Faculty Bibliography

BACKGROUND: Medical settings such as emergency departments (EDs) present an opportunity to identify and provide services for individuals with substance use problems who might otherwise never receive any form of assessment, referral, or intervention. Although screening, brief intervention, and referral to treatment models have been extensively studied and are considered effective for individuals with alcohol problems presenting in EDs and other medical settings, the efficacy of such interventions has not been established for drug users presenting in EDs. OBJECTIVES: This article describes the design of a NIDA Clinical Trials Network protocol testing the efficacy of an screening, brief intervention, and referral to treatment model in medical EDs, highlighting considerations that are pertinent to the design of other studies targeting substance use behaviors in medical treatment settings. METHODS: The protocol is described, and critical design decisions are discussed. RESULTS: Design challenges included defining treatment conditions, study population, and site characteristics; developing the screening process; choosing the primary outcome; balancing brevity and comprehensiveness of assessment; and selecting the strategy for statistical analysis. CONCLUSION: Many of the issues arising in the design of this study will be relevant to future studies of interventions for addictions in medical settings. SCIENTIFIC SIGNIFICANCE: Optimal trial design is critical to determining how best to integrate substance abuse interventions into medical care.

J. Neurochem. (2011) 118, 714-720. ABSTRACT: Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1) -receptor activation in axonal DA release regulation in dorsal striatum using a D(1) -receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single-pulse evoked extracellular DA concentration, with a maximum increase of approximately 65% in 5 muM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration clearance time. Both effects were occluded by nomifensine (1 muM), a dopamine transporter (DAT) inhibitor, suggesting that SKF-83566 acted via the DAT. We tested this by examining [(3) H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 muM. Binding studies with [(3) H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 muM). Thus, data obtained using SKF-83566 as a D(1) DA-receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of this drug at the cocaine versus DA binding site of the DAT

Background: Predictors of smoking cessation (SC) treatment outcome were explored in a multisite clinical trial of SC treatment at community-based, outpatient, substance abuse rehabilitation programs affiliated with the National Drug Abuse Treatment Clinical Trials Network. Objectives: To explore baseline demographic and clinical predictors of abstinence during treatment. Methods: Cigarette smokers from five methadone maintenance programs and two drug and alcohol dependence treatment programs were randomly assigned to SC treatment as an adjunct to substance abuse treatment as usual or to substance abuse treatment as usual. SC treatment consisted of group counseling (weeks 1-8) plus transdermal nicotine patch treatment (21 mg/day, weeks 1-6; 14 mg/day, weeks 7-8). Demographic and clinical predictors of smoking abstinence were evaluated among those patients assigned to the active SC condition (N = 153) using logistic regression. Results: Abstinence during treatment was positively associated with younger age, Hispanic or Caucasian (as opposed to African American) ethnicity/race, employment or student status, fewer cigarettes per day at baseline, lower severity of the primary substance problem at baseline, and higher methadone doses (among the subsample in methadone treatment). Conclusions and Scientific Significance: During future efforts to improve SC treatments among drug- and alcohol-dependent patients, consideration should be given to adequate treatment to reduce the severity of the primary drug or alcohol problem, tailoring treatments for patients with greater severity of smoking and of the primary substance problem, and culturally sensitive interventions. Analysis of predictors of outcome may be a useful tool for treatment development

In the laboratory, food restriction has been shown to induce neuroadaptations in brain reward circuitry which are likely to be among those that facilitate survival during periods of food scarcity in the wild. However, the upregulation of mechanisms that promote foraging and reward-related learning may pose a hazard when food restriction is self-imposed in an ecology of abundant appetitive rewards. For example, episodes of loss of control during weight-loss dieting, use of drugs with addictive potential as diet aids, and alternating fasting with alcohol consumption in order to avoid weight gain, may induce synaptic plasticity that increases the risk of enduring maladaptive reward-directed behavior. In the present mini-review, representative basic research findings are outlined which indicate that food restriction alters the function of mesoaccumbens dopamine neurons, potentiates cellular and behavioral responses to D-1 and D-2 dopamine receptor stimulation, and increases stimulus-induced synaptic insertion of AMPA receptors in nucleus accumbens. Possible mechanistic underpinnings of increased drug reward magnitude, drug-seeking, and binge intake of sucrose in food-restricted animal subjects are discussed and possible implications for human weight-loss dieting are considered

