William W. Stoops, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Internet-Based Voucher Reinforcement for Smoking Cessation: Tobacco use continues to be the number one preventable cause of morbidity and mortality in the United States. In no other population are the prevalence rates and problems of smoking more apparent and pronounced than those in rural populations, where access to treatment is limited. Current smoking cessation interventions are modestly effective, which suggest the need for therapies that are more intensive, innovative, and accessible. Voucher-based abstinence reinforcement therapy is a highly intensive approach wherein patients earn monetary vouchers that can be exchanged for goods and services contingent on documented abstinence. To improve the accessibility of this intensive therapy to smokers who want to quit smoking, a novel voucher based abstinence reinforcement therapy for smoking has been developed wherein smoking status is frequently monitored and reinforced via the internet. With this internet based intervention, real-time video of smokers providing CO samples are collected and verified for smoking status. Patients are then provided feedback and reinforcement based on their verified smoking status. This innovative approach may be well suited for rural smokers who are in need of accessible intensive smoking cessation interventions. This grant application proposes exploratory research to adapt, implement, and evaluate a novel internet based voucher reinforcement intervention for smoking cessation in heavy smokers in rural Kentucky. A pilot study is proposed in which rural smokers in Kentucky (N=80) will be randomly assigned to one of two groups: contingent vs. noncontingent vouchers group. For 6 weeks, CO samples will be collected and verified twice daily from all participants using an internet based CO monitoring system. Participants assigned to the contingent vouchers group will receive monetary vouchers if they provide a CO sample <4ppm. Participants in the noncontingent vouchers group will receive vouchers independent of their CO sample. Overall, the application proposes research to develop and evaluate an intensive and accessible smoking cessation intervention for heavy smokers in rural communites, and provide the empirical basis for future research. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Cocaine dependence continues to be a significant public health concern. Data from the National Survey on Drug Use and Health indicate that the number of Americans who had used cocaine in the past month has remained relatively stable since 2002 and cocaine remains the most frequently mentioned drug in emergency-room admissions according to the Drug Abuse Warning Network. Because of the public-health concerns and costs associated with its abuse, identifying a pharmacotherapy for the treatment of cocaine dependence is a priority for the National Institute on Drug Abuse (NIDA). Despite intense research efforts, a widely accepted medication for cocaine dependence has not yet been identified. A number of non-pharmacological treatments for cocaine dependence have also been examined. Specifically, behavioral treatments for cocaine dependence seek to reinforce non- drug related behaviors. For example, contingency management uses monetary incentives to decrease cocaine use and is associated with high rates of prolonged cocaine abstinence. Given the effectiveness, but also high relative cost, of behavioral treatments for cocaine dependence, some have theorized that pharmacotherapies may be able to enhance the effectiveness of behavioral therapies and decrease costs associated with delivery of these therapies. Indeed, pharmacotherapies (i.e., desipramine and bupropion) have been shown to enhance the effectiveness of behavioral therapies for cocaine dependence. The purpose of the experiments proposed in this application is to "reverse engineer" a human laboratory model of combined pharmacological and behavioral treatments for cocaine dependence using an already existing and validated model of contingency management, the cocaine versus money choice paradigm. The research proposed in this application has two specific aims. The first specific aim is to adapt a model of the cocaine versus money choice paradigm that is sensitive to pharmacological pretreatment (Higgins et al., 1996) and determine optimal parameters (i.e., cocaine dose, monetary values). In Experiment 1, eight non-treatment seeking cocaine-dependent subjects will choose between a range of doses of intranasal cocaine and monetary values. These data will be used to guide which cocaine dose and monetary values will be used in Experiment 2. The second specific aim is to validate the sensitivity of the cocaine versus money choice paradigm as a model of combined pharmacological and behavioral treatment. In Experiment 2, eight non-treatment seeking cocaine-dependent subjects will choose between a range of doses of intranasal cocaine and monetary values following maintenance for seven days on placebo or 300 mg bupropion. The research proposed in this application will serve to develop an efficient and valid human laboratory screen of medications for cocaine dependence. Project Narrative The research proposed in this application seeks to develop a model of combined behavioral and pharmacological treatment for cocaine dependence. With this model, we hope to more efficiently screen medications that might enhance the efficacy of contingency management, a behavioral treatment that is successful in managing cocaine dependence. