Craig R. Rush - US grants

A drug's abuse liability is an interactive function of its liability for abuse (i.e., it functions as reinforcer and maintains self-administration) and its liability of abuse (i.e., it produces adverse effects such as impaired performance and dependence). Benzodiazepines are among the most widely prescribed psychoactive drugs. While their abuse liability is low compared to other drugs of abuse, there is sufficient evidence documenting that benzodiazepines have some liability for abuse as well as significant liability of abuse. Moreover, various benzodiazepines, and benzodiazepine- like compounds, may differ in terms of their abuse. Moreover, various benzodiazepines, and benzodiazepine-like compounds, may differ in terms of their abuse liability. For example many clinicians believe high-potency benzodiazepine hypnotics, like triazolam, have a greater abuse liability than low-potency benzodiazepine hypnotics, like temazepam and flurazepam. Novel compounds like zolpidem may also have less abuse liability. This application consists of 5 laboratory experiments that aim to comprehensively assess the abuse liability of triazolam, a high potency benzodiazepine hypnotic; temazepam, a low-potency benzodiazepine hypnotic; and zolpidem, a novel imidazopyridine hypnotic that has a unique CNS binding profile. Experiments 103 will determine th abuse liability of these hypnotics in insomniacs (Exp. 1), elderly volunteers (Exp.2), and volunteers with a history of sedative abuse (Exp. 3) in order to begin to identify individuals in which the use of certain hypnotics may pose greater risks. Triazolam, temazepam and zolpidem will be administered chronically in Exp. 4 to determine if tolerance develops differentially. Determining whether tolerance develops differentially is important since it may lead to dose escalation and increased risk of dependence. Finally, Exp. 5 will determine if alcohol differentially exacerbates the deleterious effects of triazolam, temazepam and zolpidem. Determining differential interactions with alcohol is important since combining alcohol and hypnotics increases the magnitude of behavioral impairment, thereby increasing the risk to the individual and society. We propose to use insomniacs in Exp. 4 an 5, but elderly or drug abusing volunteers will be used if interesting between-drug differences are observed with these subject populations in Exp. 2 and 3. In addition to practical clinical information, testing a wide range of doses in these studies will begin to determine whether there are meaningful differences between the dose-response functions of high- and low- potency benzodiazepines. Including zolpidem, which has a unique CNS benzodiazepine-receptor binding profile relative to benzodiazepine hypnotics, will provide information concerning a drug's neuropharmacology and abuse liability. During the next several years, other compounds that have unique pharmacological profiles will become available for testing in human behavioral pharmacology studies. The availability of these drugs will allow the relationship between neuropharmacology and abuse liability to be further explored in various human populations. Thus, this FIRST Award will sere as a foundation for future R01 applications to study sedative hypnotic compounds with unique neuropharmacological profiles.

(Applicant's Abstract) The revised application is entitled "Human Cocaine Discrimination: Pharmacological Specificity". The title was changed since less emphasis is given to elucidating the neuropharmacological mechanisms underlying the discriminative stimulus effects of cocaine in human research volunteers. The revised application consists of 5 inpatient, laboratory experiments aimed at characterizing the discriminative stimulus effects of cocaine in humans. Exp. 1 will replicate the only other study that established cocaine as a discriminative stimulus in humans, and extend these findings by testing the discriminative stimulus effects of d- amphetamine and pentobarbital to further determine the pharmacological specificity of the cocaine-placebo discrimination. Exp. 2 will determine the effects of training dose on subsequent discrimination performance. Exp. 3-5 will test the discriminative stimulus effects of 6 compounds (i.e., mazindol, methylphenidate, bupropion, diethylpropion, desipramine and fluoxetine) in cocaine-trained humans. d-Amphetamine and pentobarbital will be included as a positive and negative control, respectively, in each of these experiments. Two training conditions will be used in each experiment to further explore the influence of cocaine training dose on subsequent discrimination performance. Drug-effect and mood questionnaires will be used in each experiment. The experiments proposed in this application have at least 6 important implications. First, these experiments will lay the groundwork for studying the discriminative stimulus effects of cocaine in humans. Second, these experiments will determine the influence of cocaine training dose on subsequent drug discrimination performance. Third, because some of the compounds to be tested exert their effects primarily via dopamine systems (i.e., mazindol, methylphenidate, bupropion, diethylpropion) and others via norepinephrine (i.e., desipramine) or serotonin (i.e., fluoxetine) systems, these experiments will begin to elucidate the neuropharmacological mechanisms underlying the discriminative stimulus effects of cocaine in humans, and whether these mechanisms vary across different training conditions. Fourth, because all of the compounds have previously been tested in nonhuman laboratory animals trained to discriminate between cocaine and vehicle, these experiments will begin to determine, albeit indirectly, to what extent the findings from preclinical studies generalize to humans. Fifth, the inclusion of drug-effect and mood questionnaires will provide ancillary information concerning the relationship between the discriminative stimulus and subjective effects of cocaine. Finally, because the interoceptive and discriminative stimulus effects of cocaine clearly contribute to its abuse, the experiments proposed in this application could provide information relevant to the treatment of cocaine abuse.

