects of first-trimester marijuana exposure on the children's symptoms of depression and anxiety. Second-trimester marijuana use was associated with reading comprehension and underachievement. Exposure to alcohol during the first and second trimesters predicted poorer teacher ratings of overall school performance, whereas second-trimester binge drinking predicted lower reading scores. There was no interaction between prenatal marijuana and alcohol exposure. Each was an independent predictor of aspects of academic performance. The investigators compared their findings to those of the other cohort study of prenatal marijuana exposure reported in the literature, and they discussed possible reasons for differences in findings on school performance between the two studies. The investigators also discuss the limitations of the analyses and of the generalizability of the findings. Goldschmidt, L., Richardson, G.A., Cornelius, M.D., and Day, N.L. Prenatal Marijuana and Alcohol Exposure and Academic Achievement at Age 10. Neurotoxicology and Teratology, 26, pp. 521-532, 2004.

Cognitive Outcomes of Preschool Children with Prenatal Cocaine Exposure

Researchers at Case Western Reserve University report that 4-year-old children who were exposed to cocaine in utero scored significantly lower on some specific measures of intelligence than did children who were not exposed to the drug in utero. The two groups did not differ on overall, verbal, and performance IQ scores, although exposed children were less likely to have above-average overall IQ. The study results also suggest that mentally stimulating home environments may positively affect brain development and lessen prenatal effects of cocaine. At 4 years of age, 190 cocaine-exposed and 186 nonexposed children were assessed using the Wechsler Preschool and Primary Scales of Intelligence-Revised. This test revealed that exposed children had lower scores than nonexposed children in the specific areas of information, arithmetic, and object assembly (reflecting visual-spatial skills). In arithmetic skills, cocaine-exposed boys had lower scores than girls and nonexposed boys. The researchers also compared two groups within the cocaine-exposed children, i.e., 148 cocaine-exposed children living with their biological mothers or other relatives, and 42 cocaine-exposed children living in adoptive or foster care. They found that 25 percent of cocaine-exposed children living with their mothers or relatives had overall IQ scores lower than 70, compared with only 10 percent of cocaine-exposed children in adoptive or foster care. The researchers report that caregivers in the adoptive and foster homes were better educated, and had better vocabulary and intelligence test scores than the caregivers who were family members. Additional findings indicated that adoptive or foster care was associated with a lower rate of mental retardation in the cocaine-exposed children, despite the fact that these children had been exposed to twice as much cocaine while in utero, and that the cocaine-exposed children in the more stimulating environments had IQ scores that were similar to those of nonexposed children. The findings of this study are consistent with and expand on other preschool cocaine-exposure studies that show specific (but not global) IQ deficits. The results also emphasize how important it is to examine childrearing environments when assessing developmental progress of drug-exposed children, and they also provide optimism that interventions may be effective for children who are affected by prenatal cocaine exposure. Singer, L.T., Minnes, S., Short, E., et al. Cognitive Outcomes of Preschool Children with Prenatal Cocaine Exposure. JAMA, 291(20), pp. 2248-2456, 2004.

Developmental Outcomes of 2-Year Old Cocaine-Exposed Children Relative to their Childrearing Environments

