Faculty Bibliography

Behavioral studies have demonstrated that chronic food restriction augments the rewarding and motor-activating effects of centrally injected psychostimulants and direct dopamine (DA) receptor agonists. Recently, it has been shown that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958, produces an enhanced locomotor-activating effect as well as increased activation of striatal ERK 1/2 MAP kinase, CaM kinase II, CREB, and c-fos in food-restricted (FR) relative to ad libitum fed (AL) rats. Striatal neurons that express the D-1 DA receptor coexpress dynorphin and substance P, and CREB is known to couple D-1 DA receptor stimulation to preprodynorphin (ppD) gene expression. The purpose of the present study was to examine possible genomic consequences of FR using real-time quantitative RT-PCR to measure striatal neuropeptide gene expression 3 h after i.c.v. injection of SKF-82958 (20 microg). Results indicate that, in nucleus accumbens (NAc), basal levels of ppD and preprotachykinin (ppT) mRNA are lower in FR than AL rats. This may reflect a decrease in tonic DA transmission during FR which precedes the compensatory upregulation of postsynaptic D-1 DA receptor-mediated cell signaling. In response to SKF-82958 challenge, however, FR subjects displayed greater levels of ppD and ppT mRNA in NAc than did AL subjects. A similar trend was seen in caudate-putamen (CPu). SKF-82958 also increased preproenkephalin (ppE) mRNA in Nac, but not CPu, with no difference between feeding groups. The present findings regarding ppD and ppT are consistent with prior findings of increased behavioral and cellular responses to acute D-1 DA agonist challenge in FR rats. The functional consequences of increased neuropeptide gene expression in response to acute drug challenge remain to be investigated but may include modulation of behavioral effects that emerge with repeated drug exposure, including sensitization, tolerance, and addiction

The brain melanocortin system mediates downstream effects of hypothalamic leptin and insulin signaling. Yet, there have been few studies of chronic intracerebroventricular (i.c.v.) melanocortin receptor (MCR) agonist or antagonist infusion. Although there is evidence of interaction between melanocortin and dopamine (DA) systems, effects of chronic MCR ligand infusion on behavioral sensitivity to non-ingestive reward stimuli have not been investigated. The objective of this study was to investigate effects of chronic i.c.v. infusion of the MCR agonist, MTII, and the MCR antagonist, SHU9119, on food intake, body weight, and sensitivity to rewarding lateral hypothalamic electrical stimulation (LHSS) and the reward-potentiating (i.e., threshold-lowering) effect of D-amphetamine. The MCR antagonist, SHU9119 (0.02 microg/h) produced sustained hyperphagia and weight gain during the 12-day infusion period, followed by compensatory hypophagia and an arrest of body weight gain during the 24-day post-infusion period. At no point during the experiment was sensitivity to LHSS or D-amphetamine (0.25mg/kg, i.p.) altered. The MCR agonist, MTII (0.02 microg/h) produced a brief hypophagia (3 days) followed by a return to control levels of daily intake, but with body weight remaining at a reduced level throughout the 12-day infusion period. This was followed by compensatory hyperphagia and weight gain during the 24-day post-infusion period. There was no change in sensitivity to non-ingestive reward stimuli during the infusion of MTII. However, sensitivity to D-amphetamine was increased during the 24-day post-infusion period. It therefore seems that changes in ingestive behavior that occur during chronic MCR ligand infusion may not affect the response to non-ingestive reward stimuli. However, it is possible that the drive to re-feed and restore body weight following MCR agonist treatment includes neuroadaptations that enhance the incentive effects of drug stimuli

BACKGROUND: Hepatitis C virus (HCV) rates are higher in non-injecting drug users (NIDUs) than general population estimates. Whether this elevated HCV rate is due to drug use or other putative risk behaviors remains unclear. METHODS: Recent non-injection drug users of heroin, crack and/or cocaine were street-recruited from 2000 to 2003 and underwent an interview and venipuncture for HCV antibody assays. Multiple logistic regression analyses were used to assess correlates for HCV infection. RESULTS: Of 740 enrollees, 3.9% were HCV positive. The median age (intraquartile range) was 30 (35-24) years, 70% were male and 90% were Black or Hispanic. After adjustment, HCV seropositives were significantly more likely than seronegatives to be older than 30 [adjusted odds ratio (AOR)=5.71], tattooed by a friend/relative/acquaintance [AOR=3.61] and know someone with HCV [AOR=4.29], but were less likely to have shared nail or hair clippers, razors or a toothbrush [AOR=0.32]. CONCLUSIONS: Non-commercial tattooing may be a mode of HCV transmission among NIDUs and education on the potential risk in using non-sterile tattooing equipment should be targeted toward this population. While no evidence was found for HCV transmission through NIDU equipment sharing or sexual risk behavior, further research is still warranted.

