Charles Patrick France - US grants

ABSTRACT This revised application requests 5 years of support to continue a translational research program that has made numerous important contributions to our understanding of opioid use disorder (OUD). More than 2 million Americans have OUD and the number of deaths due to opioid overdose continues to rise, in part because of the increased availability of fentanyl and its analogs that are potent, inexpensive, and easy to manufacture. This public health crisis continues despite the availability of medications that substitute for or block the abuse- related and toxic effects of opioids. New and better treatments are needed to address this crisis; ideally, an effective medication for OUD would be nonopioid with little or no abuse or dependence liability and few other adverse effects. Research proposed in this application explores the therapeutic potential of cannabidiol (CBD), a constituent of cannabis that is available increasingly due to legalization of ?medical? and ?recreational? cannabis by states as well as Federal approval of the CBD-containing medication Epidiolex®. Data from our pilot studies, from other preclinical laboratories, and from a recent study in humans69 suggest that CBD, while itself having no abuse liability, shows promise for treating various dimensions of OUD. Moreover, some studies suggest that mixtures of CBD and ?9tetrahydrocannabinol (THC; Marinol®) might be more effective than CBD alone for treating OUD. The proposed research also responds to the NIH initiative to repurpose drugs already approved for use in humans by exploring the therapeutic potential of CBD, given alone and with THC, for treating different dimensions of OUD, including drug taking, relapse, and withdrawal. CBD/THC mixtures also simulate cannabis use, which will identify any detrimental effects of cannabis use by patients taking CBD for OUD. These experiments will use well-established procedures that are ongoing in our laboratory and that are highly translatable to humans. Aim 1 will tackle drug taking and relapse by determining the effects of CBD, alone or with THC, on fentanyl self-administration in a food versus drug choice procedure and on reinstatement of responding previously reinforced by fentanyl. Aim 2 will evaluate the ability of CBD, alone or with THC, to attenuate withdrawal in morphine-dependent monkeys, and Aim 3 will investigate changes in opioid toxicity by characterizing the effects of CBD on the ventilatory-depressant, antinociceptive, and cognitive effects of opioids as well as the pharmacokinetic profile of CBD alone and in combination with opioids. The persistence of the opioid crisis underscores the need to explore potential new treatments including nonopioid medications to increase options for treating OUD. In the period of just a few years, CBD has become widely available, promoted for a broad range of indications, and used extensively despite very little rigorous research that either supports or refutes its therapeutic potential. CBD is safe, has no abuse liability, and is approved by the FDA; if the proposed studies provide proof-of-principle in nonhuman primates for using CBD to treat one or more dimensions of OUD, then clinical trials in patients could begin very soon and have an immediate impact on the opioid crisis.

Benzodiazepines and related gamma-amino butyric acid (GABA)A modulators are used widely for their anxiolytic, hypnotic and anti- convulsant effects. These same compounds are also abused, both alone and in combination with other classes of drugs (e.g., opioids), and long- term use of benzodiazepines can lead to clinically significant physical dependence. The GABAA receptor complex is the site of action of other drugs of abuse (e.g., ethanol) and GABAergic systems, in general, are thought to indirectly modulate the effects of still other drugs of abuse (e.g., cocaine). Much has been learned over the past 10 years from molecular studies on GABA receptors, yet little of this knowledge has been applied to studies in behaving organisms, particularly with regard to GABA neurobiology and substance abuse. Procedures have been developed under this grant for studying discriminative stimulus effects of GABAA modulators in rhesus monkeys and studies proposed in this application will use those procedures to investigate the neurobiology of drugs that vary in their actions on GABAergic systems. Studies under Aim 1ill will compare GABAergic and other drugs for their ability to prevent and reverse benzodiazepine withdrawal and also to mimic the subjective (discriminative) effects of benzodiazepine in normal subjects. A parallel study (Aim II) will establish a discrimination with flumazenil in monkeys treated daily with the a1-s3lective positive modulator zolpidem to test whether this widely-prescribed sedative/hypnotic produces dependence that can be differentiated from that produced by diazepam.Neuroactive steroids will be studied under Aim III to see whether th eye modify the behavioral effects of other compounds that act at the GABAA receptor complex. This study is founded on positive preliminary data with pregnanolone and a literature showing that neuroactive steroids uncouple benzodiazepine receptors from the GABAA receptor complex in vitro. Blind evaluation of compounds will continue the auspices of the Drug Evaluation Committee of the College on Drug Dependence under Aim IV. Collectively, these studies will provide important quantitative information on the nature of drug/receptor and drug/drug interactions for GABAA modulators and related drugs. These data will promote an understanding of GABAergic neurotransmission and abuse liability for a variety of clinically relevant compounds.