Researchers conducting a longitudinal study in Atlanta with children exposed to cocaine in utero have reported on analyses that examine the role of caregiving environments for these children. The investigators note that the few previous studies examining whether type of care affects the development of exposed children have been inconsistent in their findings. The current analyses focused on cognitive and social-emotional outcomes of 2-year-old cocaine-exposed toddlers. Forty-nine of 83 cocaine-exposed children were reared in parental care, and 34 were reared in non-parental care (resulting from voluntary and involuntary relinquishment of care. Findings indicated that, in general in this sample, nonparental caregivers had more economic resources, experienced less psychological distress, and provided more stimulating and responsive home environments than did birth parents who continued to care for their cocaine-exposed children. The children in nonparental care performed better in several developmental domains. Also reported was the fact that within the group of nonparental caregivers, nonkin caregiving was different from kin caregiving, and was associated with different child outcomes. The investigators discuss the challenges and methodological limitations of doing these kinds of analyses (e.g., defining who is a primary caregiver in families where children are cared for by numerous adults in the course of a day or week is very difficult). They also point out that findings from these kinds of analyses, which are being reported in the literature with increasing frequency, underscore the importance of considering the specifics of the caregiving context when evaluating the potential developmental impact of prenatal cocaine exposure. Such analyses also should provide guidance for interventions to prevent or ameliorate negative developmental outcomes. Brown, J.V., Bakeman, R., Coles, C.D., Platzman, K.A., and Lynch, M.E. Prenatal Cocaine Exposure: A Comparison of 2-Year-Old Children in Parental and Nonparental Care. Child Development, 75(4), pp. 1282-1295, 2004.

Maternal Substance Use Patterns During Pregnancy and Infant Growth Parameters at Birth

Maternal cocaine use during pregnancy has been associated with decreased growth parameters in multiple previous studies. Women who use cocaine often use other substances as well (e.g., alcohol and tobacco, both of which have been shown to have effects on birth weight). A recent publication from the Maternal Lifestyle Study (MLS) reported on how patterns of cocaine, alcohol, tobacco, and marijuana use during pregnancy were related to infant birth weight, length, and head circumference in a sample of 651 mothers and their infants. Because cocaine use has been associated with preterm delivery, only term pregnancies were evaluated for this report. The MLS is a multisite longitudinal study of in utero drug exposure that is jointly funded by NICHD and NIDA. It is the largest study of its type. Histories of substance use were obtained for the 3-month period before pregnancy and the three trimesters of pregnancy. Patterns of use were categorized for each substance as consistently high, moderate, or low/none, and increasing or decreasing. The effects on growth parameters were analyzed in multivariate linear regression analyses, with adjustment for clinical site, maternal age, prepregnancy weight, multidrug use, and socioeconomic status. Detailed results of use patterns and growth parameters are reported in the publication. Overall, with adjustments made for confounders, including multi-drug use, patterns of tobacco use during pregnancy were associated with deficits in birth weight, length, and head circumference, whereas cocaine use was linked to deficits in birth weight and head size. In addition, birth weight, length, and head circumference were significantly greater among infants born to women who used no drugs compared to women with any cocaine, opiate, alcohol, tobacco, or marijuana use during pregnancy. The investigators emphasize that a clinical implication of the study is the importance of curtailing use during pregnancy of illicit drugs as well as alcohol and tobacco. Shankaran, S., Das, A., Bauer, C.R., et al. Association between Patterns of Maternal Substance Use and Infant Birth Weight, Length, and Head Circumference. Pediatrics, 114(2), pp. e226-e234, 2004.

Immune System Parameters and Clinical Morbidity in Infants Exposed to Drugs and HIV in Utero

Recently published data from the Women and Infants Transmission Study (WITS) reported on associations between maternal drug use during pregnancy and lymphocyte subsets and clinical morbidity in uninfected infants born to HIV-infected mothers. WITS is a multi-site longitudinal study of the health of HIV-infected mothers and their children, as well as mother-to-child HIV transmission. It is jointly supported by NIAID, NICHD, and NIDA. The outcomes of HIV-exposed but uninfected infants is a major focus within WITS. The current report presents findings for infants through 2 years of age. The definition of drug use during pregnancy included use of cocaine, methadone, heroin, and other opiates. History of illness and clinical findings were recorded using standardized collection instruments for medical history and medical chart abstraction. Measurement of immune system parameters (CD4, CD8, CD19, NK cell lymphocyte percentage and absolute numbers) utilized standard laboratory procedures. A total of 401 of the 1436 uninfected infants were born to drug-using mothers. Infants born to drug-using mothers had lower gestational age and birth weight, and lower CD4 lymphocyte percentage over the first 4 months of life after adjusting for covariates and higher natural killer lymphocyte percentage. The clinical significance of the lower CD4 percentage and higher NK cell level remain unclear. The investigators suggest that future studies evaluating immunologic parameters in HIV-exposed but uninfected infants should control for the effect of drug exposure. They also indicate that additional research that includes functional assays of lymphocyte cell populations is needed in order to evaluate effects of drug exposure on immune function in addition to phenotype, whether such effects are transient or persist over time, and whether there is any clinical significance of such findings. Neu, N., Leighty, R., Adeniyi-Jones, S., et al. Immune Parameters and Morbidity in Hard Drug and Human Immunodeficiency Virus-Exposed but Uninfected Infants. Pediatrics, 113(5), pp. 1260-1266, 2004.