Methylphenidate (RITALIN), a piperidine derivative, is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Alarmingly, recent data from the Drug Enforcement Agency (DEA) indicate that methylphenidate (METH) abuse is widespread and represents a significant public-health concern. For example, between 1989 and 1993 emergency-room admissions involving METH increased by as much as 715%. There is accumulating evidence that the symptoms of childhood ADHD persist into adulthood in a significant number of cases, and adulthood ADHD is associated with high rates of psychiatric comorbidity, including cocaine (COC) abuse. Whether COC abusers with ADHD are at risk to abuse METH is unclear, and many clinicians are reluctant to prescribe stimulants to these patients because of their histories of COC abuse. The specific aim of this project is to rigorously characterize the abuse potential of METH, the most commonly prescribed medication for the treatment of childhood and adulthood ADHD. To accomplish this aim, 3 inpatient, laboratory experiments will be conducted with volunteers with histories of COC abuse. Exp. 1 will replicate and extend findings from a previous study conducted in our laboratory that showed the discriminative-stimulus and subjective effects of METH are indistinguishable from those of COC. Exp. 2 will determine the relative reinforcing effects of METH and COC. Exp. 3 will determine the influence of rate of onset on the reinforcing, subjective and physiological effects of drugs by examining the effects of sustained- and immediate- release METH. We have two primary hypotheses. First, METH and COC will produce positive subjective effects and function as reinforcers. METH and COC will differ in terms of potency, but not efficacy. Second, sustained- release METH will have less abuse potential than immediate-release METH. The experiments proposed in the present application have at least 3 basic science and clinical implications. First these experiments will determine the abuse potential of METH in individuals with histories of COC abuse. Second, these experiments will determine whether decreasing the rate of onset of METH's effect reduces its abuse potential. Rate of onset is thought to be an important determinant of a drug's abuse potential. Third, these experiments may identify compounds that have reduced abuse potential (e.g., sustained-release METH) and may guide the pharmacological treatment of COC abusers with ADHD. The proposed experiments will also allow us to assess the effects of participating in non-treatment, inpatient, drug-abuse studies and to conduct retrospective analysis to determine the influence of individual differences (e.g., amount of cocaine use, amount and kind of other drug use, gender, ethnicity, socioeconomic status, as well as scores on a structured mental status exam, the Wender-Utah Rating Scale, the Beck Depression Inventory and several measures of personality function) on the behavioral and physiological responses to stimulants.

DESCRIPTION (provided by applicant): Cocaine abuse continues to represent a significant public-health concern, and will likely remain a concern for the foreseeable future. Because of the public-health concerns associated with its abuse, identifying an effective pharmacotherapy for the treatment o cocaine abuse has been a priority with the N.I.D.A. for the last decade. Despite the intense efforts of several investigative teams, an effective pharmacotherapy for cocaine abuse has not yet been identified. Cocaine probably exerts its reinforcing effects by increasing synaptic dopamine levels by blocking the dopamine transporter. Gamma-Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of cocaine. Preclinical laboratory experiments have demonstrated that GABA agonists attenuate the effects of cocaine under a variety of behavioral arrangements. These findings suggest that GABA systems might be targeted for the development of medications for the treatment of cocaine abuse. The specific aim of the proposed research is to determine if GABA agonists attenuate the acute reinforcing and subjective effects of intranasally administered cocaine in humans. To accomplish this aim, we will conduct 3 laboratory experiments with volunteers with recent histories of cocaine use. These experiments will determine the acute reinforcing and subjective effects of cocaine following pretreatment with tiagabine (a nipecotic acid derivative), baclofen (a GABA analog), and triazolam (a benzodiazepine) (Experiments 1-3, respectively). The reinforcing effects of cocaine will be assessed with a progressive-ratio schedule similar to those used with nonhuman laboratory animals. Tiagabine is a GABA uptake blocker that increases extracellular GABA levels. Baclofen is a GABA, agonist. Triazolam is an agonist at the GABAA receptor complex that binds non-selectively to BZ, and BZ2 benzodiazepine receptor subtypes. Follow-up experiments will be conducted as needed to determine the effects of the pretreatment agent (i.e., tiagabine, baclofen or triazolam) on responding for a non-drug reinforcer (i.e., money). These studies will provide important information concerning the specificity of the effects of the pretreatment agents. The proposed research will provide important clinical information regarding the potential usefulness of GABA agonists as putative pharmacotherapies for the treatment of cocaine abuse. The proposed research will also provide important basic-science information. First, the inclusion of drug-reinforcement and subjective-effect measures will provide information concerning the relationship between the reinforcing and subjective effects of cocaine. Second, albeit indirectly, the proposed research will determine the extent to which preclinical findings generalize to humans. Finally, the proposed research will allow us to conduct retrospective analyses to determine the influence of individual differences (e.g., gender, other drug use) on the reinforcing and subjective effects of cocaine.

DESCRIPTION (provided by applicant): The present application is a request for continued funding of a project entitled "Cocaine Discrimination in Humans: Pharmacological Specificity" (DA010325). Recent data indicate that nearly 2 million Americans used cocaine in the past month. Alarmingly, between 1991 and 2001 the number of 8th, 10th, and 12th graders that reported using cocaine in the past 30 days increased 140, 86, and 50 percent, respectively. Thus, cocaine abuse continues to represent a significant public health concern, and will likely remain a problem for the foreseeable future. Intensive research efforts have been aimed at elucidating the neuropharmacological mechanisms that mediate the effects of cocaine. Drug-discrimination studies with laboratory animals that used the substitution and pretreatment methodologies have implicated a prominent role of dopamine in mediating the effects of cocaine. During the initial funding period of this project we used a drug discrimination task and the substitution methodology to demonstrate that dopamine systems are involved in mediating the discriminative-stimulus effects of cocaine in humans. We are not aware of any published studies in which the discriminative-stimulus effects of cocaine were assessed in humans following pretreatment with another drug even though drug-discrimination procedures may be particularly well suited for studying agonist-antagonist interactions. The aim of this application is to further characterize the role of dopamine in mediating the discriminative-stimulus effects of cocaine in humans using a pretreatment methodology. To accomplish this aim, 3 laboratory experiments will be conducted with volunteers with histories of cocaine abuse. The discriminative-stimulus and subjective effects of cocaine will be assessed alone and following pretreatment with mazindol, a dopamine uptake blocker (Exp. 1); fluphenazine, a D1-D2 dopamine receptor antagonist (Exp. 2); and haloperidol, a D2 dopamine receptor antagonist (Exp. 3). We predict that pretreating volunteers with a dopamine agonist or antagonist will shift the cocaine dose-response curve, leftward and rightward, respectively. The experiments proposed in this "proof-of-concept" continuation application will provide additional information concerning the role of dopamine in mediating the discriminative-stimulus effects of cocaine in humans. Elucidating the role of dopamine in mediating the effects of cocaine may guide the development of pharmacological interventions for cocaine.