Previously, a learning-free measure was used to demonstrate that chronic food restriction (FR) increases the reward magnitude of a wide range of abused drugs. Moreover, a variety of striatal neuroadaptations were detected in FR subjects, some of which are known to be involved in synaptic plasticity but have been ruled out as modulators of acute drug reward magnitude. Little is known about effects of FR on drug-conditioned place preference (CPP) and brain regional mechanisms that may enhance CPP in FR subjects. The purpose of the present study was to compare the expression and persistence of a conditioned place preference (CPP) induced by a relatively low dose of cocaine (7.0mg/kg, i.p.) in ad libitum fed (AL) and FR rats and take several brain regional biochemical measures following the first CPP conditioning session to probe candidate mechanisms that may underlie the more robust CPP observed in FR subjects. Behaviorally, AL subjects displayed a CPP upon initial testing which extinguished rapidly over the course of subsequent test sessions while CPP in FR subjects persisted. Despite previous reports of elevated BDNF protein in forebrain regions of FR rats, the FR protocol used in the present study did not alter BDNF levels in dorsal hippocampus, nucleus accumbens or medial prefrontal cortex. On the other hand, FR rats, whether injected with cocaine or vehicle, displayed elevated p-ERK1/2 and p-Ser845-GluA1 in dorsal hippocampus. FR rats also displayed elevated p-ERK1/2 in medial prefrontal cortex and elevated p-ERK1 in nucleus accumbens, with further increases produced by cocaine. The one effect observed exclusively in cocaine-treated FR rats was increased p-Ser845-GluA1 in nucleus accumbens. These findings suggest a number of avenues for continuing investigation with potential translational significance

As acute ethanol exposure inhibits N-methyl-D-aspartate glutamate (Glu) receptors, sudden withdrawal from chronic alcohol use may lead to an increased activation of these receptors with excitotoxic effects. In the longer term, brain levels of Glu and its metabolites, such as glutamine (Gln), are likely to be chronically altered by alcohol, possibly providing a measure of overall abnormal Glu-Gln cycling. However, few studies have assessed concentrations of these metabolites in clinical populations of individuals with alcohol use disorders. Glu and Gln levels were compared in groups of 17 healthy controls and in 13 participants with alcohol dependence. Within the alcohol-dependent group, seven participants had current alcohol use disorder (AUD), and six had AUD in remission for at least 1 year (AUD-R). Neurometabolite concentrations were measured with proton magnetic resonance spectroscopy ((1)H-MRS) in a predominantly gray matter voxel that included the bilateral anterior cingulate gyri. Tissue segmentation provided an assessment of the proportion of gray matter in the (1)H-MRS voxel. The Drinker Inventory of Consequences (DrInC) and Form-90 were administered to all participants to quantify alcohol consequences and use. Glu level was lower and Gln level was higher in the AUD and AUD-R groups relative to the control group; creatine, choline, myo-inositol, and total N-acetyl groups, primarily N-acetylaspartate did not differ across groups. These results were not confounded by age, sex, or proportion of gray matter in the (1)H-MRS voxel. Neurometabolite concentrations did not differ between AUD and AUD-R groups. Subsequent regressions in the combined clinical group, treating voxel gray matter proportion as a covariate, revealed that total score on the DrInC was positively correlated with Gln but negatively correlated with both Glu and gray matter proportion. Regression analyses, including DrInC scores and smoking variables, identified a marginal independent effect of smoking on Gln. The current findings of higher Gln and lower Glu in the combined AUD and AUD-R groups might indicate a perturbation of the Glu-Gln cycle in alcohol use disorders. The absence of differences in mean Glu and Gln between the AUD and AUD-R groups suggests that altered Glu-Gln metabolism may either predate the onset of abuse or persist during prolonged abstinence.

