Association between the Intron 8 VNTR Polymorphism of the DAT1 Gene and Crack Cocaine Addiction.

BACKGROUND: This study aims to compare allele and genotype frequencies of a 30-bp variable number of tandem repeats (VNTR) polymorphism of the DAT1 gene, located at intron 8, between adult crack cocaine users and nonaddicted individuals. Due to its involvement in drug addiction, this gene is a good candidate for molecular studies. METHODS: A cross-sectional sample of 239 current adult crack abusers or dependents from in- and outpatient clinics and 211 control individuals was collected in Brazil. They were evaluated using ASRS, ASI-6, WAIS-III, and MINI assessments. DNA samples extracted from whole blood were genotyped for the intron 8 VNTR in DAT1. RESULTS: Logistic regression analysis was performed and controlled for gender, age, ethnicity, educational level, and comorbidities of clinical interest (generalized anxiety disorder, suicide risk, major depressive episode, and attention deficit/hyperactivity disorder). This analysis showed that the 6R6R genotype was associated with crack cocaine addiction (OR = 1.844; CI = 1.101-3.089; p = 0.020). CONCLUSIONS: Our results are consistent with the role of DAT1 in the neurobiology of drug addiction. Nevertheless, the study of other genes, environmental factors, and their interactions is also important to gain a broader understanding of this condition.

Crack cocaine users show differences in genotype frequencies of the 3' UTR variable number of tandem repeats of the dopamine transporter gene (DAT1/SLC6A3).

BACKGROUND: Due to the mechanism of action of the dopamine transporter (DAT) in drug addiction, the DAT1 gene is a potential candidate for molecular studies. This paper aims to compare the prevalence of allele and genotype frequencies created by the 3' UTR variable number of tandem repeats (VNTR) of this gene between crack cocaine users and controls. METHODS: A cross-sectional sample of 237 current adult crack cocaine abusers or dependents (DSM-IV TR criteria) from in- and outpatient clinics in southern Brazil and 205 community controls were compared. The subjects were evaluated using the Adult ADHD Self-Report Scale, the Mini-International Neuropsychiatric Interview - short version, and the Wechsler Intelligence Scale. DNA samples were genotyped for the DAT1 3' VNTR. RESULTS: Logistic regression analysis was performed to compare the frequency of the 10.10 genotype (the putative risk genotype) to those of other genotypes. A significant difference (p = 0.04, OR = 1.758, CI = 1.026-3.012) indicating an increased frequency of the 10.10 genotype in the cases (59.9%) compared to the controls (49.3%) was verified using clinical and demographic covariates. CONCLUSIONS: This is one of the first genetic association studies on crack cocaine users in the literature. The results suggest an influence of the DAT1 gene, namely the 3' VNTR 10.10 genotype. However, more analyses will confirm and clarify its contribution as a possible risk factor for crack cocaine dependence.

Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs. METHODS: Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype. RESULTS: The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56). CONCLUSIONS: In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response.

Oxytocin Receptor Exon III Methylation in the Umbilical Cord Blood of Newborns With Prenatal Exposure to Crack Cocaine.

BACKGROUND: Prenatal cocaine exposure (PCE) is associated with behavioral, cognitive, and social consequences in children that might persist into later development. However, there are still few data concerning epigenetic mechanisms associated with the effects of gestational cocaine exposure, particularly in human newborns. AIMS: We investigated the effects of PCE on DNA methylation patterns of the Oxytocin Receptor (OXTR) gene in the umbilical cord blood (UCB). The relationship between UCB DNA methylation levels and the severity of the mother's cocaine use during pregnancy was also evaluated. METHODS: In this cross-sectional study, 28 UCB samples of newborns with a history of crack cocaine exposure in utero and 30 UCB samples of non-exposed newborns (NEC) were compared for DNA methylation levels at two genomic loci located in exon III of the OXTR gene (OXTR1 and OXTR2) through pyrosequencing. Maternal psychopathology was investigated using the Mini International Neuropsychiatric Interview, and substance use characteristics and addiction severity were assessed using the Smoking and Substance Involvement Screening Test (ASSIST). RESULTS: No differences between newborns with a history of PCE and NEC were observed in OXTR1 or OXTR2 DNA methylation levels. However, regression analyses showed that maternal addiction severity for crack cocaine use predicted OXTR1 DNA methylation in newborns. CONCLUSION: These data suggest that OXTR methylation levels in the UCB of children are affected by the severity of maternal crack cocaine usage. Larger studies are likely to detect specific changes in DNA methylation relevant to the consequences of PCE.

