Faculty Bibliography

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify gene variants associated with heroin addiction in African Americans. The emphasis was on genes involved in reward modulation, behavioral control, cognitive function, signal transduction and stress response. We have performed a case-control association analysis by screening with 1350 variants of 130 genes. The sample consisted of 202 former severe heroin addicts in methadone treatment and 167 healthy controls with no history of drug abuse. Single nucleotide polymorphism (SNP), haplotype and multi-SNP genotype pattern analyses were performed. Seventeen SNPs showed point-wise significant association with heroin addiction (nominal P< 0.01). These SNPs are from genes encoding several receptors: adrenergic (ADRA1A), arginine vasopressin (AVPR1A), cholinergic (CHRM2), dopamine (DRD1), GABA-A (GABRB3), glutamate (GRIN2A) and serotonin (HTR3A) as well as alcohol dehydrogenase (ADH7), glutamic acid decarboxylase (GAD1 and GAD2), the nucleoside transporter (SLC29A1) and diazepam-binding inhibitor (DBI). The most significant result of the analyses was obtained for the GRIN2A haplotype G-A-T (rs4587976-rs1071502-rs1366076) with protective effect (P(uncorrected) = 9.6E- 05, P(corrected) = 0.058). This study corroborates several reported associations with alcohol and drug addiction as well as other related disorders and extends the list of variants that may affect the development of heroin addiction. Further studies will be necessary to replicate these associations and to elucidate the roles of these variants in drug addiction vulnerability.

The coming decades will see exciting breakthroughs in the treatment of SUDs, such as further elucidation of the genetic mechanisms of addiction. Yet if the past is any guide to the future, each new discovery will bring with it new challenges to the core ethical obligations of honoring informed consent, protecting confidentiality, and respecting justice, while also protecting the public from harm and ensuring the good of the individual patient. For the emerging scientific shift to a biobehavioral model of addiction to transform cultural attitudes and enhance treatment and research will require the scientifically rigorous and ethically sound agency of ethicists and addiction professionals to influence public policy. The growing body of neurobiologic evidence that contests traditional assumptions about free will and responsibility will evoke more deliberate and nuanced approaches to informed consent and treatment participation and dispute the forensic orientation in drug policy. If this unprecedented paradigm change can influence health care decision making in a reasoned and balanced fashion, there is real hope that the cultural stigma, which has warranted highly stringent confidentiality protections, and the disenfranchisement underlying health disparities in addiction treatment may move in the direction of compassionate and competent care for all those who suffer from addiction.

OBJECTIVES: This report focused upon the availability of infection-related health services in substance abuse treatment programs with and without addiction services tailored for special populations (women and non-white populations). METHODS: In a cross-sectional, descriptive design, treatment program administrators across the United States within the National Drug Abuse Treatment Clinical Trials Network provided information on program characteristics, the availability of infection-related services (four medical services and three non-medical services for HIV, HCV, and STI), and barriers to providing infection-related services. RESULTS: Of 319 programs, 269 submitted surveys (84% response rate). Of these, 80% provided addiction services for special populations. Programs providing addiction services designed for at least one special population, were more likely to provide infection-related health services, especially HIV-related education (94% versus 85%, p = 0.05) and patient counseling (76% versus 60%, p = 0.03) and were more likely to include outpatient addiction services (86% versus 57%, p<0.001) and outreach and support services (92% versus 70%, p=0.01). Barriers to providing infection-related services included funding (cited by 48.3% to 74.7% of programs), health insurance (cited by 28.9% to 60.8% of programs), and patient acceptance (cited by 23.2% to 54.3% of programs). CONCLUSIONS: Despite many barriers, infection-related healthcare is available in programs with addiction treatment services tailored for special populations, especially for African Americans and Latino Americans. Tailoring substance abuse treatment along with reducing barriers to infection-related care represent public health interventions with potential to reduce the burdens and disparities associated with these infections

Findings from neuroscience research hold promise for improved treatments for and prevention of substance use disorders (SUD), but ethical concerns about psychopharmacological research involving SUD may potentially undermine scientific progress. This article reviews the literature pertaining to seven ethical requirements that elucidate a coherent framework for evaluating the ethics of clinical SUD research protocols. Those requirements are social or scientific value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for potential or enrolled subjects. An evidence-based analysis suggests that sound pharmacological research in SUD can safeguard the welfare of research participants while collecting valuable scientific data and benefiting society.