Gamma-Hydroxybutyric acid (GHB) occurs endogenously in the brain where it is thought to be a neurotransmitter. GHB is used clinically for treating alcoholism and narcolepsy and is used non-medicinally, both as a primary drug of abuse (presumably because of its sedative/hypnotic effects) and as a sedating agent in unsuspecting victims (e.g., "date rate drug"). Despite GHB having been described more than 30 years ago and despite its widespread use, both medicinally and non-medicinally, relatively little is known about the mechanism that mediates the various effects of GHB. A GHB-associated binding site has been reported, although it is not known whether this site mediates the abuse- related effects of GHB. The paucity of information on the mechanism(s) of action of GHB results from a very limited set of relevant compounds that are available for studying this neurobiologic system and the absence of pharmacologically selective and validated neurochemical and behavioral procedures for characterizing the effects of GHB and related compounds. To that end, the studies proposed in this application will first characterize the receptor binding and behavioral effects of GHB and related compounds. Second, these studies will design and synthesize new compounds for studying the pharmacology of GHB. The working hypothesis of these multidisciplinary studies is that the behavioral effects of GHB are due to its actions on specific sites in brain that are not related to either GABAA or GABAB receptors. Studies under Specific Aim I will design and synthesize potent and selective agonists and antagonists for GHB receptors. Specific Aim II will characterize the binding of GHB and other compounds, including compounds that are synthesized under Specific Aim I, to specific sites in rat brain that have been characterized by our group with [3H]NCS-382. The functional consequences of GHB binding will be examined under Specific Aim III, including a characterization of the effects of GHB and other compounds on schedule-controlled behavior and an evaluation of discriminative stimulus effects of GHB. These systematic characterizations of the binding and behavioral effects of GHB and the development of newly-synthesized compounds for GHB receptors will provide important new information regarding the mechanisms that mediate effects of GHB and related compounds.

Gamma-Hydroxybutyric acid (GHB) occurs endogenously in the brain where it is thought to be a neurotransmitter. GHB is used clinically for treating alcoholism and narcolepsy and is used non-medicinally, both as a primary drug of abuse (presumably because of its sedative/hypnotic effects) and as a sedating agent in unsuspecting victims (e.g., "date rate drug"). Despite GHB having been described more than 30 years ago and despite its widespread use, both medicinally and non-medicinally, relatively little is known about the mechanism that mediates the various effects of GHB. A GHB-associated binding site has been reported, although it is not known whether this site mediates the abuse- related effects of GHB. The paucity of information on the mechanism(s) of action of GHB results from a very limited set of relevant compounds that are available for studying this neurobiologic system and the absence of pharmacologically selective and validated neurochemical and behavioral procedures for characterizing the effects of GHB and related compounds. To that end, the studies proposed in this application will first characterize the receptor binding and behavioral effects of GHB and related compounds. Second, these studies will design and synthesize new compounds for studying the pharmacology of GHB. The working hypothesis of these multidisciplinary studies is that the behavioral effects of GHB are due to its actions on specific sites in brain that are not related to either GABAA or GABAB receptors. Studies under Specific Aim I will design and synthesize potent and selective agonists and antagonists for GHB receptors. Specific Aim II will characterize the binding of GHB and other compounds, including compounds that are synthesized under Specific Aim I, to specific sites in rat brain that have been characterized by our group with [3H]NCS-382. The functional consequences of GHB binding will be examined under Specific Aim III, including a characterization of the effects of GHB and other compounds on schedule-controlled behavior and an evaluation of discriminative stimulus effects of GHB. These systematic characterizations of the binding and behavioral effects of GHB and the development of newly-synthesized compounds for GHB receptors will provide important new information regarding the mechanisms that mediate effects of GHB and related compounds.

