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Director's Report to the National Advisory Council on Drug Abuse - September, 2006

Research Findings - Research on Pharmacotherapies for Drug Abuse

Aripiprazole Attenuates the Discriminative-Stimulus and Subject-Rated Effects of D-Amphetamine in Humans

Studies of aripiprazole in animals suggest that partial agonists at the D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial D2 agonist activity. In this study, seven participants with a history of stimulant abuse learned to discriminate 15 mg oral d-amphetamine, after which the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10 and 15 mg) , alone and in combination with aripiprazole (0 and 20 mg) were assessed. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of d-amphetamine, as well as some of the subject-rated drug effects. Lile, J.A., Stoops, W.W., Vansickel, A.R., Glaser, P.E.A., Hays, L.R. and Rush, C.R. Neuropsychopharmacology, 30, pp. 2103-2114, 2005.

Safety and Immunogenicity of a Nicotine Conjugate Vaccine in Current Smokers

This study in 68 smokers was carried out to assess the safety and immunogenicity of a nicotine conjugate vaccine, NicVAX, and its effects on smoking behavior. Participants were assigned to 1 of 3 doses of NicVAX (50, 100 or 200 g) or placebo. They were injected on days 0, 28, 56, and 182 and monitored for 38 weeks. Results showed that NicVAX was safe and well tolerated. Vaccine immunogenicity was dose-related (P<.001) with the highest dose eliciting antibody concentrations within the anticipated range of efficacy. The 30-day abstinence rate was significantly different across the 4 doses (P=.02) with the highest rate of abstinence occurring with 200 g. Hatsukami, D.K., Rennard, S., Jorenby, D., Fiore, M., Koopmeiners, J., de Vos, A., Horwith, G. and Pentel, P.R. Clin. Pharmacol. Ther., 79, pp. 456-467, 2005.

Cognitive Deficits Predict Low Treatment Retention in Cocaine Dependent Patients

Impaired cognition predicted treatment dropout from cognitive behavioral therapy (CBT) in a small sample of cocaine dependent patients. To further address the role of impaired cognition in retention and treatment outcome of cocaine-dependent patients in CBT, the P.I. expanded a previous investigation to a larger sample, added depressed cocaine patients, and added an additional cognitive assessment. Fifty-six cocaine dependent patients receiving CBT in outpatient clinical trials were assessed for cognitive performance at treatment entry with the computerized MicroCog (MC) and the Wisconsin Card Sort Test (WCST). Treatment completion was defined as 12 or more weeks. Treatment dropouts had significantly lower MC scores (poorer cognitive functioning) than completers on attention, memory, spatial ability, speed, accuracy, global functioning, and cognitive proficiency, with effect sizes in the moderate to large range. These findings were not affected by depression, demographics (age, gender, race, sex, marital status) or drug use (years of cocaine use or average weekly cocaine expenditure in the prior 30 days). In contrast, patients' performance on the WCST was in the average or near-average range, and WCST scores did not differentiate between completers and dropouts. Consistent with previous research, results suggest that mild cognitive impairments (< or =1 S.D. below the mean) negatively affect retention in outpatient CBT treatment for cocaine dependence. Future studies should examine whether there are specific effects of different executive functioning abilities on treatment outcome. Modified behavioral and pharmacologic interventions should be considered to target mild cognitive impairments to improve substance treatment outcome. Aharonovich, E., Hasin, D. S., Brooks, A. C., Liu, X., Bisaga, A., & Nunes, E. V. Cognitive Deficits Predict Low Treatment Retention in Cocaine Dependent Patients. Drug Alcohol Depend., 81, pp. 313-322, 2006.