Attention deficit hyperactivity disorder and substance use disorders.

Attention deficit hperactivity disorder (ADHD) is highly prevalent among adolescents who have substance use disorder (SUD). Several lines of evidence, although not conclusive, suggest that ADHD might have an independent effect on SUD liability. It is still to be determined, however, whether this association is mediated by conduct disorder. This article reviews ADHD and SUD.

Is attention-deficit/hyperactivity disorder associated with illicit substance use disorders in male adolescents? A community-based case-control study.

AIMS: This study aims at evaluating the association between attention-deficit/hyperactivity disorder (ADHD) and illicit substance use disorders (SUD) (marijuana, cocaine and inhalants), controlling for the association with conduct disorder (CD), in a community-based sample of adolescents. DESIGN: Case-control, community-based study. SETTING: A delimited geographical area in the South of Brazil, served by four public health clinics. PARTICIPANTS: A total of 968 male adolescents (15-20 years of age) were screened for SUD in their households. Of the subjects who were screened positive, we selected 61 cases with illicit SUD. For each case we selected, from the group which was screened negative, three controls without illicit or alcohol SUD, matched by age and proximity with the case's household. MEASUREMENTS: The screening instrument was the Alcohol Smoking and Substance Screening Test (ASSIST). SUD diagnoses were assessed by the drug section of the Mini International Neuropsychiatry Interview (MINI). Other psychiatric diagnoses were based on semistructured (Schedule for Affective Disorders and Schizophrenia for School-Age Children-epidemiological version; MINI) and clinical interviews. FINDINGS: Adolescents with ADHD presented a significantly higher odds ratio (OR) for illicit SUD than youths without ADHD, even after adjusting for potential confounders (CD, ethnicity, religion and estimated IQ) (OR = 9.12; 95% CI = 2.84-29.31, P < 0.01). CONCLUSIONS: Our results suggest an association between ADHD and illicit SUD in Brazilian adolescents that is not mediated by CD. These findings are potentially important from a prevention perspective because treatments are available for ADHD.

TBARS and BDNF levels in newborns exposed to crack/cocaine during pregnancy: a comparative study.

OBJECTIVES:: To compare levels of a marker of lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and brain-derived neurotrophic factor (BDNF) in umbilical cord blood (UCB) between newborns exposed to crack/cocaine in utero (exposed newborns [EN], n=57) and non-exposed newborns (NEN, n=99), as well as in maternal peripheral blood at delivery. METHODS:: This was a cross-sectional study. Potential confounders, including perinatal parameters, psychopathology, and use of other substances, were assessed. RESULTS:: After adjusting for potential confounders, adjusted mean BDNF was significantly higher in EN (3.86 ng/mL, 95% confidence interval [95%CI] 2.29-5.43) than in NEN (0.85 ng/mL, 95%CI 0.47-1.23; p < 0.001; Cohen effect size: 1.12), and significantly lower in crack/cocaine mothers than in control mothers (4.03 ng/mL, 95%CI 2.87-5.18 vs. 6.67 ng/mL, 95%CI 5.60-7.74; p = 0.006). The adjusted mean TBARS level was significantly lower in EN (63.97 µM MDA, 95%CI 39.43-88.50) than NEN (177.04 µM MDA, 95%CI 140.93-213.14; p < 0.001; effect size = 0.84), with no difference between mother groups (p = 0.86). CONCLUSIONS:: The changes in TBARS levels observed in EN suggest that fetuses exposed to cocaine mobilize endogenous antioxidant routes since very early stages of development. The increase in BDNF levels in EN might indicate changes in fetal development, whereas the changes in BDNF levels in mothers provide evidence of the complex metabolic processes involved in drug use during pregnancy.

Effects of crack cocaine addiction and stress-related genes on peripheral BDNF levels.