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Prescription opioid misuse and abuse are increasing problems in the United States. In the 2006 National Survey on Drug Use and Health, 5.2 million Americans had illicitly used a prescription opioid in the past month. National rates of illicit prescription opioid use are higher than those for heroin, cocaine or methamphetamine and are exceeded only by marijuana. Moreover, the number of individuals initiating illicit use of prescription opioids was greater than that for marijuana in 2004 and 2005. These findings indicate that illicit prescription opioid use represents a significant public health concern greater than that of cocaine, heroin or methamphetamine and perhaps approaching that of marijuana. The increase in illicit prescription opioid use may be due to increased availability of opioid analgesics medications with significant abuse potential. Discovery and development of opioid analgesics with reduced abuse potential may serve to decrease prescription opioid misuse and the subsequent development of opioid use disorders. Tramadol is an unscheduled atypical analgesic with opioid activity. While rare cases of tramadol abuse and physical dependence have been reported, it has reduced abuse potential relative to typical prescription opioids. The reduced abuse potential of tramadol has been attributed to its novel pharmacology. Tramadol is a mu opioid agonist, but also blocks reuptake of serotonin and norepinephrine. The specific aim of the present application is to elucidate the relative contributions of mu opioid, serotonin and norepinephrine receptor systems to the effects of tramadol using an array of pharmacologic measures relevant to its abuse potential and analgesic efficacy in human volunteers. The knowledge gained about tramadol from the proposed experiments in terms of its neuropharmacology will aid in the discovery and development of other opioid medications with reduced abuse potential. Specifically, if the non-mu mediated effects of tramadol contribute to its analgesic efficacy and reduced abuse potential, these findings would support the development of other analgesics with similar neuropharmacological mechanisms. This project will employ placebo-controlled, randomized and double blind testing procedures to evaluate the behavioral effects of tramadol across three experiments. Overall, this project will contribute important clinical information regarding the pharmacology of tramadol in relation to its analgesic efficacy and reduced abuse potential and provide basic science information about the behavioral effects of prescription opioids in humans. PUBLIC HEALTH RELEVANCE: The research proposed in this application seeks to understand better the human neuropharmacology of tramadol, an atypical analgesic with opioid action that has reduced abuse potential relative to other opioid analgesics. We are seeking to understand how the neuropharmacology of tramadol influences both its analgesic efficacy and reduced abuse potential in an effort to aid development of other analgesic medications with reduced abuse potential. Developing analgesics with reduced abuse potential may reduce the prevalence of prescription opioid misuse and subsequent opioid use disorders.

DESCRIPTION (provided by applicant): Cocaine use disorders are an unrelenting public health concern. Intensive research efforts have yielded behavioral interventions that reduce cocaine use, however, these interventions are not universally effective and treatment effects diminish over time. Development of a pharmacotherapy that enhances the efficacy of these interventions is a priority for the National Institute on Drug Abuse. In the central nervous system cocaine blocks the reuptake and induces release of dopamine and serotonin, thus a successful cocaine pharmacotherapy will likely need to target both of those neurotransmitters. Buspirone, an anxiolytic medication with limited abuse potential, is an antagonist at dopamine autoreceptors and a partial agonist at serotonin 5- HT1A receptors; both of these receptors play crucial roles in the abuse-related effects of cocaine. Dopamine autoreceptors stabilize dopaminergic tone and antagonists at these receptors can increase dopamine release. Moreover, medications with partial agonist activity have been recognized as valuable tools for managing opioid and nicotine use disorders due to their ability to stimulate receptors when neurotransmitter tone is low (i.e., during abstinence) and block receptors when neurotransmitter tone is high (i.e., following a lapse). Although buspirone produces pharmacological effects that are likely beneficial for treating cocaine dependence, we are unaware of any human laboratory research that has tested the influence of buspirone on the behavioral effects of cocaine, a notable gap in the literature considering that such research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This study will assess the reinforcing, subject- rated, cognitive, performance and physiological effects of cocaine during maintenance on buspirone. By determining how buspirone impacts the behavioral effects of cocaine, we will provide important evidence regarding the potential efficacy of this compound for managing cocaine use disorders. These results will help to broaden the current clinical neuroscience paradigm of cocaine medications development efforts beyond a focus on dopamine systems. In addition, demonstrating the initial efficacy of a commercially available drug will impact clinical research more quickly than waiting for novel molecules to be available for testing in humans. PUBLIC HEALTH RELEVANCE: A successful pharmacological adjunct for managing cocaine use disorders will likely need to target more than the dopamine system. Buspirone, an anxiolytic with limited abuse potential, is a serotonin 5HT1A receptor partial agonist and dopamine autoreceptor antagonist that may be effective in treating cocaine dependence. This project will test the influence of buspirone maintenance on the reinforcing effects of cocaine in the human laboratory to further demonstrate its potential efficacy in cocaine use disorders.