Clozapine Use and Relapses of Substance Use Disorder Among Patients With Co-occurring Schizophrenia and Substance Use Disorders

Previous correlational research with schizophrenic patients has suggested that the second-generation antipsychotic medication clozapine helps to induce remissions of substance use disorder in patients with co-occurring psychosis and substance abuse. This research, however, could be biased by selection factors. Studying patients who are currently in substance abuse remission could control for level of motivation to stop using substances and other methodological confounds.To test whether clozapine was associated with prevention of substance abuse relapses, the P.I. examined patients with schizophrenia or schizoaffective disorder who were in their first 6-month remission of substance use disorder during a prospective 10-year follow-up study. All patients received yearly multimodal assessments of substance use. Antipsychotic medications were prescribed by community doctors as part of usual clinical care. Patients using clozapine at the first 6-month period of substance abuse remission (n = 25) were much less likely to relapse over the next year compared with those on other antipsychotic medications (n = 70): 8.0% vs 40.0%, chi(2) = 8.73 (df = 1), P = .003. Although medication assignment was not randomized, several potential confounders were similar between the groups. In conclusion, clozapine should be considered for the treatment of patients with schizophrenia and co-occurring substance use disorder to prevent relapses to substance abuse. Brunette, M.F., Drake, R.E., Xie, H., McHugo, G.J., and Green, A.I. Clozapine Use and Relapses of Substance Use Disorder Among Patients With Co-occurring Schizophrenia and Substance Use Disorders. Schizophr. Bull, 2006 (EPub ahead of print).

Drug Stroop Performance: Relationships With Primary Substance of Use and Treatment Outcome in a Drug-Dependent Outpatient Sample

A modified Stroop protocol was administered to a sample of 80 dependent drug users (62 males, 18 females) prior to beginning a time-limited outpatient treatment study combining pharmacotherapy and cognitive-behavioral coping skills therapy for cocaine, marijuana, or heroin dependence. Results indicated that cocaine-dependent participants responded more slowly than marijuana-dependent participants to all stimulus words. Cocaine words yielded slower reaction times than neutral words across all treatment groups. The heroin- and cocaine-dependent groups' overall performance did not differ. There was no treatment group by drug word interaction. For cocaine-dependent participants, Stroop performance in the presence of cocaine stimuli was associated with worse treatment outcome. In conclusion, Stroop performance may have prognostic utility among drug-dependent patients in a cognitive-behavioral coping skills intervention and may highlight the mechanisms associated with changing substance use in this treatment modality. Carpenter, K. M., Schreiber, E., Church, S., and McDowell, D. Drug Stroop Performance: Relationships with Primary Substance of Use and Treatment Outcome in a Drug-dependent Outpatient Sample. Addict. Behav., 31, pp. 174-181, 2006.

Response to Cocaine, Alone and in Combination with Methylphenidate, in Cocaine Abusers with ADHD

Attention deficit hyperactivity disorder (ADHD) is prevalent in adult cocaine abusers. Yet, it remains to be determined how the response to cocaine differs in cocaine abusers with ADHD compared to cocaine abusers without ADHD. Further, since ADHD is commonly treated with stimulants, such as methylphenidate (MPH), it is important to examine whether MPH maintenance alters the response to cocaine in cocaine abusers with ADHD. Thus, the first phase of this study compared the response to cocaine in adult cocaine abusers with ADHD to those without ADHD. The second phase assessed the effects of oral sustained-release methylphenidate (MPH-SR) maintenance (40 and 60 mg) on the response to cocaine only in those with ADHD. Cocaine abusers with ADHD (N=7) and without ADHD (N=7) who were not seeking treatment remained inpatient initially for 1 week, when the effects of cocaine alone were tested (Phase 1). Cocaine abusers with ADHD remained inpatient for an additional 3 weeks, during which the effects of cocaine during oral MPH-SR maintenance were tested (Phase 2). During cocaine fixed dosing sessions, participants received four injections of i.v. cocaine (0, 16 or 48 mg/70 kg), spaced 14 min apart. During cocaine choice sessions, participants had a choice between receiving i.v. cocaine (16 or 48 mg/70 kg) or two tokens, each exchangeable for 2 US dollars. Subjective effects related to ADHD symptoms (e.g. ratings of "Able to Concentrate") were significantly lower in cocaine abusers with ADHD compared to those without ADHD when placebo cocaine was administered. Active cocaine produced similar increases in cardiovascular and positive subjective effects in both groups and there was no difference in cocaine choice between the two groups. These data suggest that the response to cocaine is not different between cocaine abusers with ADHD compared to those without ADHD. When the cocaine abusers with ADHD were maintained on MPH-SR, cardiovascular effects were increased, however, this did not warrant termination of any test session. Maintenance on MPH-SR decreased some of the positive subjective effects of cocaine. Further, maintenance on a high dose of MPH-SR decreased cocaine choice. Thus, oral MPH-SR is safe in combination with repeated cocaine doses and decreases some of the positive and reinforcing effects of cocaine in cocaine abusers with ADHD. Collins, S.L., Levin, F.R., Foltin, R.W., Kleber, H.D., and Evans, S.M. Response to Cocaine, Alone and in Combination with Methylphenidate, in Cocaine Abusers with ADHD. Drug Alcohol Depend., 82, pp. 158-167, 2006.