This study examined the effects of glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor 1 (CRHR1), and brain-derived neurotrophic factor (BDNF) genes on susceptibility to crack cocaine addiction and BDNF levels. Crack addicted patients who sought treatment (n = 280) and non-addicted individuals (n = 241) were assessed. Three SNPs in NR3C1 (rs6198, rs41423247, and rs10052957), three in CRHR1 (rs12944712, rs110402, and rs878886), and one in BDNF (rs6265) were genotyped. No significant effect was seen in the case-control analyses. Crack cocaine addicted patients showed significantly lower serum BDNF levels. Significant effects were observed for NR3C1 rs41423247 and rs10052957. These effects were restricted to non-addicted individuals and they were supported by significant gene-by-disease status interactions. For CRHR1, all SNPs were associated with BDNF levels. Although there were significant effects only in the analysis restricted to non-addicted individuals, the lack of significant results in the gene-by-disease status interaction analyses suggest a general effect on BDNF levels. The haplotype analyses presented the same effect seen in the single marker analyses. This study suggests that SNPs in the NR3C1 and CRHR1 genes may influence BDNF levels, but this effect is blunted in the context of crack cocaine addiction. Therefore, our data may be interpreted in light of several studies showing pronounced effects of crack cocaine on BDNF levels. Since peripheral BDNF is a biomarker for several psychiatric phenotypes, our results may be useful in interpreting previous associations between stress-related SNPs, drug addiction, and depression.

IL-6 and IL-10 levels in the umbilical cord blood of newborns with a history of crack/cocaine exposure in utero: a comparative study.

INTRODUCTION: Prenatal cocaine exposure (PCE) is associated with neurobehavioral problems during childhood and adolescence. Early activation of the inflammatory response may contribute to such changes. Our aim was to compare inflammatory markers (IL-6 and IL-10) both in umbilical cord blood and in maternal peripheral blood at delivery between newborns with history of crack/cocaine exposure in utero and non-exposed newborns. METHODS: In this cross-sectional study, 57 newborns with a history of crack/cocaine exposure in utero (EN) and 99 non-exposed newborns (NEN) were compared for IL-6 and IL-10 levels. Sociodemographic and perinatal data, maternal psychopathology, consumption of nicotine and other substances were systematically collected in cases and controls. RESULTS: After adjusting for potential confounders, mean IL-6 was significantly higher in EN than in NEN (10,208.54, 95% confidence interval [95%CI] 1,328.54-19,088.55 vs. 2,323.03, 95%CI 1,484.64-3,161.21; p = 0.007; generalized linear model [GLM]). Mean IL-10 was also significantly higher in EN than in NEN (432.22, 95%CI 51.44-812.88 vs. 75.52, 95%CI 5.64-145.39, p = 0.014; GLM). Adjusted postpartum measures of IL-6 were significantly higher in mothers with a history of crack/cocaine use (25,160.05, 95%CI 10,958.15-39,361.99 vs. 8,902.14, 95%CI 5,774.97-12,029.32; p = 0.007; GLM), with no significant differences for IL-10. There was no correlation between maternal and neonatal cytokine levels (Spearman test, p ≥ 0.28 for all measures). CONCLUSIONS: IL-6 and IL-10 might be early biomarkers of PCE in newborns. These findings could help to elucidate neurobiological pathways underlying neurodevelopmental changes and broaden the range of possibilities for early intervention.

Crack Cocaine Use in Adolescents: Clinical Characteristics and Predictors of Early Initiation.

OBJECTIVE: To describe the clinical characteristics of adolescents with crack cocaine dependence and possible predictors of transition from drug experimentation to crack cocaine dependence. METHODS: This cross-sectional study enrolled a consecutive sample of 90 adolescents admitted to a psychiatric inpatient unit in the city of Porto Alegre in southern Brazil for crack cocaine detoxification between May 2011 and November 2012. Comorbid psychological conditions were assessed using the Kiddie-SADS-Present and Lifetime Version, and severity of drug use was assessed using the Teen Addiction Severity Index (T-ASI). Comorbidities were compared with those in a community sample of non-drug using controls (n = 81). RESULTS: Patients' mean age was 15.6 years (85.6% boys, 14.4% girls). Seventy-nine (93.2%) met criteria for cocaine dependence (DSM-IV-TR), while 78 (91.8%) had symptoms consistent with cocaine abuse. All patients had experimented with at least 1 other addictive substance before crack cocaine: 61.4%, tobacco (mean age at first use = 11.61 years); 44.3%, alcohol (age at first use = 12.43 years); and 54.5%, cannabis (age at first use = 12.15 years). Patients had used crack cocaine 23.2 days in the last month, and the mean age at first use of crack cocaine was 13.38 years. The most common psychiatric comorbidity was conduct disorder (81.8%), followed by oppositional defiant disorder (52.3%) and attention-deficit/hyperactivity disorder (44.3%), all of which were more prevalent in the patient population than in controls (P < .001). The T-ASI questionnaire showed severe consequences of drug use in most areas of life assessed. The mean time between onset of drug experimentation and crack cocaine dependence was 2.53 (SD = 1.96) years. When Cox regression models were applied, we found that predictors of earlier progression to using crack cocaine were age at first use of any drug (hazard ratio [HR] = 0.79 [95% CI, 0.71-0.88]; P < .001) and age at admission (HR = 0.7 [95% CI, 0.57-0.87]; P = .001). CONCLUSIONS: Patients were found to have a multitude of comorbid conditions, which supports the idea of treatment by a multidisciplinary health care team. For each year of delay in the age at first drug use, the chance of crack cocaine initiation is reduced by 18%. Prevention programs aimed at delaying experimentation with addictive substances, especially "gateway" drugs, could delay the progression to crack cocaine dependence.