DESCRIPTION (provided by applicant): Cocaine is the most commonly used illicit stimulant in the United States. Despite great strides in our understanding of the neuropharmacological underpinnings of cocaine addiction in the preclinical arena, the number of cocaine users in the United States has remained relatively stable in recent years, indicating that more clinical research is necessary to translate these findings to humans in an attempt to develop more effective means of reducing cocaine use. Emerging data suggest that perturbations in glutamate transmission following cocaine use (i.e., disrupted glutamate homeostasis) contribute to the maladaptive pattern of drug taking characterized by cocaine addiction. Specifically, preclinical studies indicate that cocaine exposure results in increased motivation to take cocaine and decreased drive for non-drug reinforcers. This change in reinforcer salience corresponds with complex neuropharmacological changes in the glutamate system. Whereas preclinical data suggest that targeting glutamate systems, specifically restoring glutamate homeostasis, reduces drug reinforcer salience, this research area remains relatively unexplored in humans. Some initial studies suggest that n-acetylcysteine pretreatment normalizes glutamate levels in cocaine users and that n-acetylcysteine maintenance attenuates desire for cocaine and attention to cocaine cues in abstinent cocaine-dependent subjects. Whether restoration of glutamate homeostasis impacts motivation for drug relative to non-drug reinforcers remains to be determined in humans. The research proposed here will demonstrate that restoration of glutamate homeostasis reduces motivation to take cocaine and increases motivation to obtain a non-drug alternative reinforcer (i.e., money) in cocaine-dependent humans using progressive-ratio schedules of reinforcer availability, which are an accepted means to measure motivation. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the influence of restored glutamate homeostasis on motivation to obtain these two types of reinforcers. Cognitive tasks that assess domains relating to reinforcer choice also will be included to complement the self-administration outcomes. This study will translate findings from preclinical research and provide the initial clinical evidence tat restoration of glutamate homeostasis shifts reinforcer salience away from drug reinforcers towards non-drug reinforcers in active cocaine users. Outcomes of the experiment will not only contribute to our understanding of the clinical neuropharmacology of cocaine addiction, they also can be used to guide development of treatments for cocaine use disorders.

DESCRIPTION (provided by applicant): Cocaine (COC) addiction is an unrelenting public health concern. An effective medication has not been identified for COC dependence despite being a high priority for the National Institute on Drug Abuse for nearly 30 years and extensive efforts by the scientific and treatment communities. The results of preclinical studies have shown that monoamine releasers attenuate the reinforcing effects of COC. The results of human laboratory studies also suggest that monoamine releasers attenuate the reinforcing effects of COC although the effects are small in magnitude and dependent on the methods used to assess drug reinforcement. The results of clinical trials that tested monoamine releasers for COC abuse are mixed. Monoamine releasers vary along a continuum from DA/NE selective to 5-HT selective. Theoreticians have postulated that the 5-HT/DA releasing ratio is a critical determinant of the efficacy and specificity of a monoamine releaser to attenuate the reinforcing effects of COC. Compounds with intermediate 5-HT/DA release ratios (i.e., 30-40) were the most effective and specific in terms of reducing cocaine taking. For example, methamphetamine (5-HT/DA ratio = 31) completely and specifically eliminated responding for COC. Consistent with these findings, methamphetamine dramatically reduced COC use in a clinical trial although it is NOT a viable option for managing COC abuse because of its high abuse and diversion potential. Compounds with a desirable 5- HT/DA releasing ratio and minimal abuse potential need to be tested for COC dependence. Phendimetrazine (PHEN) is indicated for treating obesity. After oral administration, PHEN is converted to phenmetrazine, which is largely responsible for its behavioral and neuropharmacological effects. Consistent with the notion that compounds with intermediate 5-HT/DA release ratios selectively attenuate the reinforcing effects of COC, phenmetrazine (5-HT/DA ratio = 37) also completely and specifically eliminated COC-maintained responding. Moreover, PHEN reduces COC-maintained responding, but does not maintain self-administration or produce high magnitude positive subjective effects suggesting that its abuse potential is low. Although PHEN has not yet been tested as a potential pharmacotherapy for COC dependence in human laboratory experiments or clinical trials to our knowledge, the results of extant preclinical experiments suggest it may be a viable option. We will conduct two rigorous within-subject experiments to fill this gap. These studies will 1) establish the safety and tolerability of PHEN-COC combinations and 2) demonstrate that PHEN reduces COC self- administration. The results of this project will provide critical information regarding the initial efficacy of PHEN for COC dependence, which will enhance the probability of success when advanced to a clinical trial.