Buprenorphine/Naloxone Reduces the Reinforcing and Subjective Effects of Heroin in Heroin-dependent Volunteers

Although buprenorphine is effective in treating opioid dependence, optimal maintenance doses of buprenorphine or the buprenorphine/naloxone combination have not yet been established. The present study was designed to evaluate the effects of buprenorphine/naloxone maintenance (2/0.5, 8/2, 32/8 mg sublingual) on the reinforcing and subjective effects of heroin (0, 12.5, 25, 50, and 100 mg intranasal) in heroin-dependent individuals. During test weeks, participants (N=7) first sampled a dose of heroin and 20 dollars. During subsequent choice sessions, participants could choose to self-administer heroin and/or money. Participants responded under a modified progressive-ratio schedule (PR 50, ..., 2,800) during a ten-trial self-administration task. Heroin break point values and subjective responses were significantly lower under 8/2 and 32/8 mg buprenorphine/naloxone compared to 2/0.5 mg. The self-administration and subjective effects data for heroin in the presence of buprenorphine/naloxone were compared to a separate control group of recently detoxified participants (N=8) in order to obtain estimates for the apparent in vivo dissociation constant (K(A)), the efficacy estimate (tau), and the estimated fraction of receptors remaining after buprenorphine/naloxone treatment (q). The apparent in vivo dissociation constant for heroin ranged from 50 to 126 mg (K(A)) and the efficacy estimate ranged from 13 to 20 (tau). In addition, 2/0.5, 8/2, and 32/8 mg buprenorphine/naloxone dose-dependently reduced the receptor population by 74, 83, and 91%, respectively. These data demonstrate that both 8/2 and 32/8 mg buprenorphine/naloxone were well tolerated and effective in reducing the reinforcing and subjective effects of heroin, relative to the 2/0.5-mg dose. The data also show for the first time in humans that it is possible to quantify the efficacy and affinity of heroin for mu opioid receptors, and that 80-90% of mu receptors need to be inactivated in order to obtain significant reductions in heroin-induced effects. These results have important implications for future studies in which it will be possible to obtain estimates of relative affinity and efficacy of different agonists at mu opioid receptors. Comer, S.D., Walker, E.A., and Collins, E.D. Buprenorphine/Naloxone Reduces the Reinforcing and Subjective Effects of Heroin in Heroin-dependent Volunteers. Psychopharmacology (Berl), 181, pp. 664-675, 2006.

Analysis of Variations in the Tryptophan Hydroxylase-2 (TPH2) Gene in Cocaine Dependence

While the exact physiological mechanisms underlying cocaine dependence remain unclear, a growing body of evidence indicates a role for the serotonergic neurotransmitter system in the pathology of this substance use disorder. The focus of the present study is to determine whether genetic variation in the tryptophan hydroxylase-2 (TPH2) gene, which encodes the enzyme responsible for synthesis of the majority of the serotonin contained in neurons of the central nervous system, contributes to the pathophysiology of cocaine dependence. To examine this hypothesis, the investigators used a case-control study design in which the genotype and allele distributions for six single nucleotide polymorphisms (SNPs) in the TPH2 gene were compared between cocaine-dependent (n = 299) and control individuals (n = 208) of African descent. The results indicate that none of the SNPs in the TPH2 gene examined in this study associate with the cocaine-dependent phenotype. This work suggests that variations in the TPH2 gene are not a risk factor for the development of cocaine dependence, but these findings require confirmation in larger, independent samples of cocaine-dependent and control subjects. Dahl, J.P., Cubells, J.F., Ray, R., Weller, A.E., Lohoff, F.W., Ferraro, T.N. et al.. Analysis of Variations in the Tryptophan Hydroxylase-2 (TPH2) Gene in Cocaine Dependence. Addict. Biol., 11, pp. 76-83, 2006.