DESCRIPTION (provided by applicant): I am currently Professor of Pharmacology and Psychiatry at the University of Texas Health Science Center at San Antonio where I have spent >75% of my time and effort on research supported by 5 R01s and a K02 award from NIDA. My goal in submitting a Research Career Award (RCA, K05) is to allow me to continue devoting >75% of my time to drug abuse research and training. Support under the RCA mechanism (K02) for the past 10 years has allowed me to avoid most teaching and service to the University and instead to devote my time to developing a preclinical research laboratory that focuses on the behavioral and pharmacologic determinants of drug abuse, dependence and withdrawal. I also have had the freedom to pursue several new and productive collaborations on this campus and elsewhere and I have spent considerable time training and promoting the careers of young researchers. This revised application is submitted in response to PA-00-21 "Senior Scientist Award." The major scientific goals of my career development during the period for which support is requested are the following: to understand the neuropharmacologic mechanisms that mediate the dependence and withdrawal effects of opioids and benzodiazepines; to identify the mechanisms that contribute to the therapeutic as well as abuse related effects of GHB and related compounds, in part, through the discovery of new compounds; to determine how insulin-receptor pathways in brain modulate behavioral actions of stimulants; to expand research capabilities of our group to include in vivo voltammetry, genomics, and behavioral studies in mice; and to continue a major commitment to collaborations and training of young investigators in drug abuse research. Major goals for the next several years also include submission of an institutional pre- and postdoctoral training grant, work towards obtaining resources for the expansion and further renovation of our laboratory facilities, in part through the establishment of a Center of Excellence in Behavioral Pharmacology, and continued recruitment of students, particularly underrepresented minorities from South Texas, to our graduate program in pharmacology, especially the behavioral sciences. My Chairman, Dr. Frazer, and the Administration are committed to the continued growth of drug abuse research at this institution, as evidenced by their financial commitments through the recruitment of a new investigators and providing matching funding for the renovation of laboratory animal facilities. This award will allow me to continue spending the majority of my time on NIH-sponsored research and on the expansion of drug abuse research and training at the Health Science Center.

DESCRIPTION (provided by applicant): Delay discounting is rapidly emerging as an important topic in substance abuse research as it becomes clear that drug abusers value delayed rewards less than non-abusers. It is not clear whether this change in discounting is a cause or a consequence of drug taking, although there is evidence to support both possibilities. An in-depth understanding of the neural circuitry underlying delay discounting and how these substrates are affected by drugs of abuse could facilitate a better understanding of vulnerability as well as promote new advances in the treatment of substance abuse. Brain imaging technology is a powerful tool for investigating functional neural pathways. Brain imaging studies on delay discounting in humans provide valuable information, yet practical and ethical limitations necessitate complimentary studies with nonhumans. Unfortunately, currently available rodent models of delay discounting are incompatible with brain imaging in behaving subjects. Studies in this application develop a delay discounting procedure in nonhuman primates that will be compatible with brain imaging. The proposal consists of two parallel, independent specific aims (delay discounting [1] and imaging [2]) that will merge in a future RO1 application. Studies in Aim 1 develop a delay discounting procedure for rhesus monkeys, compatible with functional magnetic resonance imaging (fMRI). Separate groups of monkeys (n=4 per group) will be trained with either oral (drinking) delivery of a preferred liquid (e.g., juice) or i.v. delivery of drug (remifentanil) as the reinforcer. The delay discounting procedure with monkeys is nearly identical to procedures that are used to study delay discounting in humans and rodents. Aim 2 develops procedures and tools for acquisition, processing, and interpretation of fMRI studies, in this application in anesthetized monkeys and eventually in awake, behaving monkeys. Collectively, these developmental studies (R21) provide the foundation for a future RO1 application investigating the neural substrates underlying delay discounting and how these substrates are affected by drugs of abuse. Impulsivity is thought to be both a predisposing factor and a consequence of drug abuse;this grant develops a nonhuman primate model of delay discounting for examining the behavioral and neural consequences and causes of impulsivity. Such a model is not currently available but is essential for understanding how impulsivity and drugs interact and, therefore, how treatments for drug abuse can be tailored based on the behavioral output (e.g., impulsivity) of individuals.