substance abuse related behavior; cocaine; drug abuse; behavioral /social science research tag; human subject; clinical research;

substance abuse related behavior; cocaine; drug abuse; reinforcer; inhalation drug administration; behavioral /social science research tag; clinical research; human subject;

DESCRIPTION (provided by applicant): Methamphetamine abuse is a significant public-health concern and is the primary form of amphetamine abused in the United States. Between 1996 and 2002, the number of Americans that reported using methamphetamine increased by 250%. Amphetamine admissions to treatment program increased by nearly 500% between 1992 and 2002. Methamphetamine use made up 90% of all amphetamine treatment admissions. Because of the public-health concerns, identifying an effective pharmacotherapy for the management of methamphetamine dependence is imperative. Methamphetamine is thought to exert its. behavioral effects by promoting the release of several monoamines, including dopamine (DA), serotonin (5- HT) and norepinephrine (NE), which has prompted some theoreticians to suggest targeting multiple systems for the development of a pharmacotherapy. Partial agonists at these neurotransmitter systems may represent a novel and effective means to treat stimulant dependence. In support of this notion, partial agonists at D2 and 5-HT1A receptors attenuate many of the behavioral effects of amphetamines in laboratory animals In the present application, we propose a series of experiments to determine the efficacy of iripiprazole, an atypical antipsychotic that is a D2 and 5-HT1A partial agonist and a 5-HT2A antagonist, as a putative pharmacotherapy for methamphetamine dependence. The results of a recent experiment conducted in our laboratory suggest that aripiprazole significantly attenuates the discriminative-stimulus and some of the positive subjective effects of d-amphetamine in humans. The present project has three specific aims. The first specific aim is to characterize the behavioral pharmacology of methamphetamine in humans. The second specific aim is to assess the safety and tolerability of methamphetamine in combination with aripiprazole. The third specific aim is to determine the efficacy of aripiprazole as a putative pharmacotherapy, by examining the discriminative-stimulus, reinforcing, and subjective effects of methamphetamine in humans following chronic pretreatment with aripiprazole. The proposed research will provide initial scientific and clinical information regarding the use of aripiprazole as a pharmacotherapy for the treatment of methamphetamine dependence, and guide the design of future clinical trials.

DESCRIPTION (provided by applicant): Cocaine abuse continues to be a significant public health concern. Relapse rates to cocaine use after treatment remain discouragingly high even with the advent of sophisticated behavioral and cognitive relapse prevention therapies. Identifying an effective pharmacological adjunct will likely be necessary to further reduce cocaine relapse rates. The specific aim of this proposal is to demonstrate that aripiprazole is an effective "anti-relapse" medication for cocaine, and possibly determine the behavioral mechanism by which it exerts this effect (i.e., aripiprazole attenuates the discriminative effects of priming doses of cocaine thereby reducing subsequent drug self-administration). To accomplish this aim, we will first determine the safety and tolerability of cocaine-aripiprazole combinations by administering ascending doses of oral and intranasal cocaine doses during aripiprazole maintenance, and monitoring physiological and behavioral responses (Exp. 1). We will then demonstrate that chronic aripiprazole treatment attenuates the discriminative-stimulus effects of cocaine (Exp. 2). The discriminative-stimulus effects of drugs may be involved in relapse to drug taking behavior in that the initial or priming dose (i.e., a lapse) functions as a discriminative stimulus that signals the availability of more cocaine. Finally, Exp. 3 will demonstrate that a priming dose of cocaine (i.e., a lapse) increases subsequent cocaine taking using a novel self-administration procedure designed to model relapse, and that aripiprazole attenuates this effect. Aripiprazole was chosen for study because it is a potent partial agonist at the dopamine (DA) D2 and serotonin (5-HT) 5-HT1A receptors. Cocaine is thought to exert its effects by blocking monoamine transporters (e.g., DA and 5-HT). Partial agonists may represent a novel and effective means to prevent relapse to cocaine use because theoretically they should have the therapeutic advantages of both an agonist and an antagonist. Consistent with this notion, the results of a recent experiment conducted in our laboratory suggest that acutely administered aripiprazole significantly attenuates the discriminative-stimulus and subjective effects of d-amphetamine in humans. We are unaware of any published reports in which the effects of cocaine were assessed in humans following pretreatment with aripiprazole. The proposed research will provide the initial clinical information regarding the efficacy of aripiprazole as a putative "anti-relapse" medication for cocaine dependence. The conduct of the proposed controlled laboratory studies will provide important information (e.g., appropriate doses) that will guide the design of a subsequent clinical trial. Reducing relapse to drug use is important because intravenous abuse of cocaine may be associated with increased risk of acquired immunodeficiency syndrome (A.I.D.S.).