Interaction Between Variation in the D2 Dopamine Receptor (DRD2) and the Neuronal Calcium Sensor-1 (FREQ) Genes in Predicting Response to Nicotine Replacement Therapy for Tobacco Dependence

It has been demonstrated that a functional dopamine D2 receptor promoter variant (DRD2 -141 Ins/Del) predicts response to nicotine replacement therapy (NRT). The present study extends this finding in the same population of 363 NRT-treated subjects, by examining variation in the gene encoding the neuronal calcium sensor-1 protein (FREQ), which functions to regulate D2 receptor desensitization. The results indicate a statistically significant interaction effect of DRD2-141 and FREQ genotypes on abstinence at the end of the NRT treatment phase; 62% of the smokers with at least one copy of the DRD2 -141 Del allele and two copies of the FREQ rs1054879 A allele were abstinent from smoking, compared to 29-38% abstinence rates for other smokers in the trial. This result suggests that the interaction between variation in the DRD2 and FREQ genes, which both encode components of the D2 dopamine receptor signal transduction pathway, impacts the efficacy of NRT. Dahl, J. P., Jepson, C., Levenson, R., Wileyto, E. P., Patterson, F., Berrettini, W.H. et al.. Interaction Between Variation in the D2 Dopamine Receptor (DRD2) and the Neuronal Calcium Sensor-1 (FREQ) Genes in Predicting Response to Nicotine Replacement Therapy for Tobacco Dependence. Pharmacogenomics. J., 6, pp. 194-199, 2006.

Modafinil Attenuates Disruptions in Cognitive Performance During Simulated Night-Shift Work

Common complaints among shift workers are sleep disruptions and increased sleepiness while working, which may contribute to shift workers being more susceptible to diminished performance and work-related accidents. The purpose of this double-blind, within-participant study was to examine the effects of the alerting agent modafinil on cognitive/psychomotor performance, mood, and measures of sleep during simulated shift work. In all, 11 participants completed this 23-day residential laboratory study. They received a single oral modafinil dose (0, 200, 400 mg) 1 h after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an 'off' day. When participants received placebo, cognitive performance and subjective ratings of mood were disrupted during the night shift, relative to the day shift. Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Modafinil reversed disruptions in cognitive performance and mood during the night shift. While modafinil produced few effects on sleep measures during the night shift, the largest dose produced several sleep alterations during the day shift. These data demonstrate that abrupt shift changes produced cognitive performance impairments and mood disruptions during night shift work. Therapeutic doses of modafinil attenuated night-shift-associated disruptions, but the larger dose produced some sleep impairments when administered during day-shift work. Hart, C.L., Haney, M., Vosburg, S.K., Comer, S.D., Gunderson, E., and Foltin, R.W. Modafinil Attenuates Disruptions in Cognitive Performance During Simulated Night-Shift Work. Neuropsychopharmacology, 31, pp. 1526-1536, 2006.

Biomarkers to Assess the Utility of Potential Reduced Exposure Tobacco Products

To date, there are no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area. Hatsukami, D.K., Benowitz, N.L., Rennard, S.I., Oncken, C., and Hecht, S.S. Biomarkers to Assess the Utility of Potential Reduced Exposure Tobacco Products. Nicotine.Tob.Res., 8, pp. 169-191, 2006.

