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.
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.
|Jacques-Tiura, Angela J; Greenwald, Mark K (2016) Behavioral Economic Factors Related to Pediatric Obesity. Pediatr Clin North Am 63:425-46|
|Nasser, Azmi F; Greenwald, Mark K; Vince, Bradley et al. (2016) Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder. J Clin Psychopharmacol 36:18-26|
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|Woodcock, Eric A; Lundahl, Leslie H; Greenwald, Mark K (2015) Predictors of buprenorphine initial outpatient maintenance and dose taper response among non-treatment-seeking heroin dependent volunteers. Drug Alcohol Depend 146:89-96|
|Woodcock, Eric A; Lundahl, Leslie H; Burmeister, Margit et al. (2015) Functional mu opioid receptor polymorphism (OPRM1 A(118) G) associated with heroin use outcomes in Caucasian males: A pilot study. Am J Addict 24:329-35|
|Stoltman, Jonathan J K; Woodcock, Eric A; Lister, Jamey J et al. (2015) Exploration of the telescoping effect among not-in-treatment, intensive heroin-using research volunteers. Drug Alcohol Depend 148:217-20|
|Woodcock, Eric A; Lundahl, Leslie H; Stoltman, Jonathan J K et al. (2015) Progression to regular heroin use: examination of patterns, predictors, and consequences. Addict Behav 45:287-93|
|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; Steinmiller, Caren L; Sliwerska, Elzbieta et al. (2013) BDNF Val(66)Met genotype is associated with drug-seeking phenotypes in heroin-dependent individuals: a pilot study. Addict Biol 18:836-45|
|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|
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