Nicotine Effects on Brain Function and Functional Connectivity in Schizophrenia

Dr. Leslie Jacobsen and colleagues at Yale School of Medicine used functional magnetic resonance imaging (fMRI) to determine whether nicotine had a differential effect on cognitive performance and regional brain activation in schizophrenic patients compared to smokers with no mental illness. Since nicotine in tobacco smoke can improve functioning in multiple cognitive domains, high rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Thirteen smokers with schizophrenia and 13 smokers with no mental illness were withdrawn from tobacco and underwent functional magnetic resonance imaging (fMRI) scanning after placement of a placebo patch and again after placement of a nicotine patch. During scanning, subjects performed an n-back task with two levels of working memory load and of selective attention load. Nicotine improved performance of schizophrenic subjects and worsened performance of control subjects during the most difficult (dichotic 2-back) task condition. Nicotine also enhanced activation of a network of regions, including anterior cingulate cortex and bilateral thalamus, and modulated thalamocortical, functional connectivity to a greater degree in schizophrenic than in control subjects during dichotic 2-back task performance. This study demonstrates that in tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance. Jacobsen, L.K., D'Souza, D.C., Mencl, W.E., Pugh, K.R., Skudlarski, P. and Krystal, J.H. Biological Psychiatry, 55(8), pp. 850-858, 2004.

Retrospective Study: Influence of Menstrual Cycle on Cue-Induced Cigarette Craving

Dr. Theresa Franklin and colleagues at the University of Pennsylvania investigated whether menstrual cycle phase contributes to some of the sex differences observed in smokers. Since smoking in females is posited to be influenced more by cues whereas male smoking is influenced predominantly by the direct pharmacological actions of nicotine in the brain, this study tested the hypothesis that females may report more intense craving to smoking cue exposure than males and, further, that female craving scores may be influenced by menstrual cycle phase. The study sample consisted of 69 male and 41 female treatment-seeking subjects who smoked more than 15 cigarettes per day for more than 10 years. Self-report measures were collected from subjects prior to and immediately following exposure to visual smoking stimuli. Females were grouped according to cycle phase. Of the female subjects, 17 were classified as follicular phase females (FFemales) and 24 were classified as luteal phase females (LFemales). Contrary to our hypothesis, overall, males and all females did not differ in their level of cue-induced craving. However, when females were separated into groups by cycle phase, FFemales reported significantly less craving than either males or LFemales (p <.05). The suppressed craving response in FFemales suggests an influence of cycle phase on cue-induced craving. These results suggest that menstrual cycle phase needs to be incorporated in the development of treatments for nicotine addiction. Franklin, T.R., Napier, K., Ehrman, R., Gariti, P., O'Brien, C.P. and Childress, A.R. Nicotine & Tobacco Research, 6(1), pp. 171-175, 2004.

Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

Dr. Diana Martinez and colleagues at Columbia University used PET imaging to assess D2 receptor availability with [11C]raclopride in the subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced equally in the limbic striatum, associative striatum, and sensorimotor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). This study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-seeking behavior. Martinez, M., Broft, A., Foltin, R.W., Slifstein, M., Hwang, D-H., Huang, Y., Perez, A., Frankel, W.G., Cooper, T., Kleber, H.D., Fischman, M.W. and Laruelle, M. Neuropsychopharmacology, 29, pp. 1190-1202, 2004.

The Neural Correlates of Cue-Induced Craving in Cocaine-Dependent Women

Dr. Clinton Kilts and colleagues at Emory University School of Medicine used [O-15]HO positron emission tomography (PET) imaging to determine if there are gender-related differences in the neural correlates of cocaine craving. Changes in regional cerebral blood flow to imagery depicting cocaine use and neutral imagery were examined in 8 cocaine-dependent women and a matched group of eight cocaine-dependent men. Compared with the results in cocaine-dependent men, conditioned cocaine craving in women was associated with less activation of the amygdala, insula, orbitofrontal cortex, and ventral cingulate cortex and greater activation of the central sulcus and widely distributed frontal cortical areas. These findings suggest the presence of sex differences in the functional anatomy of cue-induced cocaine craving associated with drug dependence and may underlie apparent sex differences in the effects of cocaine abstinence and the expectations of treatment outcome. Some support for the need for sex-specific strategies for treatment of cocaine dependence is also furnished by the findings of this study. Kilts, C.D., Gross R.E., Ely T.D. and Drexler, K.P.G. American Journal of Psychiatry, 161(2), pp. 233-241, 2004.

Human Striatal Responses to Monetary Reward Depend on Saliency

Dr. Gregory Berns and colleagues at Emory University School of Medicine used functional Magnetic Resonance Imaging to determine how monetary rewards are processed in the striatum in normal human subjects. Skin Conductance responses to a monetary reward were maximal when its receipt depended on a correct response (active) and minimal when its receipt was completely independent of the task (passive). Significant caudate and nucleus accumbens activations occurred following the active compared to passive money delivery. Such activations were attributed to saliency (response-contingency) of the monetary reward rather than the motor requirement associated with the active money because striatal activations were not observed when the money was replaced by inconsequential, non-monetary visual stimuli. The present study provides evidence that the striatum's role in reward processing is dependent on the saliency associated with reward, rather than value or hedonic feelings per se. Zink, C.F., Pagnoni, G., Martin-Skurski, M., Chappelow, J.C. and Berns, G.S. Neuron, 42(3), pp. 509-517, 2004.

Functional Subdivisions within Anterior Cingulate Cortex and their Relationship to Autonomic Nervous System Function

Dr. Martin Paulus and colleagues at the University of California, San Diego used functional Magnetic Resonance Imaging to investigate the functions of subdivisions of the anterior cingulate cortex (ACC) in normal healthy subjects. Subjects performed a counting Stroop task with trial every 2.0 s in one run and every 1.5 s in the other. A cluster of activation related to response inhibition was observed in the left dorsal ACC, whereas a cluster of activation was observed in the left ventral ACC related to the interaction of speed with stimulus congruency. The activation in the ventral ACC correlated significantly with an index of parasympathetic modulation of heart rate. This study demonstrates functional subdivisions within the ACC and links the processes of cognitive interference and parasympathetic modulation with activation in specific subregions of the ACC, a structure that has been repeatedly implicated in substance abuse. Matthews, S.C., Paulus, M.P., Simmons, A.N., Nelesen R.A. and Dimsdale, J.E. Neuroimage, 22(3), pp. 1151-1156, 2004.