Cocaine abuse and dependence continue to be significant public health concerns. The number of Americans that used cocaine in the past month, the percentage of 12th-, 10th- and 8th-graders that used cocaine in the past year, and the percentage of treatment admissions involving cocaine has remained stable in recent years. In 1996, cocaine use cost society over $45 billion due to medical consequences, lost productivity and crime. Because of the public-health concerns and costs associated with its abuse, identifying a pharmacotherapy for cocaine dependence is a priority with the National Institute on Drug Abuse (N.I.D.A.). A pharmacological adjunct for cocaine dependence has not yet been identified. The results of clinical trials suggest that agonist replacement therapies (e.g., d-amphetamine) may be effective for cocaine dependence. Because cf-amphetamine reduces cocaine use, these clinical findings can be used as a reference to identify human laboratory procedures for screening putative pharmacotherapies. Identifying procedures for assessing the efficacy ofputative pharmacotherapies is important because human laboratory studies can be conducted more rapidly/and/efficiently than clinical trials. The present project has two specific aims. The first specific aim is to demonstrate the sensitivity and predictive validity of human laboratory procedures commonly used to screen putative pharmacotherapies for cocaine dependence. To accomplish this aim, we will conduct two "proof-of- concept" studies. We will first demonstrate the safety and tolerability of d-amphetamine-cocaine combinations (Exp. 1). We will then 'demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of cocaine (Exp. 2). The ability to attenuate the reinforcing effects of cocaine may be an important characteristic of an effective pharmacotherapy. The results of these studies will help elucidate the optimal conditions (e.g., dose) under which d-amphetamine might be expected to be effective. The second specific aim is to determine the efficacy of atomoxetine (Strattera[unreadable]) as a putative agonist replacement pharmacotherapy for cocaine dependence. To accomplish this aim, we will conduct two experiments to determine the effects of cocaine during atomoxetine maintenance. We will first demonstrate the safety and tolerability of atomoxetine-cocaine combinations (Exp. 3). Finally, we will determine the reinforcing effects of intranasal cocaine during atomoxetine maintenance (Exp. 4). Atomoxetine, a potent norepinephrine uptake blocker, was chosen for study because its pharmacological and behavioral effects overlap to some extent with those of d-amphetamine, but it appears to have less abuse potential. Identifying novel agonist replacement therapies is important because clinicians may be reluctant to use d-amphetamine because of its abuse potential.

PROJECT SUMMARY/ABTRACT Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role in mediating the behavioral effects of methamphetamine. -Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratory experiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effects of stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptor modulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viable strategy for the development of medications to manage methamphetamine dependence. This goal will be achieved through the conduct of two proof-of-concept experiments designed to accomplish two specific aims. The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects of methamphetamine. To accomplish this aim, we will determine the reinforcing effects of intranasal methamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratio procedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference, then, an effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. The second specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim, we will teach volunteers to discriminate intranasal methamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine will then be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e., a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide initial clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications for methamphetamine abuse. In addition to the clinical information, the proposed research will provide basic-science and translational information. First, the inclusion of drug self-administration and discrimination measures, along with subjective-effect questionnaires, will provide information concerning the relationship between the reinforcing, discriminative and subjective effects of methamphetamine. Second, because GABAA receptor modulators have been tested as pharmacotherapies for stimulant dependence in laboratory animals using similar behavioral procedures, the proposed research will determine, albeit indirectly, the extent that findings from preclinical studies generalize to humans. PROJECTIVE NARRATIVE Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications to manage methamphetamine dependence.

DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. The results of clinical trials suggest that agonist replacement therapies (e.g., d-amphetamine) may be effective for methamphetamine dependence. The present project has three specific aims. The first specific aim is to demonstrate the safety, tolerability and behavioral effects of intranasal methamphetamine in humans maintained on d-amphetamine. To accomplish this aim, we will conduct one experiment in which non-treatment seeking volunteers with recent histories of illicit stimulant use will receive ascending doses of intranasal methamphetamine while maintained on increasing doses of d-amphetamine (Exp. 1). Cardiovascular indices will be used to determine the safety and tolerability of the d-amphetamine-methamphetamine combinations while subjective-effect questionnaires will be used to characterize the behavioral effects. The results of this experiment will guide the selection of doses to be tested in subsequent studies. The second specific aim is to demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of methamphetamine. To accomplish this aim, we will determine the reinforcing effects of intranasal methamphetamine during d-amphetamine maintenance using a progressive-ratio procedure (Exp. 2). Pharmacotherapies that attenuate the reinforcing effects of methamphetamine may be effective for initiating abstinence. The third specific aim is to demonstrate that d-amphetamine maintenance attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim, volunteers will learn to discriminate intranasal methamphetamine (Exp. 3). The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e., a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide important additional clinical information regarding the efficacy of agonist replacement therapies for methamphetamine dependence. By using two sophisticated human laboratory procedures, one to model abstinence initiation (i.e., drug self-administration) and the other to model relapse prevention (i.e., drug discrimination), the proposed research will determine the mechanisms that mediate the clinical efficacy of d-amphetamine for methamphetamine dependence. By inference, then, the proposed research will identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e., initiate abstinence or prevent relapse). Finally, because d-amphetamine reduces methamphetamine use, these clinical findings can be used as a reference to determine the predictive validity of human laboratory procedures. Identifying procedures for assessing the efficacy of putative pharmacotherapies via a "beside-to-bench" or "reverse engineering" strategy is important because human laboratory studies can be conducted more rapidly and efficiently than clinical trials. PUBLIC HEALTH RELEVANCE: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the efficacy of agonist replacement therapy for methamphetamine dependence. The proposed research will also identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e., initiate abstinence or prevent relapse). Finally, the proposed research will determine appropriate human laboratory procedures for testing pharmacotherapies for methamphetamine dependence. Identifying appropriate human laboratory procedures for assessing the efficacy of pharmacotherapies for methamphetamine dependence is important because laboratory studies can be conducted more rapidly and efficiently than clinical trials.