A Double-blind, Placebo-Controlled Trial of Amantadine, Propranolol, and Their Combination for the Treatment of Cocaine Dependence in Patients with Severe Cocaine Withdrawal Symptoms

This trial evaluated the efficacy of amantadine, propranolol and their combination in cocaine dependent patients with severe cocaine withdrawal symptoms. Cocaine withdrawal symptom severity was measured by the cocaine selective severity assessment (CSSA). One hundred and ninety-nine patients with high scores on the CSSA participated in a 10-week double-blind trial. Patients were randomly assigned to receive amantadine (300mg/day), propranolol (100mg/day), a combination of amantadine (300mg/day) and propranolol (100mg/day) or matching placebo capsules. The primary outcome measure was cocaine abstinence. In the intent-to-treat sample, there were no significant differences between the four medication groups in treatment retention. The odds of cocaine abstinence showed a marginally significant increase over time in the propranolol group (p=0.06) but not in the other three groups. In highly medication-adherent patients, treatment retention was significantly better in the propranolol group compared to the placebo group (p=0.01) and the odds of cocaine abstinence increased significantly over time in the propranolol group but not in the other three groups. In the intent-to-treat sample, none of the three active treatments (propranolol, amantadine or their combination) was significantly more effective than placebo in promoting abstinence from cocaine among patients who entered treatment with more severe cocaine withdrawal symptoms. Among patients highly adherent to study medication, propranolol treatment was associated with better treatment retention and higher rates of cocaine abstinence compared to placebo. Kampman, K.M., Dackis, C., Lynch, K.G., Pettinati, H., Tirado, C., Gariti, P. et al. A Double-blind, Placebo-Controlled Trial of Amantadine, Propranolol, and Their Combination for the Treatment of Cocaine Dependence in Patients with Severe Cocaine Withdrawal Symptoms. Drug Alcohol Depend. 2006 (epub ahead of print).

Severity of Dependence and Motivation for Treatment: Comparison of Marijuana- and Cocaine-Dependent Treatment Seekers

Although marijuana dependence is prevalent, most individuals with marijuana dependence do not seek treatment. There are few data characterizing treatment seeking marijuana-dependent patients compared to patients presenting for treatment of other drugs regarding the severity of illness and motivation for treatment. Forty-two marijuana-dependent individuals were compared to 58 cocaine-dependent individuals seeking treatment. Compared to cocaine-dependent patients, those with marijuana dependence were younger and less likely to be dependent on alcohol or other drugs. Both groups had similar rates of comorbid anxiety and affective disorders. Marijuana-dependent individuals had lower total number of dependence symptoms but had a higher percentage of individuals endorsing withdrawal symptoms. Although marijuana-dependent individuals had less outpatient treatment exposure, the difference between the two groups was not significant and motivation for change, based on the University of Rhode Island Change Assessment, was similar for both groups of treatment seekers. However, the Circumstances, Motivation, Readiness for Treatment Scale suggested that cocaine-dependent individuals were more motivated for treatment. Taken together, these data suggest that treatment seeking marijuana-dependent individuals have substantial withdrawal dependence symptomatology although it is less clear if they are as motivated to seek out treatment as cocaine-dependent treatment seekers. Levin, F.R., Brooks, D.J., Bisaga, A., Raby, W., Rubin, E., Aharonovich, E. et al. Severity of Dependence and Motivation for Treatment: Comparison of Marijuana- and Cocaine-Dependent Treatment Seekers. J. Addict. Dis., 25, pp. 33-41, 2006.

A Randomized, Open-Label, Controlled Trial of Gabapentin and Phenobarbital in the Treatment of Alcohol Withdrawal

Gabapentin was compared with phenobarbital for the treatment of alcohol withdrawal in a randomized, open-label, controlled trial in 27 inpatients. There were no significant differences in the proportion of treatment completers between treatment groups or the proportion of patients in each group requiring rescue medication for breakthrough signs and symptoms of alcohol withdrawal. There were no significant treatment differences in withdrawal symptoms or psychological distress, nor were there serious adverse events. These findings suggest that gabapentin may be as effective as phenobarbital in the treatment of alcohol withdrawal. Given gabapentin's favorable pharmacokinetic profile, further study of its effectiveness in treating alcohol withdrawal is warranted. Mariani, J.J., Rosenthal, R.N., Tross, S., Singh, P., and Anand, O.P. A Randomized, Open-Label, Controlled Trial of Gabapentin and Phenobarbital in the Treatment of Alcohol Withdrawal. Am. J. Addict., 15, pp. 76-84, 2006.

