2022 Grant Awardees Research Summaries
Young Investigator Awards:
Research Project #1:
Discovering ion channel-based treatments for opioid-use disorders
Barbara Juarez, PhD, University of Washington Medical Center
The progression of opioid-use-disorder (OUD) is hypothesized to be due to changes in how distinct brain regions (or neural circuits) interact. In this model, different neural circuits are preferentially activated during separate phases of OUD, impacting symptoms across the opioid-use cycle. This includes positive symptoms during opioid intake, negative symptoms during opioid withdrawal, and craving symptoms during opioid abstinence. Many treatments in use today for OUD directly target the brain’s natural opioid systems to help mitigate withdrawal and craving symptoms that can promote relapse. However, some of these opioid-based treatments are under strict regulatory oversight, limiting their accessibility, and ultimately making it difficult for individuals to remain abstinent. Discovering non-opioid forms of treatment could help reduce opioid withdrawal symptoms and increase the likelihood of long-lasting abstinence. Ion channels expressed in the brain, which function by modulating neural excitability, are promising targets because they can work to rapidly alter neural circuit activity. With the support of Cure Addiction Now (CAN), we aim to discover how ion channels can be used to break the progression of OUD.
Research Project #2:
Intensive Momentary Assessment of Inpatient Treatment Dynamics to Predict Short- and Long-Term Treatment Outcomes in Opioid Use Disorder
Justin C. Strickland, Ph.D., Johns Hopkins University School of Medicine
Over the last 50 years the United States has experienced several acute crises related to various substance use disorders, most recently the prominent and deadly opioid overdose epidemic. Improving treatment outcomes often relies on data collected in national treatment databases, which lack the depth and breadth of information to determine the characteristics of those at greatest risk for negative treatment outcomes. With the support of Cure Addiction Now we will test an innovative momentary assessment method to predict treatment outcomes with clear implications for improving the care of people with opioid use disorder. Momentary methods capture data on subjective experience in real-time to improve the reliability and robustness of the information collected. An underutilized clinical application is evaluating momentary assessment in inpatient treatment settings. These approaches may improve outcomes by identifying patient characteristics that predict early discharge or relapse, offering a direct and actionable opportunity to identify those needing immediate help or additional resources or care at treatment discharge. The supported project will be conducted in a real-world residential treatment center where patients with opioid use disorder will complete momentary assessments of mood, craving, and decision-making throughout a residential treatment period. Metrics from momentary assessment data will be used to evaluate how within-treatment changes and patterns of mood, craving, and decision-making predict short-term and long-term treatment outcomes. This study will be integrated within an existing, real-world treatment infrastructure containing well-established treatment outcomes collected up to 1 year post discharge, enhancing the applicability of this study to broad treatment contexts. These data will directly advance addiction science by providing proof-of-concept data about a tool that can be implemented in real-world settings to aid clinical decision-making and identify patients at risk for relapse.
Research Project #3:
Characterization of NCP as a Potential Agent for the Treatment and Prevention of Opioid Use Disorder
Lee-Yuan Liu-Chen, Co-I, Temple University Lewis Katz School of Medicine
The results of surveys conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA) showed that 3.4 percent of people aged 12 or older in the US (or 9.5 million people) misused opioids (heroin or prescription pain relievers) in 2019. The Center for Disease Control and Prevention reported that estimated deaths from opioids overdose were 75,673 in the 12-month period ending in April 2021, compared to 56,064 the year before. Therefore, amidst the COVID pandemic, the opioid crisis is still raging. It is thus urgent to develop medications to treat and prevent opioid use disorders (OUDs). In this application, we propose to study a recently identified novel compound, NCP, which has shown efficacy in animal models as a non-addictive analgesic, for the prevention and treatment of OUDs.