DESCRIPTION (provided by applicant): This training program co-directed by Thomas Garrity and Carl Leukefeld proposes to support three pre and three postdoctoral trainees with a training faculty of 24 drawn from six different academic and research units of the University. The environment is rich with opportunities for biobehavioral research in facilities such as the Center on Drug and Alcohol Research, the Center for Drug and Alcohol Research and Translation, and the Residential Research Facility. Trainees will be housed in offices and laboratories of their research supervisor with 24 hour/day access to laboratories and computer facilities. This program is designed to prepare trainees to assume research responsibilities in academic, and other scientific organizations concerned with drug abuse and the behavioral aspects of health and medical care. Postdoctoral fellows will either have a doctorate in a behavioral science discipline and will be preparing for a research role in the drug abuse field, or they will be health professionals who are seeking a behavioral science research orientation in drug abuse. Predoctoral trainees will concentrate in behavioral aspects of drug abuse as part of their program for a doctorate in a behavioral science discipline. Basic elements of the program include: (1) research training designed to provide experience in utilizing the basic building blocks of research (interviewing, case study, experimental design, development and pretesting of instruments, data analysis) and independent research competence;(2) an interdisciplinary orientation which takes students beyond their basic discipline and provides exposure to key theoretical concepts and methodological issues of the related behavioral sciences along with a biobehavioral'conceptualization;(3) a program of enculturation and orientation to drug abuse, health and mental health settings;(4) opportunities to explore drug abuse topics from a medical behavioral perspective through courses offered by training faculty;and (5) opportunities for research around relevant questions in drug abuse behavior that can constitute significant learning experiences for postdoctoral fellows and a dissertation project for predoctoral trainees. The program for postdoctoral fellows will be individually geared to the objectives of the fellows and will build on their previous knowledge and experience.

DESCRIPTION (provided by applicant): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence, for example, could yield treatments for managing COC dependence. Obesity is also a significant public health concern. Although obesity and COC dependence are typically considered distinct clinical entities, both diseases involve perturbations of central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has spurred development of medications to promote weight loss. A combination of bupropion (BUP) and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to demonstrate the initial efficacy, safety, and tolerability of BUP-NTX combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking, COC-dependent participants will be randomized to different maintenance doses of BUP (i.e., BUP is a between-subject factor). Participants (N=12) in each BUP cohort will be maintained concurrently on NTX (i.e., NTX is a within-subject factor). The reinforcing effects of intranasal COC will be determined after participants in each BUP cohort are maintained for 4-7 days on each of the NTX doses (i.e., COC is a within-subject factor). COC (0, 25, 50, 100 mg) will be tested with multiple dose combinations of BUP (0, 100, 200, 300 mg/day) and NTX (0, 25, 50 mg/day). The proposed study will also identify the optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses ofa novel drug combination, BUP and NTX, for COC dependence, which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated modest efficacy when tested as mono-therapies; 2) the use of a sophisticated drug self-administration procedure; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC dependence; and 4) demonstrating the initial efficacy and optimal doses of a combination of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly. In these ways, the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of COC dependence.

DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse is an unrelenting public health concern. While behavioral therapies are effective for reducing MA use, many patients enrolled are unable to achieve significant periods of abstinence suggesting other strategies are needed. Despite being a high priority for the National Institute on Drug Abuse (NIDA) and extensive efforts by the scientific and treatment communities, an effective medication for MA abuse has not been identified. MA acts as a substrate for monoamine transporters and is taken into the nerve terminal where it promotes the release of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into the synapse by preventing the accumulation of neurotransmitter in storage vesicles and by carrier-mediated exchange. MA abuse is largely attributed to its ability to increase synaptic DA levels. However, targeting DA systems has not identified a broadly effective pharmacotherapy for managing MA abuse. MA also promotes 5- HT release, which mediates the reinforcing effects of MA. MA abuse is also characterized by perturbations in DA and 5-HT systems. Thus, an effective medication for MA abuse will likely need to target 5-HT systems in addition to DA, which is an innovative strategy. Buspirone (BUSP), an anxiolytic medication with limited abuse potential, is a partial agonist at serotonin 5-HT1A receptors, an antagonist at DA auto receptors, and a selective antagonist at DA D3 receptors. Partial agonists 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). DA auto receptors stabilize dopaminergic tone and antagonists at these receptors can increase DA release. DA D3 receptors play a critical role in motivation to take drugs. Despite a favorable pharmacological profile and positive preclinical results, we are unaware of any human laboratory research that tested the influence of BUSP on the abuse-related effects of MA. Human laboratory research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This proposed study will assess the reinforcin, subject-rated, performance, and physiological effects of MA during maintenance on BUSP. Human drug reinforcement procedures have good predictive validity for the clinical efficacy of MA pharmacotherapies. By determining how BUSP impacts the behavioral effects of MA, we will provide important evidence regarding the potential efficacy of this compound for managing MA use disorders. These results will help to broaden the current clinical neuroscience paradigm of MA medications development efforts beyond a focus on DA 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.

DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are significant public-health concerns. Treatment admissions for MA use increased at an alarming rate from 1998 to 2007 in the US. Behavioral treatments reduce MA use. However, many patients enrolled in behavioral treatment programs are unable to achieve a significant period of abstinence suggesting other strategies like pharmacotherapy are urgently needed. G-Aminobutyric-acid (GABA) and opioid systems modulate dopamine. GABAA receptor modulators (e.g., oxazepam [OXP]) and opioid antagonists (e.g., naltrexone [NTX]) attenuate the abuse-related effects of amphetamines. The attenuation of the abuse-related effects of amphetamine by GABAA receptor modulators or opioid antagonists, while statistically significant, is modest in magnitude. Novel strategies are needed to enhance the efficacy of these drugs. Targeting GABA and opioid systems simultaneously is an innovative strategy in that combining NTX and OXP may produce greater attenuation of the abuse-related effects of MA. A rigorous within-subject experiment will be conducted in non-treatment-seeking, MA-abusing participants. NTX (0 and 50 mg/day) and OXP (0 and 40 mg/day), alone and in combination, will be tested with MA (0, 10, 20 and 30 mg). The four NTX-OXP maintenance conditions will be tested in random order. Similarly, within each NTX-OXP condition, the MA doses will be tested in random order. The reinforcing effects of intranasal MA doses will be determined after four days of maintenance on each of the NTX-OXP conditions using a sensitive progressive-ratio procedure. The ability to attenuate the reinforcing effects of drugs is a reliable predictor of an effective pharmacotherapy. We hypothesize that combining NTX and OXP will produce an additive or supra-additive reduction in the reinforcing effects of MA relative to the constituent drugs alone. This research will provide critical information regarding the initil efficacy a novel drug combination, NTX and OXP, for MA dependence. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated some efficacy when tested as mono-therapies; 2) testing a GABAA receptor modulator that has minimal abuse potential and dependence liability, which will likely be more acceptable to clinicians; 3) the use of a sensitive drug self-administration procedure; 4) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of NTX-OXP combinations for MA dependence; and 5) demonstrating the initial efficacy of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly. In these ways, the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of MA dependence.

