The overarching goal of this competing renewal is to investigate systematically the mechanisms of stress- potentiated opioid seeking and biobehavioral responses. The proposed aims build programmatically on the very productive human laboratory paradigm and significant findings from this project's initial funding cycle. We combine a sensitive choice progressive ratio (exponentially escalating response requirement) procedure, well- established subjective drug effect and mood state measures, innovative hippocampal/prefrontal cortical vs. dorsal striatal-dependent learning tasks, and physiological indices of sympathetic- and HPA-mediated responses (i.e. heart period variability, blood pressure, body temperature, and salivary cortisol and 1-amylase). The primary drug-seeking outcomes will be analyzed using sensitive behavioral economic methods. Three proposed studies will systematically extend this useful laboratory model in significant, innovative and impactful directions (including validation of alternative stressors). The proposed study designs are sound and employ within-subject, randomized crossover, placebo-controlled, double-blind methodology. Our goal is to advance theoretical understanding (e.g. biobehavioral responses should be differentially sensitive to the stressors) and generate hypotheses for practical applications (e.g. medication development).
Aim 1. Fully characterize yohimbine-potentiated opioid seeking and biobehavioral responses using an optimized model (methods adjusted based on Prelim. Study 4 findings) and compare to a naturalistic stressor (moderately loud, intermittent, inescapable soundtrack of crying/distressed infants).
Aim 2. Use an alternative neuropharmacological stressor paradigm (reboxetine/hydrocortisone dose combinations) to determine whether activation of noradrenergic (Not applicable) and glucocorticoid transmission increases opioid seeking and biobehavioral responses.
Aim 3. Determine whether neuromodulating agents at 12A-adrenergic (guanfacine 1 mg), 5-HT1A (buspirone 30 mg), CB1 (cannabidiol 1000 mg), and GABAB (baclofen 40 mg) receptors differentially modulate yohimbine- potentiated opioid seeking and biobehavioral responses.

Public Health Relevance

Yohimbine (YOH), an 12-adrenoceptor antagonist, is a neuropharmacological stressor that has been shown in preclinical studies to increase drug seeking. In this competing renewal application, we propose to build on our productive human laboratory model of opioid seeking. Our aims are to: (1) characterize YOH-potentiated opioid seeking and biobehavioral responses using an optimized model (methodological adjustments based on our preliminary data) and compare to a naturalistic stressor;(2) use an alternative neuropharmacological paradigm (reboxetine/hydrocortisone dose combinations) to determine whether direct manipulation of noradrenergic and glucocorticoid transmission increases opioid seeking and biobehavioral responses;and (3) determine whether neuromodulating agents at 12A-adrenergic, 5-HT1A, CB1, and GABAB receptors differentially modulate YOH- potentiated opioid seeking and biobehavioral responses.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Gordon, Harold
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Wayne State University
Schools of Medicine
United States
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Greenwald, Mark K; Comer, Sandra D; Fiellin, David A (2014) Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. Drug Alcohol Depend 144:1-11
Greenwald, Mark K; Lundahl, Leslie H; Steinmiller, Caren L (2013) Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology (Berl) 225:811-24
Papke, Gina; Greenwald, Mark K (2012) Motivational assessment of non-treatment buprenorphine research participation in heroin dependent individuals. Drug Alcohol Depend 123:173-9
Roddy, Juliette; Steinmiller, Caren L; Greenwald, Mark K (2011) Heroin purchasing is income and price sensitive. Psychol Addict Behav 25:358-64
Greenwald, Mark K (2010) Effects of experimental Unemployment, Employment and Punishment analogs on opioid seeking and consumption in heroin-dependent volunteers. Drug Alcohol Depend 111:64-73
Greenwald, Mark K; Steinmiller, Caren L (2009) Behavioral economic analysis of opioid consumption in heroin-dependent individuals: effects of alternative reinforcer magnitude and post-session drug supply. Drug Alcohol Depend 104:84-93
Roddy, Juliette; Greenwald, Mark (2009) An economic analysis of income and expenditures by heroin-using research volunteers. Subst Use Misuse 44:1503-18
Greenwald, Mark K (2008) Behavioral economic analysis of drug preference using multiple choice procedure data. Drug Alcohol Depend 93:103-10
Greenwald, Mark K (2008) Opioid abstinence reinforcement delays heroin lapse during buprenorphine dose tapering. J Appl Behav Anal 41:603-7
Steinmiller, Caren L; Greenwald, Mark (2007) Factors associated with nonmedical use of prescription opioids among heroin-abusing research volunteers. Exp Clin Psychopharmacol 15:492-500

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