Opioid drugs act on three receptors: mu, delta, and kappa opioid receptors (MOR, DOR and KOR, respectively). Opioid analgesics preferentially activate the MOR, but they also cause addiction and respiratory depression. While both MOR agonists and KOR agonists produce analgesia, they cause opposite hedonic states, euphoria and dysphoria, respectively. Our preliminary data show that in mice NCP, activating both KOR and MOR with a higher KOR activity, is an effective analgesic without abuse liability. The rationale for developing dual MOR/KOR compounds for OUD treatment is based, in part, on the finding that the MOR partial agonist buprenorphine has been used effectively for the treatment of OUD. Further, the novel KOR full agonist nalfurafine reduced rewarding effects of prescription opioids, such as morphine and oxycodone, in animals. In this study, we will test the hypothesis that NCP will reduce the rewarding effects of oxycodone and will also suppress cue- or drug priming-induced reinstatement of opioid drug seeking, rat models of opioid relapse. If NCP is proven to reduce rewarding effects of opioids and to prevent relapse to opioids, it will open a novel mechanistic approach to develop drugs for the treatment and prevention of OUDs.
Research Project #4:
Elucidating the Anti-addictive Mechanism of Ibogaine and TBG
David E. Olson, Ph.D., University of California, Davis
The prefrontal cortex (PFC) plays a critical role in regulating reward and controlling drug-seeking behavior. Atrophy of neurons in this brain region is thought to contribute to the pathophysiology of substance use disorder (SUD), and compounds capable of rectifying these deleterious structural changes could potentially have broad therapeutic implications. Psychedelic compounds, such as ibogaine, have a long history of demonstrated efficacy for treating multiple addictive disorders (alcohol, opioid, psychostimulant, nicotine, etc.), and their anti-addictive effects can last for months following a single administration. Recently, our group demonstrated that psychedelics promote structural and functional neural plasticity in the PFC, possibly explaining both their broad therapeutic scope and their long-lasting effects. However, the therapeutic development of these compounds has been hindered by the fact that they induce profound changes in perception, with many also producing cardiotoxicity through hERG inhibition and/or activation of 5-HT2B receptors. Through careful chemical design, our group has engineered analogs of psychedelics that promote cortical plasticity and have anti-addictive properties without hallucinogenic effects. While we have demonstrated that the plasticity-promoting properties of these non-hallucinogenic ligands are mediated through activation of 5-HT2A receptors, the target responsible for their anti-addictive properties ibogaine and related molecules is not known. To fill this gap in knowledge, we propose to use genetic and pharmacological tools to validate or invalidate 5-HT2A receptors as the anti-addictive targets for ibogaine and the related non-hallucinogenic analog TBG. We also propose studies to understand the role of neural plasticity in the anti-addictive properties of these compounds. Without understanding which specific receptor(s) endows ibogaine and related compounds with anti-addictive properties, we will never be able to produce medicines with optimal pharmacological profiles. The proposed experiments will 1) provide insight regarding the basic neurobiology related to a new mechanistic approach for treating SUD, 2) de-risk investment in anti-addictive, non-hallucinogenic 5-HT2A ligands, and 3) enable pharmaceutical companies to prioritize compounds with optimal pharmacological profiles. Ultimately, the work described here will advance drug discovery efforts to identify a safe and effective general solution to treating multiple addictive disorders using a single compound and will prove instrumental to the evolution of next-generation neurotherapeutics.