DESCRIPTION (provided by applicant): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence, for example, could yield treatments for managing COC dependence. Obesity is also a significant public health concern. While obesity and COC dependence are typically considered distinct clinical entities, both involve perturbations of central biogenic amie systems. The obesity epidemic has spurred development of medications to promote weight loss. The Food and Drug Administration (FDA) recently approved a combination of topiramate (TOP) and phentermine (PHEN) for obesity. The overarching goal of this application is to demonstrate the initial efficacy, safety, and tolerability of TOP-PHEN combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking, COC-dependent participants will be randomized to different TOP maintenance doses (i.e., TOP is a between-subject factor). Participants (N=12) in each TOP cohort will be maintained concurrently on PHEN (i.e., PHEN is a within-subject factor). The reinforcing effects of COC will be determined after participants in each TOP cohort are maintained for 7 days on each PHEN dose (i.e., COC is a within-subject factor). COC (4 [placebo], 40, 80 mg) will be tested with each dose combination of TOP (0, 100, 200 mg/day) and PHEN (0, 15, 30 mg/day). The proposed study will therefore identify the optimal TOP-PHEN dose combination that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses of a novel drug combination, TOP and PHEN, for COC dependence, which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposal include: 1) testing a drug combination effective for a disorder, obesity, that shares neurobiological and behavioral substrates with COC addiction; 2) the use of drug self-administration procedures; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of TOP-PHEN combinations for COC addiction; 4) demonstrating the initial efficacy of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly; 5) facilitating communications between scientists studying distinct clinical entities (e.g., obesity and COC addiction); and 6) spurring sponsor interest in addiction pharmacotherapy because demonstrating the efficacy of the TOP-PHEN combination would support a novel indication for this product in a new population and extend patent life. The proposed project will shift the current research paradigm in pharmacotherapy development and have a significant impact on COC abuse treatment.

DESCRIPTION (provided by applicant): Cocaine abuse is an unrelenting public-health concern. Behavioral therapies are considered the standard of care for reducing cocaine use and preventing relapse. However, even with intense behavioral interventions, rates of relapse to cocaine use are discouragingly high (i.e., 60-95% of patients return to drug use). Novel strategies are urgently needed to improve treatment outcomes for cocaine-use disorders. The overarching goal of this project is to assess the feasibility, acceptability and initial efficacy o an innovative cocaine-based inhibitory-control training procedure. This goal will be accomplished through the conduct of a Stage I pilot trial. Cocaine-dependent participants will be enrolled and randomized to receive inhibitory-control training to cocaine or neutral images (N=20/condition). This proposed intervention, cocaine- based inhibitory-control training, will be delivered using an innovative computer program which teaches cocaine abusers to inhibit a pre-potent response to cocaine or neutral cues. The primary hypothesis is the proposed procedures are feasible and acceptable to the participants. Feasibility will be assessed by determining time needed to enroll the target sample; adaptive randomization outcomes; maintenance of blind for blinded study personnel; participant attendance, completion and adherence to study procedures. Acceptability will be determined using a Treatment Acceptability Questionnaire. The secondary hypothesis is that participants receiving cocaine-based inhibitory-control training will reduce their drug use to a greater extent than their counterparts in the neutral-image condition. Reduced cocaine use will be demonstrated by fewer positive-urine samples using qualitative urinalysis and a reduction in levels of benzoylecgonine as determined by quantitative urinalysis (i.e., ELISA). The third hypothesis is that participants receiving cocaine-based inhibitory-control training will show improved inhibitory control and neurocognitive functioning relative to their counterparts in the neutral-image condition. Improved inhibitory control, impulsivity and cognitive functioning will be demonstrated using a battery of clinical instruments and laboratory tasks. The proposed research is highly innovative in that it will provide critical information regarding the feasibilit, acceptability, initial efficacy of cocaine-based inhibitory-control training to reduce drug use and improve inhibitory control and neurocognitive functioning in cocaine-dependent participants. Cocaine-based inhibitory- control training is also easy to administer (i.e., 15 minutes), inexpensive, need not be administered by a clinician, and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence, thereby quickly impacting clinical research and practice. The cocaine-based inhibitory-control training program could also be converted to a smart-phone for administration outside the clinic. Administering training outside of the clinic would allow patients to receive more frequent booster sessions, further improving sustained abstinence by allowing them to be exposed to therapy as needed.