BACKGROUND: Effective on January 1, 2001, New York State enacted the Expanded Syringe Access Demonstration Program (ESAP), which allows syringes to be sold in pharmacies without a prescription or dispensed through doctors, hospitals, and clinics to persons 18 years of age or older and permits the possession of those syringes for the purposes of injecting drugs. OBJECTIVE: To assess changes in receptive syringe sharing since the inception of the ESAP. METHODS: Sociodemographic characteristics and syringe use data regarding the last injection episode were combined from 3 projects (n = 1181) recruiting injection drug users in ongoing studies in Harlem and the Bronx in New York City from January 2001 through June 2003. These data were analyzed as serial cross sections by calendar quarter. RESULTS: Receptive sharing decreased significantly over time, from 13.4% in the first quarter to 3.6% in the last quarter. Obtaining the last injection syringe from an ESAP source (mostly pharmacies) increased significantly over time, from 7.5% in the first quarter to 25.0% in the last quarter. In multiple logistic regression analysis, variables that were significantly associated with less receptive sharing were syringe exchange and ESAP syringe source as well as time since ESAP inception. Female gender and white race/ethnicity were significantly associated with greater receptive sharing. CONCLUSIONS: The increase in the use of pharmacies and other ESAP syringe sources in this sample has been accompanied by a decline in receptive sharing.

A placebo controlled, double-blind trial of mecamylamine treatment of cocaine dependence was performed in methadone or LAAM maintained subjects who met DSM-IV criteria for cocaine dependence. After an eight-week placebo run-in screening period, 35 subjects were randomly assigned to receive either mecamylamine (6 mg/day) or placebo transdermal patches for a 16-week treatment period. Outcome measures included quantitative urine benzoylecognine (BE) levels, self-report of cocaine use, cocaine craving, global impression scores, mood, retention, and safety. Mecamylamine was well tolerated, and study retention did not differ by treatment group. Evidence for cocaine use, based on urine BE levels and cocaine abstinence rates, did not differ by treatment group. Self reported cocaine use, cocaine craving, and global impression scores showed moderate improvement in both groups, with a significantly greater reduction in cocaine craving (p < 0.05) and self-rated severity of cocaine dependence (p < 0.05) in the placebo group. This pilot study does not support the effectiveness of mecamylamine for the treatment of cocaine dependence in methadone or LAAM maintained patients

OBJECTIVES: We examined the relation between childhood sexual abuse and injection drug use initiation among young adult injection drug users. METHODS: We used mixed effect linear models to compare age at first injection among 2143 young injection drug users by first sexual abuse age categories. RESULTS: The participants were predominantly male (63.3%) and White (52.8%). Mean age and age at first injection were 23.7 and 19.6 years, respectively; 307 participants (14.3%) reported childhood sexual abuse. After adjustment for gender, race/ethnicity, noninjection drug use before first injection drug use, and recruitment site, childhood sexual abuse was independently associated with younger age at first injection. CONCLUSIONS: Childhood sexual abuse was associated with earlier initiation of injection drug use. These data emphasize the need to integrate substance abuse prevention with postvictimization services for children and adolescents.

OBJECTIVES: We investigated individual- and neighborhood-level factors associated with adolescent initiation of injection drug use. METHODS: Injection drug users (IDUs) who had been injecting 2 to 5 years underwent HIV testing and completed a sociobehavioral risk survey. Modeling techniques accounting for intraneighborhood correlations were used in data analyses. RESULTS: Adolescent-initiating IDUs were less likely than adult-initiating IDUs to report high-risk sex and injection behaviors and more likely to report high-risk networks. African American IDUs from neighborhoods with large percentages of minority residents and low adult educational levels were more likely to initiate injection during adolescence than White IDUs from neighborhoods with low percentages of minority residents and high adult education levels. CONCLUSIONS: Racial segregation and neighborhood-level educational attainment must be considered when drawing inferences about age at initiation of injection drug use and related high-risk behaviors

AIMS: To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence. DESIGN: A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study. INTERVENTION: After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests. RESULTS: Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed. CONCLUSION: This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence

AIMS: To conduct a medication screening trial study on the efficacy of celecoxib versus placebo for the treatment of cocaine dependence. DESIGN: A modified blinded, parallel group study in an outpatient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Twenty-three participants were enrolled in the treatment phase of the study. INTERVENTION: After a 2-week screening period, subjects were assigned randomly to receive either celebrex (200 mg/day) or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs and extrapyramidal side-effects tests. RESULTS: Study retention was similar across both treatment groups and safety measures indicated that celecoxib was moderately tolerated. Cocaine use, as measured by self-report and urine BE levels at end of treatment, indicated weaker improvement in the celecoxib group. Reductions in the intensity of cocaine craving were also weaker in the celecoxib group. Cocaine abstinence rates, global impression scores and all other related psychometric measures did not differ significantly between treatment groups. CONCLUSION: This study does not support the effectiveness of celecoxib for the treatment of cocaine dependence