Effects of Integrated Simon and Spatial Stroop on Attentional Control

Using event-related fMRI, investigators from the University of Colorado examined the neural mechanisms of attentional control involved in the Simon task (interference people experience when there is a stimulus-response conflict) as compared to a spatial Stroop task (interference people experience when two attributes of the same stimulus conflict with each other). These tasks activated the dorsolateral prefrontal cortex and posterior regions that serve as a source of attentional control. There were also specific brain regions activated to a significantly greater degree by one task and/or only by a single task. The brain regions significantly more activated by the Simon task were those sensitive to detection of response conflict, response selection, and planning (Anterior Cingulate cortex, supplementary motor areas and precuneus), and visuospatial-motor association areas. In contrast, the regions significantly more activated by the Stroop task were those involved in biasing the processing toward the task-relevant attribute (inferior parietal cortex). These findings suggest that the interference effects of these two tasks are caused by different types of conflict but both invoke similar sources of top-down modulation. Liu, X., Banich, M.T., Jacobson, B.L. and Tanabe, J.L. Neuroimage, 22(3), pp. 1097-1106, July 2004.

Structural Abnormalities in the Brains of Human Subjects Who Use Methamphetamine

Using high-resolution magnetic resonance imaging (MRI) and new computational brain-mapping techniques, UCLA researchers were able to visualize, for the first time, the profile of structural deficits in the human brain associated with chronic methamphetamine (MA) abuse. ROI's included the cortex, hippocampus, white matter, and ventricles. MA abusers and age-matched controls were evaluated. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of MA abusers (averaging 11.3% below control). On average, MA abusers had 7.8% smaller hippocampal volumes than control subjects and significant white matter hypertrophy. Hippocampal deficits were mapped and correlated with memory performance on a word-recall test. Findings suggested that chronic MA abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. MA may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex thereby inducing neuroadaptation, neuropil reduction, or cell death. Thompson, P.M., Hayashi, K.M., Simon, S.L., Geaga, J.A., Hong, M.S., Sui, Y., Lee, J.Y., Toga, A.W., Ling, W. and London, E.D. Journal of Neuroscience, 30, pp. 6028-6036, 2004.

Smoking-Induced Ventral Striatum Dopamine Release

To test if dopamine (DA) release in the ventral striatum underlies the reinforcing properties of nicotine, UCLA researchers used [(11)C]raclopride bolus-plus-continuous-infusion positron emission tomography (PET) to determine smoking-induced ventral striatum DA release in humans. Dependent smokers underwent PET scan with bolus plus continuous infusions. During the session, subjects had a 10-minute break outside the PET apparatus during which half (n=10) smoked a cigarette and the other half did not. The group that smoked had greater reductions in [(11)C]raclopride binding potential in ventral striatum ROI than the group that did not smoke, particularly in the left ventral caudate/nucleus accumbens and left ventral putamen. Significant correlations were found between pre-post smoking break in craving ratings and change from pre-post in binding potential for these two regions. Nicotine-dependent subjects who smoked during a break in PET scanning had greater reductions in [(11)C]raclopride binding potential (an indirect measure of dopamine release) than nicotine-dependent subjects who did not smoke. The magnitude of binding potential changes was comparable to that found in studies that used similar methods to examine the effects of other addictive drugs. Brody, A.L., Olmstead, R.E., London, E.D., Farahi, J., Meyer, J.H., Grossman, P., Lee, G.S., Huang, J., Hahn, E.L. and Mandelkern, MA. American Journal of Psychiatry, 61(7), pp. 1211-1218, 2004.

Effects of Bupropion on Attenuation of Cue-Induced Cigarette Craving and Anterior Cingulate Cortex Activation

In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion hydrochloride reduces overall craving in dependent smokers, Drs. Brody, London and colleagues at UCLA conducted a preliminary study to determine if treatment with bupropion hydrochloride attenuated cue-induced cigarette craving and associated brain metabolic activation. Healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion hydrochloride) underwent two PET scanning sessions in randomized order--one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion hydrochloride diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion hydrochloride, including its enhancement of catecholaminergic neurotransmission. Brody, A.L., Mandelkern, M.A., Lee, G., Smith, E., Sadeghi, M., Saxena, S., Jarvik, M.E. and London, E. Psychiatry Research: Neuroimaging, 130(3), pp. 269-281, 2004.