Preliminary Observations of Paranoia in a Human Laboratory Study of Cocaine

Cocaine-induced paranoia (CIP) has recently shown a relationship to genetic factors that may moderate disulfiram treatment response in cocaine-dependent individuals. However, little research has examined CIP under controlled laboratory conditions. This study examined subjective and physiological responses to a 0.4 mg/kg dose of smoked cocaine in a human laboratory setting with 23 male and 21 female cocaine users. Twenty-nine of 44 participants (67%) reported feeling Paranoid/Suspicious in response to cocaine. Those who reported feeling Paranoid/Suspicious were more likely to be older and male. Further studies are warranted to investigate the mechanisms of gender influence on CIP, and CIP in pharmacotherapy development for cocaine-dependent individuals. Mooney, M., Sofuoglu, M., Dudish-Poulsen, S., and Hatsukami, D.K. Preliminary Observations of Paranoia in a Human Laboratory Study of Cocaine. Addict. Behav., 31, pp. 1245-1251, 2006.

Attitudes and Knowledge about Nicotine and Nicotine Replacement Therapy

Nicotine replacement therapies (NRTs) represent an effective means of promoting smoking cessation, but they remain underutilized. Negative attitudes and false beliefs about nicotine and nicotine replacement may cause NRT underutilization. In a randomized, controlled, single-blind study of nicotine gum, 97 smokers were assessed on their attitudes and knowledge about nicotine, nicotine replacement, and smoking cessation therapy. Information from these self-report measures was used in an intervention that provided tailored, brief feedback to promote positive attitudes and accurate knowledge about NRT. Considerable variability in pretreatment attitudes and knowledge was observed across individuals. Moreover, attitudes and knowledge showed a consistent pattern of intercorrelation and were systematically related to smoking characteristics (e.g., prior use of NRT, nicotine dependence, treatment completion). The brief feedback intervention led to a significant global elevation in attitudes about nicotine, NRT, and assisted cessation but not knowledge about nicotine. Changes in attitudes and knowledge were not significantly related to gum use or smoking cessation. Recommendations for the appropriate application of brief feedback are offered. Mooney, M.E., Leventhal, A.M., and Hatsukami, D.K.. Attitudes and Knowledge about Nicotine and Nicotine Replacement Therapy. Nicotine. Tob. Res., 8, pp. 435-446, 2006.

Tobacco-Specific Nitrosamines in New Tobacco Products

New tobacco products, designed to attract consumers who are concerned about the health effects of tobacco, have been appearing on the market. Objective evaluation of these products requires, as a first step, data on their potentially toxic constituents. Tobacco-specific nitrosamines (TSNAs) are an important class of carcinogens in tobacco products, but virtually no data were available on their levels in these products. In the present study, the investigators analyzed several new products-Ariva, Stonewall, Exalt, Revel, Smokey Mountain, and Quest-for TSNAs and compared their TSNA levels with those in nicotine replacement products and conventional smokeless tobacco and cigarette brands. TSNAs were not detected in Smokey Mountain, which is a tobacco-free snuff product. The lowest levels among the new products containing tobacco were in Ariva and Stonewall (0.26-0.28 microg/g wet weight of product). The highest levels in the new products were found in Exalt (3.3 microg/g tobacco), whereas Revel and Quest had intermediate amounts. Only trace amounts were found in nicotine replacement products, and conventional brands had levels consistent with those reported in the literature. These results demonstrate that TSNA levels in new tobacco products range from relatively low to comparable with those found in some conventional brands. Stepanov, I., Jensen, J., Hatsukami, D., and Hecht, S.S. Tobacco-Specific Nitrosamines in New Tobacco Products. Nicotine. Tob. Res., 8, pp. 309-313, 2006.