RATIONALE: Previous studies have suggested that chronic food restriction (FR) increases sensitivity of a neural substrate for drug reward. The neuroanatomical site(s) of key neuroadaptations may include nucleus accumbens (NAc) where changes in D-1 dopamine (DA) receptor-mediated cell signaling and gene expression have been documented. OBJECTIVES: The purpose of the present study was to begin bridging the behavioral and tissue studies by microinjecting drugs directly into NAc medial shell and assessing behavioral effects in free-feeding and FR subjects. MATERIALS AND METHODS: Rats were implanted with microinjection cannulae in NAc medial shell and a subset were implanted with a stimulating electrode in lateral hypothalamus. Reward-potentiating effects of the D-1 DA receptor agonist, SKF-82958, AMPAR antagonist, DNXQ, and polyamine GluR1 antagonist, 1-na spermine, were assessed using the curve-shift method of self-stimulation testing. Motor-activating effects of SKF-82958 were also assessed. RESULTS: SKF-82958 (2.0 and 5.0 mug) produced greater reward-potentiating and motor-activating effects in FR than ad libitum fed (AL) rats. DNQX (1.0 mug) and 1-na spermine (1.0 and 2.5 mug) selectively decreased the x-axis intercept of rate-frequency curves in FR subjects, reflecting increased responding for previously subthreshold stimulation. CONCLUSIONS: Results suggest that FR may facilitate reward-directed behavior via multiple neuroadaptations in NAc medial shell including upregulation of D-1 DA receptor function involved in the selection and expression of goal-directed behavior, and increased GluR1-mediated activation of cells that inhibit nonreinforced responses

Substance Abusers have a large number of medical and psychiatric problems, and 70-90% are smokers. The aim of this analysis was to examine the prevalence and correlates of medical and psychiatric problems in this sample of drug dependent patients who were participants in a multi-site study of smoking cessation interventions while engaged in substance abuse treatment. Descriptive analyses showed at baseline, 72.8% of participants had at least one medical problem and 64.1% had at least one psychiatric diagnosis. Medical problems correlated strongly with age, smoking severity, and pack-years; Psychiatric problems correlated with gender and ethnicity. Smoking cessation treatment was associated with a moderate reduction in the ASI Medical composite score. More research is needed on the possible effects of combined treatment of substance abuse and concurrent medical and psychiatric problems. Offering smoking cessation in conjunction with primary care may be a way to address the health needs of this population.

BACKGROUND: Despite the availability and demonstrated effectiveness of office-based buprenorphine maintenance treatment (BMT), the systematic examination of physicians' attitudes towards this new medical practice has been largely neglected. OBJECTIVE: To identify facilitators and barriers to the potential or actual implementation of BMT by office-based medical providers. DESIGN: Qualitative study using individual and group semi-structured interviews. PARTICIPANTS: Twenty-three practicing office-based physicians in New England. APPROACH: Interviews were audiotaped, transcribed, and entered into a qualitative software program. The transcripts were thematically coded using the constant comparative method by a multidisciplinary team. RESULTS: Eighty percent of the physicians were white; 55% were women. The mean number of years since graduating medical school was 14 (SD = 10). The primary areas of clinical specialization were internal medicine (50%), infectious disease (20%), and addiction medicine (15%). Physicians identified physician, patient, and logistical factors that would either facilitate or serve as a barrier to their integration of BMT into clinical practice. Physician facilitators included promoting continuity of patient care, positive perceptions of BMT, and viewing BMT as a positive alternative to methadone maintenance. Physician barriers included competing activities, lack of interest, and lack of expertise in addiction treatment. Physicians' perceptions of patient-related barriers included concerns about confidentiality and cost, and low motivation for treatment. Perceived logistical barriers included lack of remuneration for BMT, limited ancillary support for physicians, not enough time, and a perceived low prevalence of opioid dependence in physicians' practices. CONCLUSIONS: Addressing physicians' perceptions of facilitators and barriers to BMT is crucial to supporting the further expansion of BMT into primary care and office-based practices