Partial Recovery of Brain Metabolism in Methamphetamine Abusers after Protracted Abstinence

Researchers at Brookhaven assessed whether brain metabolism recovers with protracted abstinence following methamphetamine (MA) abuse. Brain glucose metabolism was measured in five MA abusers with PET and [18F]fluorodeoxyglucose. They were evaluated after both a short (<6 months) and protracted (12-17 months) abstinence interval. Eight abusers were tested only after protracted abstinence, and their data was compared to 11 subjects who were not drug users. Significantly greater thalamic, but not striatal, metabolism was seen following protracted abstinence relative to metabolism assessed after a short abstinence interval, and this increase was associated with improved performance in motor and verbal memory tests. Relative to the comparison subjects, the MA abusers tested after protracted abstinence had lower metabolism in the striatum (most accentuated in the caudate and nucleus accumbens) but not in the thalamus. The researchers conclude that persistent decreases in striatal metabolism in MA abusers could reflect long-lasting changes in dopamine cell activity, and decreases in the nucleus accumbens could account for the persistence of amotivation and anhedonia in detoxified MA abusers. The recovery of thalamic metabolism could reflect adaptation responses to compensate for the dopamine deficits, and the associated improvement in neuropsychological performance further indicates its functional significance. These results suggest that while protracted abstinence may reverse some of the drug-induced alterations in brain function, other deficits persist. Wang, G.J., Volkow, N.D., Chang, L., Miller, E., Sedler, M., Hitzemann, R., Zhu, W., Logan, J., Ma, Y. and Fowler, J.S. American Journal of Psychiatry, 161(2), pp. 42-48, 2004.

Antiretroviral Treatment Alters Relationship Between MCP-1 and Neurometabolites in HIV Patients

Prior studies found higher CSF MCP-1 levels in patients with HIV-associated dementia compared to those in neuroasymptomatic patients. Linda Chang and her colleagues hypothesized that CSF MCP-1 levels might correlate inversely to neuronal metabolites. The relationships between neurometabolites and macrophage chemoattractant protein (MCP-1) in serum and cerebrospinal fluid (CSF) were evaluated in HIV patients before and after antiretroviral treatment. Thirty-nine antiretroviral-naive HIV patients were evaluated prospectively with proton magnetic resonance spectroscopy (1H MRS), and serum and CSF MCP-1 measurements prior to highly active antiretroviral therapy (HAART); 31 of these patients completed follow-up studies after 3 months of HAART but only 24 had follow-up CSF studies. After HAART, brain metabolites and clinical signs showed no change despite improvements in systemic and CSF variables. CSF, but not serum, MCP-1 levels correlated inversely with the neuronal component (from PCA) prior to treatment. Conversely, after 3 months of HAART, the glial component (from PCA) correlated positively with CSF MCP-1 levels. These findings suggest that higher CSF MCP-1 levels are associated with neuronal dysfunction in untreated patients. Chang, L., Ernst, T., St. Hillaire, C. and Conant, K. Antiviral Therapy, 9(3), pp. 431-440, 2004.

Exposure to Appetitive Food Stimuli Markedly Activates the Human Brain

The increased incidence of obesity in our society demands more study, in general, and interactions between the environment and metabolism. Researchers at the Brookhaven National Laboratories assessed the response of the human brain to the presentation of appetitive food stimuli during food presentation using PET and FDG. Metabolic changes in response to food presentation were examined in 12 healthy normal body weight subjects who were food deprived before the study. Food presentation significantly increased metabolism in the whole brain, and these changes were largest in superior temporal, anterior insula, and orbitofrontal cortices. The increases in the right orbitofrontal cortex were the ones that correlated significantly with the increases in self-reports of hunger and desire for food. The marked increase in brain metabolism by the presentation of food provides evidence of the high sensitivity of the human brain to food stimuli. This high sensitivity coupled with the ubiquitousness of food stimuli in the environment is likely to contribute to the epidemic of obesity. In particular, the activation of the right orbitofrontal cortex, a brain region involved with drive, may underlie the motivation to procure food, which may be subjectively experienced as "desire for food" and "hunger" when exposed to food stimuli. Wang, G.J., Volkow, N.D., Telang, F., Jayne, M., Ma, J., Rao, M., Zhu, W., Wong, C.T., Pappas, N.R., Geliebter, A. and Fowler, J.S. Neuroimage, 21(4), pp. 790-797, 2004.