DESCRIPTION (provided by applicant): This revised R13 application requests support for a meeting, entitled Behavior, Biology and Chemistry: Translational Research in Addiction (BBC), to be held annually in San Antonio in 2011-2013. The 2-day meeting continues highly successful BBC meetings in 2009 and 2010 that were attended by a diverse group of addiction researchers, from undergraduate students to senior scientists and encompassing a wide range of disciplines, from molecular biology to psychiatry. BBC meetings receive a high level of financial and institutional support from the hosting university (University of Texas Health Science Center) as well as other universities. This transdisciplinary mixture of junior and senior investigators, pre- and post-graduate students provides role models for young scientists while at the same time gives them an opportunity to present results from their own research in a context where there is a lower threshold for presentation, compared with most national meetings. The transdisciplinary and translational theme of the BBC meeting will foster new scientific initiatives and promote thinking that is outside the constraints of traditional disciplines. The format of the meeting contributes to training a new generation of biomedical researchers and, in the process, provides an intensive exposure to new and exciting topics in addiction research. A single symposium at each meeting will bring together experts in a specific area to provide a state-of-the-art overview of an important issue in addiction research;the remainder of the meeting is open to any topic in addiction biology. The meeting includes open communications (two sessions for student presentations) and a poster session. Invited speakers will make presentations that bridge chemistry, biology and behavior in addiction research. The specific aims of this meeting are as follows: I) facilitate interactions among chemists, biologists and behavioral scientists, thereby stimulating cross-fertilization of ideas and conceptualizations among disciplines;II) provide an attractive and affordable venue for young scientists, especially underrepresented minorities and women, in the addiction field to present their research and to learn about state-of-the-art research on the behavioral biology of addiction;and III) provide a freely available electronic archive of the plenary symposium and other keynote lectures. PUBLIC HEALTH RELEVANCE: This application requests support to continue a highly successful scientific meeting that brings together students, junior and senior scientists from different disciplines (molecular biology to psychiatry) in order to promote new collaborations and creative transdisciplinary and translational thinking about novel targets for developing medications for addiction. This meeting will promote new scientific initiatives and introduce young scientists, especially underrepresented minorities and women, to cutting-edge research in addiction biology.

DESCRIPTION (provided by applicant): Impulsivity, an increased tendency to act without thought or deliberation, is common in psychiatric disorders and often is observed in drug abusers. Although impulsivity might be a predisposing trait that contributes to the development of substance abuse, it might also be a result of drug use, thereby promoting ongoing abuse and possibly relapse. Studies have examined how acute administration of drugs affects impulsivity;however, most drug abuse involves repeated drug administration and often the development of physical dependence, yet few studies have examined how impulsivity is affected by chronic drug administration and its discontinuation. Impulsivity is multidimensional and several procedures have been developed for studying different but equally important dimensions of impulsivity;in one procedure, delay discounting, subjects choose between a smaller reinforcer that is delivered without delay and a larger reinforcer that is delivered after a delay. Increased responding for the smaller, immediately available reinforcer is thought to reflect greater impulsivity. Studies in this application examine effects of acute and chronic opioid treatment, and its discontinuation, on delay discounting in animals because in humans delay discounting is sensitive to opioid treatment and its discontinuation. Data from humans suggest that impulsivity contributes to drug abuse and that drug abuse increases impulsivity;delay discounting might also vary across different reinforcers (e.g., money versus drug). Proposed studies build on preliminary data showing that delay discounting is affected by daily administration of very small doses of morphine, suggesting that abuse of even small doses of drugs (e.g., prescription opioids) could significantly increase impulsivity. These studies examine how acute and chronic treatment with a prototypic 5 opioid receptor agonist (morphine), as well as discontinuation of treatment, impact delay discounting in adult male rhesus monkeys. Studies under AIM 1 build on preliminary studies and compare acute drug effects on delay discounting in monkeys responding for a non-drug reinforcer to effects in monkeys responding for a drug reinforcer;these studies test whether delay discounting is differentially altered when responding is maintained by different reinforcers and also test the pharmacologic selectively of these drug effects. Using the same monkeys, AIM 2 evaluates how chronic treatment with morphine and its discontinuation alter delay discounting under the non-drug and drug reinforced procedures;these studies examine the effects of daily treatment on delay discounting, whether tolerance develops to those effects, how discontinuation modifies delay discounting, and how the time course of changes in this measure of impulsivity correlates with indices of withdrawal. These studies examine the unexplored possibility that abuse of even small doses of opioids increases impulsivity that can be enduring;increased impulsivity might contribute to ongoing drug abuse, relapse, and other high risk behavior long after drug withdrawal is no longer evident. PUBLIC HEALTH RELEVANCE: Impulsivity puts you at risk for drug abuse, but might also be caused by it, although little is known about how drug use, especially chronic drug use, impacts impulsivity. This grant examines the effects of chronic drug administration and its discontinuation (withdrawal) on delay discounting to determine how common drugs of abuse affect impulsivity.

