This U54 Center will use translational research as a tool for medication development in cocaine use disorder (CocUD).The overall goal of Project 3 is to assess novel compounds in cocaine self-administration and cue reactivity models to provide key preclinical profiles of potential therapeutics for CocUD. This information is necessary to design future human studies to assess abstinence induction in active users of cocaine or relapse prevention in abstinent subjects. The initial compound to be studied in Project 3 will be pimavanserin, a selective 5-HT2AR antagonist which also displays inverse agonist activity in functional assays. Preclinical studies have demonstrated that selective 5-HT2AR antagonist/inverse agonists (e.g., M100907) consistently reduce both cue- and cocaine-evoked reinstatement in cocaine self-administration assays in animals. Given that pimavanserin is on track for potential approval by the U.S. Food and Drug Administration for use in the treatment of psychosis during Parkinson's disease, the ultimate availability of this novel medication will allow future evaluation for suppression of relapse in human subjects. Project 3 will employ a portfolio of validated animal models for CocUD to develop a comprehensive preclinical profile of pimavanserin prior to human studies, including assessment of the efficacy of acute and chronic pimavanserin in preclinical models of cocaine intake (fixed and progressive ratio self-administration) and cue reactivity (attentional orientation toward drug-associated cues). In addition, our research has demonstrated that a selective 5-HT2AR antagonist plus a selective 5-HT2cR agonist evoke synergistic suppression in preclinical models of CocUD, and combinatorial treatment with lorcaserin plus pimavanserin will be the second medication to be assessed. Finally, we present evidence that high impulsive action (rapid response impulsivity) predicts high cue reactivity as measured by attentional bias toward cocaine-associated cues in cocaine-dependent human subjects and in rats. For this reason, as an exploratory aim, we will assess the impact of impulsivity on the response to pimavanserin as well as pimavanserin plus lorcaserin. These translational approaches will provide a cohesive dataset to support the novel pharmacotherapeutic prospect that pimavanserin alone or in combination with lorcaserin may support behavioral recovery in CocUD.
The outlined strategy will elucidate the efficacy of potential therapeutic medications to suppress relapse predictive events in cocaine use disorder. These experiments will lend support to the prospects that may be useful to improve behaviors that contribute to relapse, and set the stage for the use of such compounds therapeutically in humans.
|Moeller, F Gerard; Cunningham, Kathryn A (2018) Innovative Therapeutic Intervention For Opioid Use Disorder. Neuropsychopharmacology 43:220-221|
|Conroy, Stacey C; Bjork, James M (2018) Death Ambivalence and Treatment Seeking: Suicidality in Opiate Addiction. Curr Treat Options Psychiatry 5:291-300|
|Johns, Sade E; Wang, Qin; Straub, Lisa K et al. (2018) Impulsivity and decision making in older and younger cocaine-dependent participants: A preliminary study. Am J Addict 27:557-559|
|Ma, Liangsuo; Steinberg, Joel L; Wang, Qin et al. (2017) A preliminary longitudinal study of white matter alteration in cocaine use disorder subjects. Drug Alcohol Depend 173:39-46|
|Neelakantan, Harshini; Holliday, Erica D; Fox, Robert G et al. (2017) Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats. ACS Chem Neurosci 8:1065-1073|
|Bjork, James M; Burroughs, Thomas K; Franke, Laura M et al. (2017) Rapid-Response Impulsivity Predicts Depression and Posttraumatic Stress Disorder Symptomatology at 1-Year Follow-Up in Blast-Exposed Service Members. Arch Phys Med Rehabil 98:1646-1651.e1|
|Azadeh, Shabnam; Hobbs, Brian P; Ma, Liangsuo et al. (2016) Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence. Neuroimage 125:813-824|
|Bjork, James M; Burroughs, Thomas K; Franke, Laura M et al. (2016) Laboratory impulsivity and depression in blast-exposed military personnel with post-concussion syndrome. Psychiatry Res 246:321-325|
|Ma, Liangsuo; Steinberg, Joel L; Moeller, F Gerard et al. (2015) Effect of cocaine dependence on brain connections: clinical implications. Expert Rev Neurother 15:1307-19|
|Ramesh, Divya; Keyser-Marcus, Lori A; Ma, Liangsuo et al. (2015) Prevalence of traumatic brain injury in cocaine-dependent research volunteers. Am J Addict 24:341-7|
Showing the most recent 10 out of 11 publications