? DESCRIPTION (provided by applicant: Despite prevention and intervention efforts, prevalence of cocaine (COC) use and dependence remains stable, which suggests innovative strategies are needed, like pharmacotherapy. COC blocks dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters. COC addiction is characterized by perturbations of these systems making monoamine uptake inhibition a logical target for medications development. Over 30 trials determined the efficacy of monoamine uptake inhibitors for COC dependence, but only DA-SERT and NET inhibitors were effective in a majority of the trials in which they were tested. Continuing to target monoamine uptake inhibition is warranted, but novel pharmacological strategies are needed to enhance efficacy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for managing COC dependence: Triple Monoamine-Uptake Inhibition. Triple monoamine uptake inhibitors are under development, but are not yet available for use with humans. Triple monoamine-uptake inhibition can; however, be achieved by combining available medications. Duloxetine (DUL), an antidepressant, has high affinity for the SERT and NET (ki = 0.8 and 7.5 nM, respectively), but lower affinity for the DAT (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DAT (ki = 34 nM), but lower affinity for the SERT and NET (ki = >10,000 and 339 nM, respectively). We will combine DUL and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non- treatment-seeking, COC-dependent participants will be randomized to different maintenance doses of delayed- release DUL (i.e., DUL dose is a between-subject factor). Participants (N=16) in each DUL cohort will be maintained concurrently on long-acting MTH (i.e., MTH dose is a within-subject factor). The reinforcing effects of COC will be determined after participants in each DUL cohort are maintained for 4 days on each of the MTH doses (i.e., COC dose is also a within-subject factor). COC self-administration will be the primary outcome measure because the ability to attenuate the reinforcing effects of drugs is a reliable predictor of an effective pharmacotherapy. We hypothesize DUL-MTH combinations will produce an additive or supra-additive reduction in the reinforcing effects of COC relative to the constituent drugs alone. Innovations include: 1) testing a novel strategy, triple monoamine-uptake inhibition; 2) testing a combination of marketed drugs as opposed to waiting for compounds under development to be available for use in humans, thereby quickly impacting clinical research; 3) the use of once-daily dosing formulations of DUL and MTH which will improve compliance when advanced to clinical trials; 4) the use of a sophisticated drug self-administration procedure; 5) testing multiple doses of DUL and MTH alone and in combination to identify the optimal dose combination to enhance the probability of success when advanced to a clinical trial; and 6) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations.

ABSTRACT/SUMMARY Alcohol-use disorder (AUD) is an unrelenting public-health concern. AUD is characterized by perturbations of central monoamine (i.e., dopamine [DA], serotonin [5HT], and norepinephrine [NE]) systems making them a logical target for medications development. Individual monoamine-uptake inhibitors were moderately effective in a majority of the trials in which they were tested for managing AUD. Continuing to target monoamine-uptake inhibition for AUD is warranted, but novel strategies are needed to identify a highly efficacious pharmacotherapy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for managing AUD: Triple Monoamine-Uptake Inhibition. Triple monoamine-uptake inhibitors are under development, but are not yet available commercially for human use. Combining available medications, however, makes it possible to achieve triple monoamine-uptake inhibition. Duloxetine (DUL), an antidepressant, has high affinity for the 5HT (ki = 0.8 nM) and NE (ki = 7.5 nM) transporters, but lower affinity for the DA transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34 nM), but lower affinity for the 5HT (ki = >10,000 nM) and NE (ki = 339 nM) transporters. We will combine DUL and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non-treatment-seeking AUD participants will be randomized to different maintenance doses of delayed-release DUL (i.e., DUL dose is a between-subject factor). Participants (N=16) in each DUL cohort will be maintained concurrently on increasing doses of long-acting MTH (i.e., MTH dose is a within-subject factor). Alcohol (ALC) self-administration will be determined after participants in each DUL cohort are maintained for 6 days on each MTH dose. A reverse-engineered ALC self-administration (ALC SA) procedure with good predictive validity for clinical efficacy will be used to demonstrate the initial efficacy of DUL-MTH combinations. ALC craving will also be assessed. We hypothesize DUL-MTH combinations will produce an additive or supra-additive reduction in ALC SA relative to the constituent drugs alone. Innovations include: 1) testing a novel pharmacological strategy, triple monoamine-uptake inhibition, for AUD; 2) testing a combination of marketed drugs as opposed to waiting for compounds under development to be available for testing in humans, thereby impacting clinical research and practice more quickly; 3) the use of once daily dosing formulations of the constituent compounds which will improve compliance when advanced to clinical trials or practice; 4) the use of a sophisticated ALC SA procedure; 5) testing multiple doses of DUL and MTH alone and in combination to identify the most effective, safe and tolerable dose combination which will enhance the probability of success when advanced to a clinical trial or practice; and 6) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations for AUD.

ABSTRACT/SUMMARY Methamphetamine (MA) use disorder (MUD) is a significant public-health concern. The number of past month MA users increased dramatically (i.e., 60%) between 2010 and 2014, while the number of overdose deaths involving MA increased 2.7-fold. In 2015, 872,000 individuals had MUD, which accounted for over 8% of treatment admissions in the USA and 225,000 individuals initiated MA use. Dramatic increases in MA seizures by law-enforcement agencies suggest the problem may worsen. MUD is characterized by perturbations in central monoamine systems making them logical targets for developing a pharmacotherapeutic MUD. The proposed research will demonstrate the initial efficacy of an innovative strategy for MUD: Triple Monoamine-Uptake Inhibition. Triple monoamine uptake inhibitors are under development, but are not yet available. Triple monoamine-uptake inhibition can, however, be achieved by combining medications. Duloxetine (DUL) has high affinity for the serotonin (5HT) and norepinephrine (NE) transporters (ki = 0.8 and 7.5 nM, respectively), but lower affinity for the dopamine (DA) transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34 nM), but lower affinity for the 5HT and NE transporters (ki ? 10,000 and 339 nM, respectively). Combine DUL and MTH will functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non- treatment-seeking MUD participants are randomized to different maintenance doses of DUL (i.e., 0, 60 mg/day; DUL is a between-subject factor). Participants (N=14) in each DUL cohort will be maintained concurrently on MTH (i.e., 0, 20, 40, 60 mg/day; MTH is a within-subject factor). MA self-administration will be determined after participants in each DUL cohort are maintained for four days on each of the MTH doses (i.e., MA is a within- subject factor). MA self-administration is the primary outcome measure because the ability to attenuate drug reinforcement is a reliable predictor of an effective pharmacotherapy. We predict DUL-MTH combinations will produce an additive or supra-additive reduction in MA self-administration relative to the drugs alone. Innovations include: 1) testing a novel pharmacological strategy; 2) testing a combination of marketed drugs as opposed to waiting for novel compounds to be available for testing in humans, thereby impacting clinical research and practice more quickly; 3) use of a sophisticated drug self-administration procedure; 4) testing different doses of DUL and MTH alone and in combination to identify the most efficacious dose combination which increases the probability of success when advanced to a clinical trial; 5) providing three-way (i.e., MA, DUL, MTH) safety data that is often required by the FDA for approval of medication combinations for substance-use disorders; and 6) providing the impetus for conducting Phase II clinical trials to further demonstrate the efficacy of DUL-MTH combinations. This project will have a significant impact on clinical research and practice by identifying a first-in class pharmacotherapeutic for MUD.