ABSTRACT Alcohol (ALC) use disorder (AUD) is an unrelenting public health concern. Several medications have been approved for treating AUD, but these pharmacotherapies are not widely used, nor are they universally effective or appropriate to use in all AUD patients due to contraindications. To address the continued need to improve AUD treatment, identifying novel AUD pharmacotherapies is a high NIAAA priority. Preclinical studies show that chronic or binge-like ALC administration decreases extracellular glutamate levels, which are then increased during ALC withdrawal. These elevated glutamate levels observed during ALC withdrawal can be reduced with further ALC administration, driving a cycle of heavy ALC use and withdrawal periods that characterize AUD. The changes in glutamate homeostasis that occur during the cycle of chronic ALC intoxication and withdrawal have been attributed to altered glutamate transport (e.g., changes in cystine- glutamate exchanger [xCT] and glial glutamate transporter [GLT-1] expression and function). Normalization of extracellular glutamate levels (i.e., restoration of glutamate homeostasis) through administration of compounds like n-acetylcysteine (NAC), which increase expression of the xCT and GLT-1 following drug exposure, attenuates maladaptive brain changes produced by ALC, as well as ALC self-administration and behavioral sensitization in preclinical models. Preclinical data provide a strong scientific premise for the hypothesis that restoration of glutamate homeostasis is a promising pharmacotherapeutic approach for AUD, yet this research area remains unexamined in prospective clinical studies. The overarching goal of this application is to demonstrate that restoration of glutamate homeostasis with NAC is a viable strategy for treating AUD. This goal will be achieved through the conduct of a rigorous within-subject, placebo-controlled study that has been modeled from previous successfully reverse-engineered human laboratory approaches. This research will demonstrate the initial efficacy, safety and tolerability of NAC for treating AUD. This work will directly translate findings from preclinical research and provide basic science information about the glutamatergic mechanisms underlying the pharmacodynamic effects of ALC in humans. The proposed research will also expand the scope of current AUD treatment research by focusing on glutamate homeostasis, which has strong preclinical evidence supporting its critical role in AUD but remains unstudied in clinical research.