DESCRIPTION (provided by applicant): This new application entitled "Training in drug abuse research: behavior and neurobiology" requests five years of funding to support a maximum of four postdoctoral fellows per year for interdisciplinary training in drug and alcohol abuse. Fellows primarily engaged in drug and alcohol research take two required courses and attend seminars, journal clubs, an annual retreat, and monthly chalk talks. Fellows will receive training in research and experimental design while participating in collaborative projects spanning at least two laboratories with different expertise and techniques. Training in translational investigation occurs in studies spanning molecular, animal, and human research. Scheduled activities provide career development, preparation for seeking an independent position, and training in the responsible conduct of research. Drug and alcohol abuse research and education at the University of Texas Health Science Center at San Antonio (UTHSCSA) is growing rapidly and the proposed postdoctoral training program is the first step in establishing an NIH-supported program that eventually will include predoctoral training as well. A Program Director with extensive mentoring and research experience will be assisted by Internal and External Advisory Committees. Participating NIH-supported faculty include senior and junior investigators who collectively have research expertise in the following areas in drug and alcohol abuse: molecular and receptor pharmacology;biochemical and neurochemical pharmacology;electrophysiology;preclinical behavioral pharmacology;and clinical trials. This program provides rigorous interdisciplinary training in behavioral and neurobiological research, thereby addressed a national demand for addiction scientists who can succeed in the current translational research environment. PUBLIC HEALTH RELEVANCE: This postdoctoral training program builds on a rapidly growing community of drug and alcohol abuse researchers and trainees at UTHSCSA. The well recognized need for addiction scientists with interdisciplinary training is addressed by this program in which trainees conduct research on collaborative projects spanning more than one laboratory and more than one experimental approach. An experienced Program Director along with 17 other preceptors and an expert External Advisory Committee will oversee the progress and further growth of drug and alcohol abuse training at UTHSCSA.

DESCRIPTION (provided by applicant): The positive reinforcing properties of drugs of abuse are thought to result from enhanced activity in meso-limbic dopamine (DA) systems. In addition to direct blockade of DA transmission by classical and atypical antipsychotics, an alternative approach to diminishing central DA activity is via stimulation of serotonin 5-HT2C receptors. The research described in the present proposal will evaluate one such 5-HT2C agonist lorcaserin, already well advanced in clinical development in other indications, for its attenuation of cocaine abuse-related behavior in the rhesus monkey. Data obtained in this non-human primate (NHP) should better predict clinical effects in humans than data from rodents. The aim is to determine whether the NHP data would provide encouragement, or not, for the clinical testing of lorcaserin for treating cocaine abuse in humans. The experiments will evaluate lorcaserin for attenuation of cocaine-induced hyperactivity; cocaine maintained self-administration behavior and the internal stimulus properties of cocaine in a drug discrimination procedure. To demonstrate that lorcaserin could be useful for treating cocaine abuse in humans, these experiments should show that lorcaserin is effective in attenuating cocaine abuse- related behavior in NHP at doses without intrinsic effects on behavior.

? DESCRIPTION (provided by applicant): Opioid receptor agonists remain the drugs of choice to treat moderate to severe pain, but their use is limited by adverse effects including tolerance, dependence, abuse, and respiratory depression. A recent increase in overdoses and deaths is fueling concerns about opioids that further limit their legitimate medical use. A growing body of evidence indicates that the therapeutic window of an opioid can be increased by combining it with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Like opioids, cannabinoid receptor agonists have antinociceptive effects and are used to treat pain; however, their use is limited because of adverse effects, including abuse, and because they are effective under a very limited range of conditions when administered alone. Converging lines of evidence indicate that opioid/cannabinoid combinations might be very effective and safe for treating pain. For example, our studies show that in monkeys the potency of opioids to produce antinociception is increased significantly by cannabinoids at doses that do not increase the potency of opioids for producing reinforcing or discriminative stimulus effects. Those results were obtained following acute administration of drugs, although treatment of pain often requires repeated drug treatment. Despite the potential clinical utility of opioid/cannabinoid combinations, little is known about th consequences of repeated daily administration of combinations; the proposed studies extend our initial findings to repeated drug administration to more closely model treatment in pain patients. These studies test the hypothesis that the adverse effects of opioids, that limit their clinical use, are reduced or avoided by combining small doses of an opioid with a cannabinoid. Aim 1 compares the long- term effects of daily dosing with the high efficacy opioid receptor agonist fentanyl administered alone and in combination with the high efficacy cannabinoid receptor agonist CP55,940 to test the hypothesis that administration of an opioid/cannabinoid combination reduces or prevents the development of opioid tolerance and physical dependence. Aim 2 assesses the abuse potential (positive reinforcing effects) of opioid/cannabinoid combinations using a choice procedure in which monkeys choose between fentanyl alone and a combination of fentanyl and CP55,940. Aim 3 characterizes other potential adverse effects of opioid/cannabinoid combinations (sedation, impaired complex task performance, and respiratory depression) and possible pharmacokinetic interactions between fentanyl and CP55,940. These studies will characterize opioid/cannabinoid combinations that increase the therapeutic window of opioids by selectively decreasing the dose of opioid necessary for therapeutic effects, thereby reducing and possibly avoiding the occurrence of adverse effects that currently limit the legitimate medical use of opioids. Using a species and procedures that are highly translatable to humans, these studies will provide proof-of-concept for this innovative approach to pain treatment.