Cerebral Reserve Capacity: Implications for Alcohol and Drug Abuse

This review article discusses cerebral reserve capacity (or functional reserve), which refers to the brain's ability to maintain function when confronted by degenerative processes. There is accumulating evidence that the magnitude of reserve capacity is important in determining the onset and progression of the clinical manifestations of neurodegenerative brain diseases. The concept of cerebral functional reserve has important implications for alcohol and drug abuse morbidity. First, given the high genetic contribution to substance abuse, there is an increased likelihood that the parents of substance abusers were substance abusers themselves. Substance abuse during pregnancy can inhibit brain growth, resulting in reduced brain size and reduced reserve capacity (and therefore less ability to compensate for loss of function later in life). Second, substance abuse is often coupled with poverty, and both substance abuse and poverty are associated with some of the same conditions that reduce brain growth. The authors comment on the most important public health implications of the cerebral reserve capacity model for drug and alcohol addiction. Fein, G. and Di Sclafani, V. Alcohol, 32(1), pp. 63-67, 2004.

The Effects of Controlled Deep Breathing on Smoking Withdrawal Symptoms in Dependent Smokers

This study was designed to assess the effect of controlled deep breathing on smoking withdrawal symptoms. In two laboratory sessions, dependent smokers refrained from smoking for 4 h. During a deep breathing session, participants were instructed to take a series of deep breaths every 30 min. During a control session, participants sat quietly. Controlled deep breathing significantly reduced smoking withdrawal symptoms, including craving for cigarettes and negative affect (tense, irritable), while resulting in the maintenance of baseline arousal (wide awake, able to concentrate) levels. Furthermore, a history of heavy smoking was associated with greater increases in arousal during the deep breathing session. The results of this preliminary study suggest that controlled deep breathing may be useful for relieving symptoms of smoking withdrawal. McClernon, F.J., Westman, E.C. and Rose, J.E. Addictive Behaviors, 29(4), pp. 765-772, 2004.

A Mu-Opioid Polymorphism Conferred Substantial Attributable Risk to Heroin Addiction in a Homogeneous Population Sample

Dr. Kreek and associates studied a Swedish sample including a subsample in which participants identified themselves and both parents as Swedish descent and found presence of the G allele in the A118G polymorphism in exon 1 of the OPRM1 gene conferred an odds ration of 2.3 in the total sample and 2.7 in the only-Swedish sample. This was associated with an attributable risk (estimated proportion of cases in the population who are affected due to the given at-risk genotype) of 18.0. Since, this association has not been found previously in Caucasian populations, it is suggested that the reason may be the diversity of the allele frequencies across different samples within the "Caucasian" category. It was shown by this group that encoded receptors in those who have the A118G allele have increased affinity for the endogenous mu-opioid ligand, beta-endorphin, and increased activation of G protein-activated inwardly rectifying potassium channels following binding by beta-endorphin. Bart, G., Heilig, M., LaForge, K.S., Pollak, L., Leal, S.M., Ott, J. and Kreek, M.J., Molecular Psychiatry, advance online publication (23 March 2004); doi:10.1038/

Prevalence of Drug Use and Duration of Problematic Use is Greater in Men Than Women, but Severity and Age of Onset Seems to be Equal