ABSTRACT Promoting reductions in problem behaviors is common in medical practice wherein at-risk individuals are counseled to make moderate, sustainable changes in lifestyle. Reducing the percentage of heavy drinking days in individuals with alcohol use disorder is an accepted intervention target in alcohol addiction treatment, yet for other drug use disorders, complete abstinence remains the standard for demonstrating treatment efficacy. Interventions that promote reductions in drug use should improve biopsychosocial outcomes. Little research has been conducted to demonstrate benefits of reduced drug use, however. Demonstrating the benefits of reduced cocaine (COC) use would significantly advance treatment development by challenging expectations for outcomes from possible interventions. COC use produces a number of biopsychosocial detriments (e.g., cardiovascular toxicity, disrupted immune function, increased psychiatric comorbidities) that could be ameliorated by COC use reduction. No studies have prospectively or comprehensively evaluated this possibility to date, although preliminary data support this hypothesis. To fill this critical knowledge gap, we propose a randomized, controlled 12-week trial in which financial incentives will be used to reduce COC use. Subjects will be randomly assigned to one of three groups (n=66 completers/ group): 1) high value financial incentives for COC abstinence in which frequency of COC use is expected to be substantially reduced or completely eliminated, 2) low value financial incentives for COC abstinence in which frequency of COC use is expected to be reduced or 3) a non-contingent control group, in which frequency of COC use is expected to remain stable. This study aims to demonstrate that reduced COC use improves physiological and biochemical indicators of cardiovascular and immune fitness, as well as psychosocial function. The overarching hypothesis is that individuals assigned to the active treatment conditions will display improvements in biopsychosocial domains compared to individuals assigned to the non-contingent control group. A ?dose-response? is also expected whereby individuals assigned to the high value condition will display greater reductions in COC use, and consequently greater improvements, relative to the low value condition. This research will advance the field by: 1) using multifaceted health outcomes to provide prospective evidence supporting reduced drug use as a viable endpoint for COC treatment development, 2) identifying biochemical indicators of health improvements associated with reduced COC use and 3) laying the foundation for a paradigm-shifting definition of COC treatment success, thereby challenging expectations for outcomes in behavioral and pharmacological intervention development. These innovations will accelerate identification of promising treatments for cocaine use disorder, resulting in a sustained and powerful impact on scientific and clinical practice.

ABSTRACT Cocaine use disorder continues to be a significant public health concern. Despite great strides in our understanding of the neurobiological underpinnings of cocaine addiction in preclinical models, a limited amount of research has translated those findings into clinical populations. Such translation is crucial to identify neurobiological circuits that contribute to the problems posed by cocaine use disorder and guide treatment based on those clinical neuroscience findings. One area of intense interest in preclinical research is the role of the orexin (also known as hypocretin) system in addiction. Through extrahypothalamic transmission, the orexin system plays a key part in motivation for maladaptive rewards like drugs of abuse. Antagonism of the orexin system attenuates motivation for cocaine, escalation of cocaine intake and reinstatement of cocaine seeking behavior. The first and only clinically available orexin antagonist, suvorexant (Belsomra®), attenuates motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding in non-human animals. Orexin antagonism generally does not alter adaptive behaviors like food or water intake, nor does it change cocaine-induced locomotion. Taken together, these preclinical findings suggest that orexin system antagonism selectively reduces motivation for cocaine, as well as other maladaptive cocaine-associated behaviors. Although a robust preclinical literature supports the premise that orexin antagonism attenuates motivation for cocaine, along with cocaine?s other abuse-related effects, this area remains unstudied in humans. The overarching goal of this project is to translate promising preclinical findings into clinical populations, thereby demonstrating that the orexin system plays a key role in motivation for cocaine in humans. To this end, non-treatment seeking human subjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine in experimental sessions following maintenance on a range of oral suvorexant doses. A placebo-controlled, double-blind, within-subjects design will be used such that all subjects experience all dose conditions in random order. After sampling a cocaine dose, subjects will make choices between that dose and an alternative reinforcer on a concurrent progressive-ratio choice task that was developed and validated in our laboratory. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the relative influence of orexin antagonism on motivation to obtain these two types of reinforcers. A battery of subjective drug-effect measures and cognitive tasks will also be completed to evaluate how orexin antagonism influences other cocaine- associated outcomes in humans. This research will translate findings from preclinical research and provide the initial evidence that orexin antagonism reduces motivation for cocaine, as well as other cocaine-associated maladaptive behaviors in active cocaine users. The proposed work seeks to expand the scope of current clinical neuroscience research on cocaine addiction by focusing on orexin.