The Status of Disulfiram: A Half of a Century Later

For more than 55 years, disulfiram has been approved by the Food and Drug Administration for the treatment of alcohol dependence. It is a unique medication that relies on "psychological threat" to avoid disulfiram-ethanol reactions. This paper reviews the history of disulfiram treatment, the current status of disulfiram treatment, the ensuing developments in disulfiram use in treating various addictions, and future directions. Clinical trials using disulfiram for the treatment of alcohol, cocaine, or co-occurring alcohol + cocaine dependence were included in this review. Disulfiram efficacy studies focusing on supervised, implant, and combination pharmacotherapies were also examined. In clinical trials, disulfiram has demonstrated inconsistent results in helping patients to abstain from alcohol, and patients poorly adhere to a disulfiram-treatment regimen. This has raised questions about disulfiram's practicality in the treatment of alcohol dependence. Recently, however, disulfiram has gained attention as a complementary agent to newer pharmacological medications, such as an opiate antagonist that specifically reduces alcohol craving. One hypothesis is that disulfiram would assist patients in gaining psychological control over drinking when given in conjunction with an opiate antagonist that would act directly on reducing alcohol craving. Preliminary evidence also suggests that disulfiram treatment could be a viable treatment for cocaine dependence because it was shown to reduce cocaine use among nonalcoholic, cocaine-dependent patients. Suh, J. J., Pettinati, H.M., Kampman, K.M., and O'Brien, C.P. The Status of Disulfiram: A Half of a Century Later. J. Clin. Psychopharmacol., 26, pp. 290-302, 2006.

Interaction of Amphetamines and Related Compounds at the Vesicular Monoamine Transporter

Amphetamine-type agents interact with the vesicular monoamine transporter (VMAT2), promoting the release of intravesicular neurotransmitter and an increase in cytoplasmic neurotransmitter. Some compounds, like reserpine, "release" neurotransmitter by inhibiting the ability of VMAT2 to accumulate neurotransmitter in the vesicle, while other types of compounds can release neurotransmitter via a carrier-mediated exchange mechanism. The purpose of this study was to determine, for 42 mostly amphetamine-related compounds, their mode of interaction with the VMAT2. Authors used a crude vesicular fraction prepared from rat caudate to assay VMAT2 activity. Test compounds were assessed in several assays including: a) inhibition of [(3)H]dihydro tetrabenazine binding, b) inhibition of vesicular [(3)H]dopamine uptake, and c) release of pre-loaded [(3)H]dopamine and [(3)H]tyramine. Several important findings derive from this comprehensive study. First, this work indicates that most agents are VMAT2 substrates. Two, these data strongly suggest that amphetamine-type agents deplete vesicular neurotransmitter via a carrier-mediated exchange mechanism rather than via a free-base effect, although this conclusion needs to be confirmed via direct measurement of vesicular pH. Three, these data fail to reveal differential VMAT2 interactions among agents which do and do not produce long-term 5-HT depletion. Four, the data reported revealed the presence of two pools of [(3)H]amine within the vesicle, that which is free, and that which is tightly associated with the ATP/protein complex that helps store amine. Finally, the VMAT2 assays the authors have developed should prove useful for guiding the synthesis and evaluation of novel VMAT2 agents as possible treatment agents for addictive disorders. Partilla, J.S., Dempsey, A.G., Nagpal, A.S., Blough, B.E., Baumann, M.H., Rothman, R.B., J Pharmacol Exp Ther. July 11, 2006 [Epub ahead of print].

A Novel Nicotinic Acetylcholine Receptor Antagonist Radioligand for PET Studies

Using positron emission tomography (PET) with a specific and selective radioligand targeting nicotinic acetylcholine receptor (nAChR) would allow us to better understand various nAChR related CNS disorders. The use of radiolabeled nAChR antagonists would provide a much safer pharmacological profile, avoiding most peripheral side effects that might be generated from radiolabeled nAChR agonists even at the tracer level; thus, PET imaging with nAChR antagonists would facilitate clinical application. A potent and selective nAChR antagonist was labeled and characterized with PET in non-human primates. Its high brain uptake, high signal-to-noise ratio, and high specific binding strongly suggest a great potential to carry out imaging studies in humans. In addition, the use of a C-11 radiotracer would allow us to perform multiple PET studies in the same individual within a short time frame. The presence of an iodine atom in the molecule also allows the possibility to label with radioiodine for SPECT studies. Ding, Y.S., Kil, K.E., Lin, K.S., Ma, W., Yokota, Y., and Carroll, I.F., Bioorg Med Chem Lett. 16(4), pp. 1049-1053, February 15, 2006.