Among the many analyses conducted by Dr. Iacono and colleagues among families of the Minnesota Twin-Family Study, an assessment of twins' parents revealed that despite the greater prevalence of drug use among men, dependence symptoms and drug-associated difficulties were not different from those of women. Two exceptions were hallucinogens where there was no difference in duration of use but there was an earlier onset in women, and amphetamines where women had more frequent use of them. The latter may be related to eating disorders since more women with amphetamine abuse were anorexic. Also, the differences and similarities observed could not be attributed to age differences in the cohorts, assertive mating (marrying with individuals with like profiles), or ability to report symptoms. These data provide insight into characteristics of drug use between men and women. Holdcraft, L.C. and Iacono, W.G. Drug and Alcohol Dependence, 74, pp. 147-158, 2004.

Suggestive Links on Chromosomes 9 and 11 for Increased Risk for Cigarette Smoking

Dr. Gelernter and colleagues at Yale University performed a genome-wide scan in affected individuals and their families identified through an anxiety clinic and defined on the basis of cigarettes smoked—more than a pack/day for one year or _ pack/day for 10 years. Linkage was observed near markers, D11S4046, D9S283 and D9S1677. The marker on chromosome 11 is in a region where linkage to alcohol dependence and linkage disequilibrium to substance dependence has been reported previously. The chromosome 9 region has been previously linked to panic disorder. There was also support for linkage on chromosomes 14, 16, and X. Confirmation with additional studies of finer mapping need to be done, but it is of interest that the chromosome 11 region contains potential candidate genes including brain-derived neurotrophic factor (BDNF), the DRD4 locus, the TPH locus and the tyrosine hydroxylase locus. Gelernter, J., Liu, X., Hesselbrock, V., Page, G.P., Goddard, A. and Zhang, H. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 128B, pp. 94-101, 2004.

Homozygous DRD2-Taq A2/A2 Individuals in Bupropion Therapy Have Reduced Symptoms of Nicotine Withdrawal

Dr. David and colleagues at Brown University randomly assigned 30 smokers to bupropion hydrochloride or placebo. They were assessed before medication and 14 days afterward on a withdrawal scale. It was found that, as a group, those on bupropion therapy had fewer symptoms of craving, irritability, and anxiety than those on placebo, but subsequent analysis showed that this result was due to those with the homozygous A2A2 allele. This suggests that bupropion attenuates specific symptoms of the nicotine withdrawal syndrome and that this effect may be modified by genotype for the dopamine D2 receptor. David, S.P., Niaura, R., Papandonatos, G.D., Shadel, W.G., Burkholder, G.J., Britt, D.M., Day, A., Stumpff, J., Hutchison, K., Murphy, M., Johnstone, E., Griffiths, D.E. and Walton, R.T. Nicotine and Tobacco Research, 5(6), pp. 935-942, 2003.

Additive Increase in Impulsivity in Bipolar Patients with Substance Abuse

Dr. Moeller and colleagues investigated whether impulsivity was linked to bipolar disorder and substance abuse thereby suggesting a reason for poor outcome in treatment. Trait questionnaire (Barratt Impulsiveness Scale) as well as laboratory performance measures (Immediate/Delayed Memory task) were administered to inpatients with bipolar disorder who were also interviewed for substance abuse. While trait impulsiveness was increased in patients with either substance abuse or bipolar disorder, there was an even greater increase in those with both disorders after correcting for age. Performance impulsivity was increased in those with substance abuse regardless of whether they had bipolar disorder. Among subjects with bipolar disorder, after correction for age, impulsivity scores were increased in those with substance abuse. Performance impulsivity was increased in bipolar patients without substance abuse during a manic episode or it was increased in bipolar patients with substance abuse between episodes. These results suggest that bipolar patients with a history of substance abuse may be more refractory to treatment because of a complicating underlying (additional) pathology. Swann, A.C., Doughtery, D.M., Pazzaglia, P.J., Pham, M., and Moeller, F.G. Bipolar Disorder, 6, pp. 204-212, 2004.


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