SUMMARY/ABSTRACT Stimulant abuse is a serious public health problem with untold medical, societal, and economic impact worldwide. Despite decades of research into the neurobiology of drug abuse, there are no FDA-approved pharmacotherapies for stimulant abuse. One strategy to reduce the time required to get candidate medications into the clinic is to repurpose drugs, already approved by the FDA for other indications, to treat stimulant abuse, and one strategy to improve the therapeutic effectiveness of a drug is to administer it in combination with second drug with a complimentary mechanism of action. We and others have shown that drugs that block the effects of DA (buspirone [Buspar®]; a DA D2-like [D2, D3, & D4] receptor antagonist, FDA-approved for treating anxiety) or modulate DA transmission (lorcaserin [Belviq®]; a serotonin [5-HT]2C receptor agonist, FDA-approved for treating obesity) attenuate the reinforcing and/or relapse-related effects of stimulants such as cocaine in animals. Based on very promising pilot studies in male and female rhesus monkeys, we hypothesize that a combination therapy comprising fixed-doses of drugs that target both pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission will have a therapeutic effect (e.g., decrease in drug-taking) that is greater than the effect of either drug alone (i.e., supra-additive interaction). Our preliminary data support this hypothesis and suggest that combining buspirone with lorcaserin will yield a highly translatable and novel approach to treat stimulant abuse. Studies under Aim 1 test the hypotheses that mixtures of drugs targeting pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission result in a supra-additive inhibition of the reinforcing (progressive ratio and cocaine-food choice) and relapse-related (reinstatement) effects of cocaine, and that these effects differ as a function of sex (e.g., females being less sensitive to buspirone alone, but more sensitive to lorcaserin:buspirone mixtures). Aim 2 tests the hypotheses that the cardiovascular and locomotor effects of lorcaserin and buspirone are not altered when combined in a mixture, and that mixtures of lorcaserin and buspirone do not exacerbate, and may blunt, the cardiovascular effects of cocaine; these effects are not expected to differ as a function of sex. The proposed studies build on compelling preliminary data and test the novel hypothesis that a combination therapy comprising fixed-doses of FDA-approved drugs that target pre-synaptic (5-HT2C receptors; lorcaserin) and post-synaptic (DA D3 receptors; buspirone) regulators of DA neurotransmission are more potent and/or effective at reducing the reinforcing and relapse-related effects of cocaine than would be expected based on the effect of either drug alone (i.e., a supra-additive interaction), without also exacerbating the cardiovascular effects of cocaine. These studies will not only provide new information (within 4 years) about the effects of drug mixtures targeting 5-HT2C and DA D3 receptors, but because lorcaserin and buspirone are already approved by the FDA for use in humans, these results will be highly translatable to the clinic, significantly reducing the time and cost required to determine the effectiveness of mixtures of lorcaserin and buspirone to treat cocaine abuse.