Recent Advances in the Treatment of Cocaine Abuse: Central Nervous System Immunopharmacotherapy

Cocaine addiction continues to be a major health and societal problem in spite of governmental efforts devoted toward educating the public of the dangers of illicit drug use. A variety of pharmacotherapies and psychosocial programs have been proposed in an effort to provide a method for alleviation of the physical and psychological symptoms of cocaine abuse. Unfortunately, these methods have been met with limited success, illustrating a critical need for new effective approaches for the treatment of cocaine addiction. Recently an alternative cocaine abuse treatment strategy was proposed using intranasal administration of an engineered filamentous bacteriophage displaying cocaine-sequestering antibodies on its surface. These phage particles are an effective vector for CNS penetration and are capable of binding cocaine, thereby blocking its behavioral effects in a rodent model. The convergence of phage display and immunopharmacotherapy has allowed for an investigation of the efficacy of protein-based therapeutics acting within the CNS on the effects of cocaine in animal models and has uncovered a new tool in the battle against cocaine addiction. Dickerson, T.J., and Janda, K.D. AAPS J. 7(3):E579-586, October 19, 2005.

Development of New Brain Imaging Agents Based Upon Nocaine-Modafinil Hybrid Monoamine Transporter Inhibitors

11C-labeled(+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin -3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl) -1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities authors speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT. Musachio, J.L., Hong, J., Ichise, M., Seneca, N., Brown, A.K., Liow, J.S., Halldin, C., Innis, R.B., Pike, V.W., He, R., Zhou, J., and Kozikowski, A.P. Bioorg Med Chem Lett. 16(12), pp. 3101-3104, June 15, 2006.

Dopamine Transporter (DAT) Inhibitors Alleviate Specific Parkinsonian Deficits in Monkeys: Association with DAT Occupancy In Vivo

This study was undertaken to test the hypothesis that viable dopamine neurons in Parkinson's disease express the dopamine transporter (DAT) and release dopamine (DA). Authors postulated that potent DAT inhibitors, with low affinity for the serotonin transporter (SERT), may elevate endogenously released extracellular dopamine levels to provide therapeutic benefit. General methods: The therapeutic potential of eight DAT inhibitors was investigated in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) cynomolgus monkeys (Macaca fasicularis), with efficacy correlated with DAT occupancy as determined by PET imaging in striatum. Four potent DAT inhibitors, with relatively high norepinephrine transporter, but low SERT affinities, that occupied the DAT improved activity in parkinsonian monkeys, whereas three high affinity DAT inhibitors with low DAT occupancy did not. O-1163 occupied the DAT but had short-lived pharmacological effects. The benztropine analog difluoropine increased general activity, improved posture, reduced body freeze, and produced disturbances at high doses. O-1369 alleviated parkinsonian signs in advanced parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze and sedation, but not significantly reducing bradykinesia or increasing locomotor activity. In comparison with the D2-D3- DA receptor agonist quinelorane, O-1369 elicited oro-facial dyskinesias, whereas quinelorane did not improve posture or reduce balance and promoted stereotypy. Authors conclude that DAT inhibitors with therapeutic potential combine high DAT affinity in vitro, high DAT occupancy of brain striatum in vivo, with enduring daytime effects that do not extend into the nighttime. Advanced parkinsonian monkeys (80% DAT loss) respond more effectively to DAT inhibitors than mild parkinsonian monkeys (46% DAT loss). The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants preclinical investigation. Madras, B.K., Fahey, M.A., Goulet, M., Lin, Z., Bendor, J., Goodrich, C., Meltzer, P.C., Elmaleh, D.R., Livni, E., Bonab, A.A., and Fischman, A.J. J Pharmacol Exp Ther. August 2, 2006 [Epub ahead of print].


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