Contact PD/PI: Kern, Philip A. NRSA-Training-001 (003) PROJECT SUMMARY ? TL1 TRAINING PROGRAM The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to sustain and enhance the current pre-doctoral and post-doctoral TL1 program, currently in its ninth year of National Institutes of Health (NIH) support. By providing a multidisciplinary training program that integrates trainees across diverse fields and offers rigorous and solid translational research education, the TL1 program has effectively prepared clinicians- and scientists-in-training for careers as leaders in clinical and translational science. The UK TL1 program features substantial collaborations across a robust cohort of productive investigators, a talented pool of qualified applicants, solid infrastructure and strong institutional support. The program takes advantage of the physical juxtaposition of UK?s six health care colleges (Medicine, Nursing, Pharmacy, Public Health, Health Sciences, Dentistry) and key disciplines on the main campus (e.g. Engineering, Social Work, Biology, Psychology, Education) to train scholars across wide-ranging fields necessary for successful clinical and translational research (CTR). The program supports career development of scholars with research interests that cross the lifespan (prenatal through elderly) and the full spectrum of clinical and translational science, including translational, clinical, community/policy studies and CTR methods/processes (e.g., biomedical informatics) focusing on a broad array of health topics. The TL1 trainees are making important contributions to science through published work, and all of the program graduates are actively engaged in CTR. This program and other CCTS-sponsored efforts are engaging underserved students in projects focused on health disparities of Kentucky and the Central Appalachian area. We are requesting renewed NIH support for eight TL1 scholars. The foundation of the proposed program will continue to be practical research experiences within multidisciplinary teams guided by experienced mentors along with educational and training offerings, such as certificate, Master?s and PhD degrees, to ensure successful career development of these future CTR leaders. Scholar competency assessments, based on the Clinical Research Appraisal Inventory, serve to guide new program offerings with the theory that trainees who have high confidence in their skills are more likely to pursue a career in CTR. UK CCTS-developed pipeline programs targeting professional and graduate students, including new initiatives to support health equities researchers and trainees from under-represented groups, will ensure the availability of a strong pool of candidates for the TL1 program. In sum, the TL1 program is designed to accelerate career development of future leaders in the translational science workforce who will be prepared to address today?s complex research challenges and spearhead advances in human health. Project Summary/Abstract Page 1236 Contact PD/PI: Kern, Philip A. NRSA-Training-001 (003) BIBLIOGRAPHY AND REFERENCES CITED 1. Fowler BJ, Gelfand BD, Kim Y, Kerur N, Tarallo V, Hirano Y, Amarnath S, Fowler DH, Radwan M, Young MT, Pittman K, Kubes P, Agarwal HK, Parang K, Hinton DR, Bastos-Carvalho A, Li S, Yasuma T, Mizutani T, Yasuma R, Wright C and Ambati J. Nucleoside reverse transcriptase inhibitors possess intrinsic anti- inflammatory activity. Science 346:1000-3, 2014. PMCID:PMC4274127. 2. Ambati J, Fowler B and Ambati K, inventors; Compositions and Methods for Treating Retinal Degradation patent 20180044327. 2018 Feb 15, 2018. 3. Sherwood AR, Johnson MB, Delgado-Escueta AV and Gentry MS. A bioassay for Lafora disease and laforin glucan phosphatase activity. Clin Biochem 46:1869-76, 2013. PMCID:PMC3864130. 4. Albuquerque R, Vora P and Bell N, inventors; Provision Patent: System and Method for Assessment of Choroidal Blood Flow Noninvasively Using Color Amplification patent 13177N/2191US 5. The CTSA Program at NIH: Opportunities for Advancing Clinical and Translational Research. Available at http://www.nationalacademies.org/hmd/Activities/Research/CTSAreview.aspx. Accessed 2019 6. Brown CA, Jiang Y, Smith CD and Gold BT. Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities. Cortex 104:58-74, 2018. PMCID:PMC6008234. 7. Gupta VA, Sousa M, Kraitman N, Annabathula R, Vsevolozhskaya O, Leung SW and Sorrell VL. Coronary artery calcification predicts cardiovascular complications after sepsis. J Crit Care 44:261-6, 2018. 8. Areephanthu CJ, Bole R, Stratton T, Kelly TH, Starnes CP and Sawaya BP. Impact of Professional Student Mentored Research Fellowship on Medical Education and Academic Medicine Career Path. Clin Transl Sci 8:479-83, 2015. PMCID:PMC4626384. 9. Bandura A. Self-efficacy: toward a unifying theory of behavioral change. Psychol Rev 84:191-215, 1977. 10. Mullikin EA, Bakken LL and Betz NE. Assessing Research Self-Efficacy in Physician-Scientists: The Clinical Research APPraisal Inventory. Journal of Career Assessment 15:367-87, 2007. 11. Robinson GF, Switzer GE, Cohen ED, Primack BA, Kapoor WN, Seltzer DL, Bakken LL and Rubio DM. A shortened version of the Clinical Research Appraisal Inventory: CRAI-12. Acad Med 88:1340-5, 2013. PMCID:PMC3758379. 12. Pusek S, Knudson B and Tsevat J. Personalized training pathways for translational science trainees: building on a framework of knowledge, skills and abilities across the translational science spectrum. J Clin Transl Sci 2020 (in press). References Cited Page 1237