Research Project #5:
Towards a high-throughput mouse model for opioid addiction
Garret Stuber, Ph.D., University of Washington
Opioid addiction has a tremendous toll on society, but a mechanistic understanding of how exposure to opioids such as heroin ultimately results in compulsive drug-taking and -seeking behavior in some individuals, but not others, is still poorly understood. A longstanding idea is that drug-induced enduring alterations in neural circuit function occur, which underlie enhanced drug-seeking, taking, and relapse behaviors that are hallmarks of addiction. To identify novel brain and circuit targets for addiction intervention, preclinical rodent models are utilized because brain cell types are genetically accessible, and mice are readily compatible with modern systems neuroscience approaches such at two-photon calcium imaging. The current gold standard addiction model in the field is the rat model of drug self-administration. While the rat self-administration model has high face validity, it remains very challenging for the field at large to apply modern neuroscience tools to the rat because of challenges with cell type specific genetic targeting (i.e few transgenic lines). Additionally, there are numerous practical considerations that limit the use of the rat self-administration model. Rats are expensive to house and maintain compared to mice, require more space and personnel for running experiments with a lower number of total subjects. Over the last two decades neuroscience research utilizing mice has grown exponentially. Almost all the major technological advances in neuroscience and genomics can readily be applied in mice compared to rats. However, addiction models in mice have advanced very little over this same period. While a handful of highly technically proficient and perseverative labs has established mouse self-administration research, it remains out of the hands of research community in general, because its high degree of technical difficulty, attrition of experimental subjects due to lost catheter patency, high variability of self-administration behavior between experimental subjects. Here, we propose to address these limitations by developing a new model of opioid self-administration using head-fixed mice. Our goal for this project is to develop a behavioral ecosystem for drug self-administration procedures that extends our recently developed operant wheel system for sucrose self-administration to incorporate intravenous delivery of opioids. Head fixed models of behavior are highly rigorous and reproducible and require little experimenter intervention which translates to an increased capacity of the number of experimental subjects that can be run by a single experimenter. This system will also be open source, with an approximate cost of less than $1,000 per system, which will reduce the barrier of entry for many labs. Overall, new head-fixed self-administration procedures will accelerate the rate of discovery of both biological targets and therapeutics for opioid addiction.
2021 Grant Awardees Research Progress Report
as of 10/1/2021
Research Project #1:
Developing a Strategy to Prevent Relapse to Opioid, Nicotine, Alcohol and Cocaine Use with a Single Use Medication
Courtney A. Miller, PhD, Scripps Research
Substance use disorder (SUD) is a chronic, relapsing disorder with a severe lack of treatment options. Associations that have formed during periods of drug use serve as powerful relapse factors by triggering motivation to seek the drug. Recently, we identified the molecular ATPase and driver of synaptic actin polymerization, nonmuscle myosin II (NMII), as a biological target for the selective disruption of these associations. A single treatment with the NMII inhibitor Blebbistatin (Blebb) produces an immediate, seemingly permanent loss of motivation for methamphetamine (METH) and amphetamine (e.g. Adderall) by targeting the associated memories. This occurs without the need for retrieval and without affecting other types of memories, including those associated with other drugs of abuse. In addition to its efficacy in animal relapse models following a single treatment, several properties made Blebb an excellent starting point for medication development. Paramount among these are the molecule’s high brain penetration (thus, lower doses can be used) and rapid clearance from the body and brain (limiting unwanted peripheral and central effects on the body). Unfortunately, Blebb’s activity at cardiac muscle myosin II (CMMII), a protein critical for heart function, was a liability. Through work funded by the NIH, including NIDA, we have developed a preclinical candidate compound, MT-110, that retains Blebb’s high brain penetrance and rapid clearance, but no longer inhibits CMMII. The result is a dramatically improved safety profile and a therapeutic index (ratio of the lowest dose that achieves the desired effect and the highest tolerable dose) of at least 25x. We have filed a non-provisional patent in the US and ten other countries, declared a preclinical candidate, and are now preparing to file an IND with FDA and designing our first in human Phase 1 trial. Recognizing that it would be powerful to utilize the Blebb-based NMII inhibitor to target motivation for other widely used drugs of abuse, particularly opioids, alcohol, nicotine and cocaine, we have begun working on a strategy. Blebb disrupts restabilization of these memories when animals are exposed to reminders associated with the drug of abuse. However, for individuals that use drugs, associations capable of motivating drug seeking can number in the hundreds and even be unconscious motivators. Therefore, it is not feasible for subjects to actively retrieve all “triggers” in a clinical setting for reconsolidation targeting. Interestingly, recent evidence in animal and human studies indicates a similar disruption can be achieved by pairing a reconsolidation disrupting intervention with a small amount of the drug of abuse itself. We now have promising preliminary preclinical data using this strategy that points to the potential for MT-110 in cocaine, nicotine and opioid use disorders. Additional studies to validate and extend these findings are underway.