We explored patient, therapist, and program variability in the alliance in relation to drug and alcohol use during treatment, and whether alliance mediates the relation of program characteristics to drug/alcohol use. Data (N = 1,613 patients) were drawn from a randomized clinical trial investigating the efficacy of an intervention that provided alliance and outcome feedback to 112 counselors across 20 community-based outpatient substance abuse treatment clinics in the northeast United States. Program characteristics were measured using the Organization Readiness for Change scale. Using multilevel modeling, we found that alliance was related to both drug and alcohol use during the past week at the patient and program levels of analysis, but not the counselor level. Several program characteristics were related to average drug and alcohol use. The alliance was not a mediator of these relationships. Program variability in the alliance is important to the alliance-outcome relationship in the treatment of substance abuse. Better outcomes can be achieved by improving both organizational functioning and the patient-counselor alliance

Respondent driven sampling (RDS) was originally developed to sample and provide peer education to injection drug users at risk for HIV. Based on the premise that drug users' social networks were maintained through sharing rituals, this peer-driven approach to disseminate educational information and reduce risk behaviors capitalizes and expands upon the norms that sustain these relationships. Compared with traditional outreach interventions, peer-driven interventions produce greater reductions in HIV risk behaviors and adoption of safer behaviors over time, however, control and intervention groups are not similarly recruited. As peer-recruitment may alter risk networks and individual risk behaviors over time, such comparison studies are unable to isolate the effect of a peer-delivered intervention. This analysis examines whether RDS recruitment (without an intervention) is associated with changes in health-seeking behaviors and network composition over 6 months. New York City drug users (N = 618) were recruited using targeted street outreach (TSO) and RDS (2006-2009). 329 non-injectors (RDS = 237; TSO = 92) completed baseline and 6-month surveys ascertaining demographic, drug use, and network characteristics. Chi-square and t-tests compared RDS- and TSO-recruited participants on changes in HIV testing and drug treatment utilization and in the proportion of drug using, sex, incarcerated and social support networks over the follow-up period. The sample was 66% male, 24% Hispanic, 69% black, 62% homeless, and the median age was 35. At baseline, the median network size was 3, 86% used crack, 70% used cocaine, 40% used heroin, and in the past 6 months 72% were tested for HIV and 46% were enrolled in drug treatment. There were no significant differences by recruitment strategy with respect to changes in health-seeking behaviors or network composition over 6 months. These findings suggest no association between RDS recruitment and changes in network composition or HIV risk, which supports prior findings from prospective HIV behavioral surveillance and intervention studies.

BACKGROUND: Models of cocaine addiction emphasize the role of disrupted frontal circuitry supporting cognitive control processes. However, addiction-related alterations in functional interactions among brain regions, especially between the cerebral hemispheres, are rarely examined directly. Resting-state functional magnetic resonance imaging (fMRI) approaches, which reveal patterns of coherent spontaneous fluctuations in the fMRI signal, offer a means to quantify directly functional interactions between the hemispheres. We examined interhemispheric resting-state functional connectivity (RSFC) in cocaine dependence using a recently validated approach, voxel-mirrored homotopic connectivity. METHODS: We compared interhemispheric RSFC between 25 adults (aged 35.0 +/- 8.8) meeting DSM-IV criteria for cocaine dependence within the past 12 months but currently abstaining (>2 weeks) from cocaine and 24 healthy comparisons (35.1 +/- 7.5), group-matched on age, sex, education, and employment status. RESULTS: We observed reduced prefrontal interhemispheric RSFC in cocaine-dependent participants relative to control subjects. Further analyses demonstrated a striking cocaine-dependence-related reduction in interhemispheric RSFC among nodes of the dorsal attention network, comprising bilateral lateral frontal, medial premotor, and posterior parietal areas. Further, within the cocaine-dependent group, RSFC within the dorsal attention network was associated with self-reported attentional lapses. CONCLUSIONS: Our findings provide further evidence of an association between chronic exposure to cocaine and disruptions within large-scale brain circuitry supporting cognitive control. We did not detect group differences in diffusion tensor imaging measures, suggesting that alterations in the brain's functional architecture associated with cocaine exposure can be observed in the absence of detectable abnormalities in the white matter microstructure supporting that architecture