ABSTRACT Deaths from opioid overdose continue to rise; from 2015-2016, there was a 28% increase in the number of fatal overdoses. Fentanyl derivatives are inexpensive, easy to synthesize, potent, and marketed to unsuspecting abusers as heroin or other drugs. Moreover, the effects of fentanyl derivatives are reportedly more difficult to reverse with naloxone, compared with reversal of heroin. Pharmacotherapies for opioid abuse include the µ opioid receptor agonists methadone and buprenorphine that are effective in many patients, although both drugs have limitations, including diversion and abuse, and they can have serious unwanted effects, including respiratory depression and death. The opioid receptor antagonists naltrexone and naloxone avoid the abuse liability and adverse effects of methadone and buprenorphine; however, short durations of action and surmountability limit their effectiveness. A medication with a longer duration of action that prevents and reverses the effects of opioids in a manner that is not surmounted by increasing doses of agonist could improve significantly treatment of abuse and save lives by providing insurmountable extended protection after rescue from overdose. Our pilot studies in monkeys show that the pseudoirreversible, µ opioid receptor selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses as well as protects against respiratory depression by heroin, with a single injection being effective for a week or longer. Proposed studies build on these compelling data and examine the long-term antagonist properties and the pharmacokinetics of MCAM in combination with commonly abuse opioids, including ultra-potent fentanyl analogs. MCAM is hypothesized to be better than naloxone and naltrexone in reversing and preventing the effects of opioid receptor agonists and, in particular, high efficacy agonists that exert behavioral effects when occupying relatively few opioid receptors. Its pseudoirreversible binding is expected to make antagonism by MCAM more difficult to surmount and to provide longer antagonist action than the currently used opioid receptor antagonists. Aim 1 will characterize long-term antagonism of heroin self-administration by MCAM in a food/drug choice procedure. Aim 2 will examine the ability of MCAM to antagonize the positive reinforcing and respiratory depressant effects of fentanyl and ultra- potent analogs alone and in mixtures with heroin or cocaine. Aim 3 will characterize the pharmacokinetic profile of MCAM, heroin, fentanyl and its derivatives, and cocaine, alone and in mixtures. Using a highly translatable species, this project will examine a novel opioid receptor antagonist that has the potential to save lives by preventing and reversing the adverse, and often lethal, effects of opioids. The availability of another safe, effective, and long-acting treatment could be advantageous for many patients (e.g., problems with compliance would be reduced by an extended-release, pseudoirreversible antagonist) and in many treatment settings (e.g., rural areas where the opioid epidemic is worsening and regular contact with treatment providers is not practical).

ABSTRACT This application responds to PA-20-142 and is the second competing continuation of a postdoctoral training program entitled ?Training in drug abuse research: behavior and neurobiology? at the University of Texas Health Science Center at San Antonio (UTHSCSA). This Program has become an integral component of the recently launched Addiction Research, Treatment & Training Center of Excellence, the umbrella organization for a large variety of activities related to substance use disorder (SUD) on campus and extending into the San Antonio community. During the current period of support, all 6 training positions were filled with fellows selected from a pool of highly qualified applications. Since 2016, a total of 14 trainees have been or are currently supported by the Program, including 11 women (78%); 4 of the trainees (28%) are underrepresented minorities. Among 10 fellows that completed training, 8 are in academic positions. During the current period of support, trainees published 40 manuscripts (28 as first author), submitted 11 grant applications, and made 111 presentations at scientific meetings. Increasingly trainees are participating in community outreach activities, advocating for SUD research, education, and treatment. This Program sponsors numerous career development activities, many of which are attended by students and fellows, in addition to trainees in this Program. The well- funded research programs of the 18 Regular and 3 Junior faculty mentors span cell signaling to neurochemistry, preclinical behavioral pharmacology, and human clinical trials. The Program enjoys outstanding financial and other support from UTHSCSA (e.g., 10% salary for the Director), including an Office of Postdoctoral Affairs that offers many programs on career development, grant writing, and teaching, among others. Program Leadership includes a Director, Associate Director, Coordinator, and an Internal Advisory Committee. An External Advisory Committee evaluates the Program as part of an annual Advisory Committee Meeting in San Antonio; the details and operation of the Program as well as the training experience of fellows have improved as a result of recommendations by the Advisory Committees. The training environment at UTHSCSA is outstanding and includes excellent seminars, grand rounds, journal clubs (including the Addiction Journal Club hosted by this Program), formal training in rigor and reproducibility, formal training in the responsible conduct of research, and an annual international SUD meeting entitled Behavior, Biology & Chemistry: Translational Research in Addiction. This competing continuation requests 5 additional years of support for 6 positions in this highly successful, vibrant Program that is contributing to the NIDA mission of recruiting and training the next generation of SUD researchers.