Searching for a neurobiological basis for self-medication theory in ADHD comorbid with substance use disorders: an in vivo study of dopamine transporters using (99m)Tc-TRODAT-1 SPECT.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) frequently co-occur. Although several studies have shown changes in striatal dopamine transporter (DAT) density in these disorders, little is known about the neurobiological basis of the comorbidity. The aim of this study was to evaluate striatal DAT density in treatment-naive ADHD adolescents with SUD (ADHD + SUD) and without SUD (ADHD), compared to SUD adolescents without ADHD (SUD) and healthy control subjects (HC). PATIENTS AND METHODS: Sixty-two male age-matched subjects diagnosed with DSM-IV criteria were included: ADHD + SUD (n = 18), SUD (n = 14), HC (n = 19), and ADHD (n = 11). Urine tests confirmed participants' drug use. All subjects performed SPECT scans with Tc-TRODAT-1 to evaluate DAT density in the striatum. RESULTS: The mean right striatum specific binding were 1.68 (ADHD), 1.38 (ADHD + SUD), 1.19 (HC), 1.17 (SUD), and in left striatum 1.65 (ADHD), 1.39 (ADHD + SUD), 1.19 (HC), and 1.17 (SUD). The ADHD group presented significantly higher striatal DAT density compared with ADHD + SUD, SUD, and HC groups. Adolescents with ADHD + SUD had significantly lower DAT density than those with ADHD, but significantly higher DAT density than those with SUD only and no significant difference from the healthy control group. CONCLUSION: The ADHD + SUD group had lower striatal DAT density in comparison with ADHD without SUD. It is possible to speculate that the use of cannabis and cocaine is responsible for the lower striatal DAT density in this group which would help in understanding the neurobiological basis for the self-medication theory in ADHD adolescents.

Is ADHD a risk factor independent of conduct disorder for illicit substance use? A meta-analysis and metaregression investigation.

OBJECTIVE: To investigate meta-analytically if the association between ADHD and illicit substance use (ISU) is maintained when controlling for conduct disorder/oppositional-defiant disorder (CD/ODD). METHOD: A systematic literature review was conducted through Medline from 1980 to 2008. Data extracted and selections made by one author were reviewed by another. RESULTS: Fifteen articles presented odds ratios (ORs) for the development of ISU in individuals with ADHD controlling for CD/ODD. In total, the study covered results for more than 1,000 individuals. The combined OR for studies that included in their analysis exclusively ISU was 1.35 (0.90-2.03), p = .15, heterogeneity = 55%. Lack of control for socioeconomic status was related with a weaker association between ADHD and ISU. CONCLUSION: The existing data do not indicate that ADHD increases the risk of ISU beyond the effects of CD/ODD. However, the combination of all existing data is limited in power to detect a small increase in chance.

TBARS and BDNF levels in newborns exposed to crack/cocaine during pregnancy: a comparative study

Objectives: To compare levels of a marker of lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and brain-derived neurotrophic factor (BDNF) in umbilical cord blood (UCB) between newborns exposed to crack/cocaine in utero (exposed newborns [EN], n=57) and non-exposed newborns (NEN, n=99), as well as in maternal peripheral blood at delivery. Methods: This was a cross-sectional study. Potential confounders, including perinatal parameters, psychopathology, and use of other substances, were assessed. Results: After adjusting for potential confounders, adjusted mean BDNF was significantly higher in EN (3.86 ng/mL, 95% confidence interval [95%CI] 2.29-5.43) than in NEN (0.85 ng/mL, 95%CI 0.47-1.23; p < 0.001; Cohen effect size: 1.12), and significantly lower in crack/cocaine mothers than in control mothers (4.03 ng/mL, 95%CI 2.87-5.18 vs. 6.67 ng/mL, 95%CI 5.60-7.74; p = 0.006). The adjusted mean TBARS level was significantly lower in EN (63.97 µM MDA, 95%CI 39.43-88.50) than NEN (177.04 µM MDA, 95%CI 140.93-213.14; p < 0.001; effect size = 0.84), with no difference between mother groups (p = 0.86). Conclusions: The changes in TBARS levels observed in EN suggest that fetuses exposed to cocaine mobilize endogenous antioxidant routes since very early stages of development. The increase in BDNF levels in EN might indicate changes in fetal development, whereas the changes in BDNF levels in mothers provide evidence of the complex metabolic processes involved in drug use during pregnancy.