BACKGROUND: This study investigated whether subgroups of alcohol-dependent patients responded differently to naltrexone versus placebo in the NIAAA COMBINE study. In particular, the A versus B and the Early Onset versus Late Onset typologies were examined. Relative to Type A alcoholics, Type B alcoholics are characterized by greater severity, earlier onset, stronger family history, more childhood risk factors (e.g., conduct disorder), and greater frequency of comorbid psychiatric and substance use disorders. METHODS: COMBINE study participants were categorized as Type A or Type B using k-means cluster analysis and variables from 5 domains that have been shown to replicate the original Babor typology efficiently. Early Onset was defined as alcohol dependence beginning before age 25. For the planned analyses, the sample was reduced to the 618 participants receiving naltrexone alone or placebo, either with medical management (MM) alone or with MM plus the Combined Behavioral Intervention (CBI). The a priori primary outcome was percent heavy drinking days during treatment in the groups receiving MM without CBI. RESULTS: Among those receiving MM without CBI, Type A alcoholics had better drinking outcomes with naltrexone than placebo, whereas medication condition did not influence outcomes significantly in the Type Bs. Age of onset was not significantly related to outcome. For those receiving CBI, no significant effects were found for either typology. CONCLUSIONS: In this sample, the beneficial effects of opioid antagonism were limited to Type A alcoholics receiving treatment in a MM model. Future studies should investigate the relationship between clinically relevant genotypes, phenotypes such as typologies, and treatment response. More work is also needed to develop practical algorithms for phenotypic assignment.

RATIONALE: Food restriction (FR) enhances learned and unlearned behavioral responses to drugs of abuse and increases D-1 dopamine (DA) receptor-mediated activation of extracellular signal-regulated kinases (ERK) 1/2 MAP kinase in nucleus accumbens (NAc). While a role has been established for ERK signaling in drug-mediated associative learning, it is not clear whether ERK regulates unconditioned behavioral effects of abused drugs. OBJECTIVES: The purpose of this study was to determine whether blockade of ERK signaling, using the brain-penetrant MEK inhibitor, SL-327, decreases behavioral or NAc cellular responses to acute drug treatment and their augmentation by FR. MATERIALS AND METHODS: Separate experiments assessed the effects of SL-327 (50 mg/kg, intraperitoneally) on (1) the reward-potentiating effect of D-amphetamine in an intracranial self-stimulation protocol, (2) the locomotor-activating effect of the D-1 agonist, SKF-82958, and (3) Fos-immunostaining induced in the NAc by SKF-82958. RESULTS: FR rats displayed enhanced responses to drug treatment on all measures. SL-327 had no effect on sensitivity to rewarding brain stimulation or the reward-potentiating effect of D-amphetamine. The MEK inhibitor, U0126, microinjected into the NAc was also without effect. The locomotor-activating effect of SKF-82958 was unaffected by SL-327. In contrast, SL-327 decreased NAc Fos-immunostaining and abolished the difference between feeding groups. CONCLUSIONS: These results support the conclusion that ERK signaling does not mediate unlearned behavioral responses to drug treatment. However, the upregulation of ERK and downstream transcriptional responses to acute drug treatment may underlie the reported enhancement of reward-related learning in FR subjects