Research Project #2:
Role of chemosensory processing in choroid plexus circuit in drug addiction
Paul J. Kenny, Ph.D. and Stephanie P.B. Caligiuri, M.D.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York
Sensitivity to the aversive properties of addictive drugs influences vulnerability to substance use disorders (SUDs). Indeed, aversive reactions to drugs of abuse upon their first usage decreases the likelihood that subsequent use will transition from occasional to habitual. Little is known about the mechanisms of drug aversion. Taste systems guide ingestive behaviors to ensure survival by detecting sweet, salty, & umami flavors, which represent carbohydrates, electrolytes, and protein respectively. Taste systems also detect sour and bitter tastes, which often reflects spoiled or poisonous substances. Intriguingly, most addictive drugs are bitter-tasting plant-derived alkaloids, a class of compounds known to activate taste-2 receptors (T2Rs). In addition to their abundant expression in the oral cavity, accumulating evidence suggest that T2Rs are also expressed outside the oral cavity. Individuals carrying genetic variation in genes that encode components of the T2Rs and related signaling machineries are at increased risk of developing SUDs. With the support of Cure Addiction Now (CAN), we are testing the hypothesis that oral and/or extra-oral T2Rs are activated by opioids and other classes of addictive drugs, and that this action contributes to their aversive properties that protect against SUDs. Using genome editing technologies and cellular assays of T2R function, we have collected compelling data suggesting that drugs of abuse stimulate T2R signaling. We have also shown that the same neurons in brain aversion centers that are activated by consumption of noxious bitter compounds such as quinine are also recruited by drugs of abuse. Moreover, we have shown that genetic manipulations that selectively perturb T2R signaling attenuated aversive responses to drugs of abuse and increases their consumption. Perhaps most surprisingly, we found that T2R-mediated aversive sensory information related to drugs of abuse is routed to the choroid plexus in the fourth ventricle, a secretory organ in the brain, and that manipulating genes in the choroid plexus regulates aversive behavioral responses to addictive drugs. These data reveal a novel chemosensory mechanism that regulates addiction-relevant behavioral responses to drugs of abuse that may serve as a substrate for the development of target therapeutics for SUDs.
Social media handles:
Twitter: @DrSCaligiuri @PaulJK27
Research Project #3:
The Kappa Opioid Receptor: A Therapeutic Target for Negative Affect in Pain and Addiction
Catherine Cahill, Ph.D. and Edythe London, Ph.D., UCLA
Anhedonia is the impaired capacity to experience pleasure from naturally rewarding objects and events. It is defined as a state of ‘markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day’. While it is relatively undertreated, it occurs in many neuropsychiatric disorders including substance use disorders and chronic pain. Considering the high comorbidity between negative affective states, such as depression and chronic pain, it is not surprising that anhedonia may be a driver of opioid addiction, where opioid misuse is a predictor of anhedonia.
Kappa opioid receptor agonists produce dysphoria, depressive-like symptoms and psychotomimetic effects in humans, and they elicit aversion and depressive-like behaviors in preclinical models. A novel kappa receptor antagonist JNJ-67953964 produced anti-anhedonic effects in a recent, multicenter, double-blind, placebo-controlled, randomized clinical trial. Given the involvement of this receptor in negative affective states and the positive preliminary clinical study in alleviating anhedonia, our studies focus on kappa receptors with the goal of facilitating the development of medications for Opioid Use Disorder.
Our first aim was to determine the association of kappa binding in limbic regions of brain with measures of negative affect in a model of chronic pain. To date, we have demonstrated kappa receptor binding in the striatum using microPET and 18F]LY2459989, a novel kappa radiotracer. Binding of this tracer was blocked by both a kappa-receptor selective antagonist the nonselective opioid antagonist naloxone. We have also conducted longitudinal studies were animals were imaged over time to correlate changes in receptor binding with the development of negative affective states. Analysis of these data are ongoing.
Studies in people who misuse heroin show that acute opioid withdrawal increases opioid craving and seeking behavior, and that the severity of withdrawal predicts the response to treatment. We therefore have conducted microPET imaging in opioid-dependent rats during the acute phase of opioid withdrawal. Analysis of these studies are ongoing.