Attention deficit/hyperactivity disorder: is there a correlation between dopamine transporter density and cerebral blood flow?

Attention deficit/hyperactivity disorder (ADHD) is one of the most frequent behavioral problems in school-age children. Although the etiology remains unclear, the involvement of the dopaminergic system has been suggested by genetic studies that report an overexpression of the dopamine transporter (DAT) gene. In spite of these abnormalities being directly related to the decrease of dopamine (DA) in the striatum (STR), abnormalities in brain perfusion have also been observed in cortical-subcortical structures. Functional neuroimaging studies have suggested that the DA concentration may cause changes in the cerebral blood flow (CBF). The objective of our study was to evaluate the relationship between DAT density in STR and cortical-subcortical impairment in CBF. Based on the hypothesis that there is a correlation between DA availability and brain perfusion, we postulated that individuals with ADHD, with a higher DAT density in the basal ganglia, will have lower perfusion in the fronto-striatal-cerebellar networks. We used Tc-99m TRODAT-1 SPECT to measure DAT density and Tc-99m ECD SPECT to assess brain perfusion. Ten adolescents diagnosed with ADHD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were investigated. Analysis with Statistical Parametric Mapping 5 corrected for multiple comparisons, using small volume correction, showed a significant negative correlation between the DAT density in the STR and CBF in the cingulate gyrus, frontal lobe, temporal lobe, and cerebellum (pFDR <0.01). Our findings suggest that higher DAT density in the STR was associated with a decrease in the regional CBF in the cortical and subcortical attention network.

IL-6 and IL-10 levels in the umbilical cord blood of newborns with a history of crack/cocaine exposure in utero: a comparative study / Níveis de IL-6 e IL-10 no sangue de cordão umbilical de recém-nascidos com história de exposição intrauterina ao crack/cocaína: um estudo comparativo

Introduction Prenatal cocaine exposure (PCE) is associated with neurobehavioral problems during childhood and adolescence. Early activation of the inflammatory response may contribute to such changes. Our aim was to compare inflammatory markers (IL-6 and IL-10) both in umbilical cord blood and in maternal peripheral blood at delivery between newborns with history of crack/cocaine exposure in utero and non-exposed newborns. Methods In this cross-sectional study, 57 newborns with a history of crack/cocaine exposure in utero (EN) and 99 non-exposed newborns (NEN) were compared for IL-6 and IL-10 levels. Sociodemographic and perinatal data, maternal psychopathology, consumption of nicotine and other substances were systematically collected in cases and controls. Results After adjusting for potential confounders, mean IL-6 was significantly higher in EN than in NEN (10,208.54, 95% confidence interval [95%CI] 1,328.54-19,088.55 vs. 2,323.03, 95%CI 1,484.64-3,161.21; p = 0.007; generalized linear model [GLM]). Mean IL-10 was also significantly higher in EN than in NEN (432.22, 95%CI 51.44-812.88 vs. 75.52, 95%CI 5.64-145.39, p = 0.014; GLM). Adjusted postpartum measures of IL-6 were significantly higher in mothers with a history of crack/cocaine use (25,160.05, 95%CI 10,958.15-39,361.99 vs. 8,902.14, 95%CI 5,774.97-12,029.32; p = 0.007; GLM), with no significant differences for IL-10. There was no correlation between maternal and neonatal cytokine levels (Spearman test, p ≥ 0.28 for all measures). Conclusions IL-6 and IL-10 might be early biomarkers of PCE in newborns. These findings could help to elucidate neurobiological pathways underlying neurodevelopmental changes and broaden the range of possibilities for early intervention.