Opioid use disorder (OUD) is a leading public health crisis in the United States. Individuals with opioid use disorder frequently use other substances, including cocaine. Past year opioid withdrawal was associated with 4 times greater odds of current cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects but also increases overdose risk, as evidenced by preclinical and clinical findings. Approved OUD pharmacotherapies are modestly effective, but these medications are not indicated for treating cocaine co-use, highlighting the need for a novel intervention approach to improve outcomes in co-morbid OUD and cocaine use disorder. Mechanistically, drug-motivated behaviors are regulated by glutamate signaling within corticostriatal circuitry. Both opioid and cocaine self-administration (SA) down-regulate the glial glutamate transporter (GLT- 1), and alter synaptic plasticity measured as changes in dendritic spines and AMPA-to-NMDA current ratios (A/N) within the nucleus accumbens core (NAcore). Thus, glutamatergic plasticity is a conserved neural mechanism underlying drug motivation in both opioid and cocaine use. The combined effects of opioid and cocaine co-use on glutamatergic systems, however, are unknown. n-Acetylcysteine (NAC) has shown translational promise for treating multiple drug use disorders, including cocaine and opioids. NAC is capable of restoring glutamatergic alterations induced by either drug alone, likely by increasing glutamate clearance from the synapse following drug use through upregulation of GLT-1. Clinically, we have shown that NAC reduces the incentive salience of cocaine-related stimuli, which controls drug seeking. As well, others have shown that NAC normalizes glutamate function in cocaine-dependent individuals. Whether NAC reduces drug intake and reverses glutamatergic alterations induced by co-use of opioids and cocaine is unknown. The work proposed here will begin to fill those crucial knowledge gaps. Our overarching hypotheses are that (1) persistent brain glutamate changes induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence and withdrawal and (2) that NAC will ameliorate glutamatergic dysregulation, and thus will reduce both oxycodone and cocaine use. We propose a two phase, translational project supported by the R21/R33 mechanism. In the first phase (R21), we will characterize NAcore glutamatergic signaling in opioid and cocaine co-use as a neural biomarker for pharmacotherapeutic targeting with NAC using preclinical laboratory methods. Upon meeting the milestones set forth for the R21, we will conduct the second phase (R33), in which we will determine the influence of NAC on glutamate function and reinforcing effects of cocaine in co-morbid opioid and cocaine use disorder using human laboratory methods. The milestones completed during this translational project will elucidate glutamatergic dysregulation underlying opioid and cocaine co-use, laying the groundwork for effective pharmacotherapeutic treatment for this pattern of polysubstance abuse through targeting glutamate signaling.

ABSTRACT Cocaine use disorder continues to be a significant public health concern. Despite strides in our understanding of the neurobiological underpinnings of cocaine addiction in preclinical models, a limited amount of research has translated those findings into clinical populations. Such translation is crucial to identify neurobiological circuits that contribute to the problems posed by cocaine use disorder and to guide treatment based on those clinical neuroscience findings. Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5- HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptor subtypes have been implicated in the abuse-related effects of cocaine, including its primary reinforcing effects (i.e., cocaine taking behavior). 5-HT1b receptors play a particularly important role in cocaine effects, likely because they are highly expressed in the mesocorticolimbic system. Preclinical data show that zolmitriptan, a commercially available selective 5-HT1b agonist migraine medication approved for human use, selectively attenuates the reinforcing and other abuse-related effects of cocaine. The overarching goal of this project is to advance these promising preclinical findings into clinical populations, thereby demonstrating that the 5-HT1b system plays a key role in the effects of cocaine in humans. To this end, 20 non-treatment seeking human subjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine (0, 10 and 30 mg/70 kg) in experimental sessions after 3 days of maintenance on oral zolmitriptan (0, 2.5, 5 and 10 mg). A placebo-controlled, double-blind, within-subjects design will be used such that all subjects experience all dose conditions in random order. The study will require an approximately 1-month admission to our inpatient unit. After sampling a cocaine dose, subjects will make nine choices between that dose and an alternative reinforcer (US$6.00) on a concurrent progressive-ratio choice task that was developed and validated in our laboratory. A battery of subjective drug-effect measures and tasks that assess distinct domains of impulsivity will be completed during the same experimental sessions in which cocaine choice is assessed. The research proposed here will directly translate findings from preclinical research and provide the initial clinical evidence that 5-HT1b activation, achieved through administration of zolmitriptan, reduces the reinforcing and other abuse-related effects of cocaine, as well as cocaine-associated impulsivity. This study will also provide basic science information about the serotonergic mechanisms underlying the pharmacodynamic effects of cocaine in humans. As such, the outcomes will advance our understanding of the clinical neurobiology of cocaine addiction.