Introdução A exposição pré-natal à cocaína está associada a problemas neurocomportamentais durante a infância e adolescência. A ativação precoce da resposta inflamatória pode contribuir para tais alterações. Nosso objetivo foi comparar marcadores inflamatórios (IL-6 e IL-10) no sangue do cordão umbilical e no sangue periférico materno na hora do parto, entre recém-nascidos expostos ao crack intraútero e recém-nascidos não expostos. Métodos Neste estudo transversal, 57 recém-nascidos expostos ao crack intraútero (RNE) e 99 recém-nascidos não expostos (RNNE) foram comparados quanto aos níveis de IL-6 e IL-10. Dados sociodemográficos e perinatais, psicopatologia materna, consumo de nicotina e outras substâncias foram sistematicamente coletados em casos e controles. Resultados Após o ajuste para potenciais confundidores, a média de IL-6 foi significativamente maior nos RNE em comparação aos RNNE [10.208,54, intervalo de confiança (IC95%) 1.328,54-19.088,55 versus2.323,03, IC95% 1.484,64-3.161,21; p = 0,007; modelo linear generalizado (MLG)]. A média ajustada de IL-10 foi significativamente maior nos RNE do que nos RNNE (432,2189, IC95% 51,44-812,88 versus 75,52, IC95% 5,64-145,39, p = 0,014; MLG). Medidas pós-parto ajustadas de IL-6 foram significativamente maiores nas mães que usaram de crack/cocaína (25.160,05, IC95% 10.958,15-39.361,99 versus 8.902,14, IC95% 5.774,97-12.029,32; p = 0,007; MLG), sem diferenças significativas para IL-10. Não houve correlação entre níveis maternos e neonatais de citocinas (teste de Spearman, p ≥ 0,28 para todas as medidas). Conclusões IL-6 e IL-10 podem ser biomarcadores precoces da exposição pré-natal a cocaína em recém-nascidos. Esses resultados podem ajudar a elucidar as vias neurobiológicas subjacentes a alterações do desenvolvimento e aumentar a gama de possibilidades para intervenção precoce.

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.

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. OBJECTIVES: 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). METHODS: 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. RESULTS: 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). DISCUSSION: 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.

The acute effect of methylphenidate on cerebral blood flow in boys with attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is the most commonly prescribed treatment for attention-deficit/hyperactivity disorder (ADHD). The therapeutic mechanisms of MPH are not, however, fully understood. We studied the effects of MPH on brain activity in male children and adolescents with ADHD, using the blood flow radiotracer technetium-99m ethyl cysteinate dimer ((99m)Tc-ECD) and single-photon emission tomography (SPET). The study was randomized, double blind, and placebo controlled (MPH group, n=19; placebo group, n=17), Radiotracer was administered during the performance of the Continuous Performance Test and before and after 4 days of MPH treatment. Statistical parametric mapping (SPM99) analysis showed a significant reduction in regional cerebral blood flow in the left parietal region in the MPH group compared with the placebo group (P<0.05, corrected for multiple comparisons). Our findings suggest that the posterior attentional system, which includes the parietal cortex, may have a role in the mediation of the therapeutic effects of MPH in ADHD.

Co-ocorrência entre transtorno de déficit de atenção/hiperatividade e uso de substâncias psicoativas / Co-ocorrency between attention deficit hyperactivity disorder and psychoactive substances

Existe forte associação entre o transtorno de déficit de atenção/hiperatividade (TDAH) e o transtorno por uso de substâncias psicoativas (TUSP) em estudos clínicos e comunitários. Estimam-se que aproximadamente 30 por cento dos sujeitos com TUSP apresentem comorbidade com o TDAH, taxa significativamente maior do que a vista na população geral. Vários estudos vêm analisando o possível efeito do TDAH no risco de desenvolvimento de TUSP. O presente artigo revisa a literatura disponível às seguintes questões: a) natureza da associação entre o TDAH e o TUSP; b) efeitos do TDAH no TUSP; c) tratamento do TDAH na concomitância do diagnóstico de TUSP. Por fim, é oferecida uma integração das diferentes informações, sob um enfoque predominantemente clínico.

Attention deficit/hyperactivity disorder (ADHD) is highly associated with substance use disorders (SUDs), both in clinical and community studies. Approximately 30 percent of subjects with SUDs present with comorbid ADHD, a prevalence rate significantly higher than that seen in the general population. The effect of ADHD on the development of SUDs have been subject to extensive studies. This article reviews the existing literature regarding: a) the nature of the association between ADHD and SUDs; b) the impact of ADHD on SUDs; c) the treatment of ADHD which co-occurs with SUDs. Finally an overview, from a predominantly clinical perspective, an integration of those data is proposed.